From neuroimmune circuits to targeted therapy of chronic pruritus

Torben Ramcke; Daniel H Kaplan

doi:10.1016/j.pharmr.2026.100121

. 2026 Jan 29;78(2):100121. doi: 10.1016/j.pharmr.2026.100121

From neuroimmune circuits to targeted therapy of chronic pruritus

Torben Ramcke ^1,^∗, Daniel H Kaplan ¹

PMCID: PMC13084607 PMID: 41831428

Abstract

Chronic pruritus (CP) is a debilitating symptom of various human diseases and significantly reduces quality of life, underscoring its clinical relevance. CP can accompany non–skin-borne diseases such as chronic kidney disease, but it is also a hallmark of many dermatological diseases. Most pruritic skin diseases are characterized by dysregulated immune responses, indicating a close relationship between CP and skin inflammation. Major breakthroughs over the last 2 decades have transformed our understanding of how immune cells and the nervous system interact to promote itch and scratching behavior in pruritic inflammatory skin diseases such as atopic dermatitis. This bidirectional neuroimmune crosstalk is fundamental for understanding the mechanistic basis of CP and opens new avenues for targeted treatment strategies. This translational review provides an up-to-date overview of the biological basis of itch, its clinical implications, and modern therapeutic options for CP; pruritic inflammatory skin diseases constitute a central focus. The first part summarizes the anatomical structures and physiological processes underlying itch transmission, with emphasis on neuroimmune communication. Endogenous itch-inducing molecules, or pruritogens, are a central element of this crosstalk and drive CP at the neurocutaneous interface. The second part of the review discusses these pruritogens in detail, with particular attention to their clinical relevance for the treatment of CP across dermatological and selected nondermatological conditions.

Significance Statement

Chronic pruritus is a debilitating symptom of many human diseases, including pruritic inflammatory skin diseases such as atopic dermatitis. This review provides an up-to-date overview of the biological basis of itch, highlights neuroimmune crosstalk in particular, and discusses the clinical and therapeutic relevance of pruritogens acting at the neurocutaneous interface.

I. Introduction

Itch, or pruritus, is an unpleasant sensation triggered by various environmental stimuli, such as an insect bite. The itch motivates us to scratch or rub the affected skin region for instant relief. Notably, the itch-scratch cycle is conserved in many mammalian species, indicating an evolutionary advantage.¹ In this sense, itch can be considered beneficial because it draws our attention to exogenous threats and prompts us to repel them from the skin through the mechanical act of scratching or rubbing. Moreover, recent findings indicate that the mechanical scratching boosts the cutaneous immune response to fight pathogens, as outlined in detail later.²

Generally speaking, pruritus is common and, in most cases, a harmless physiological reaction. A worldwide cross-sectional study indicated that 39.8% of individuals reported itch in the last 7 days, with women (40.7%) and the elderly (43.3%) being significantly more affected.³ However, itch and scratching behavior take on a pathological character when they manifest intensely without a reasonable purpose, particularly when they persist for an extended period. Chronic pruritus (CP) is defined as itch persisting for 6 weeks or longer.⁴ CP has a high epidemiological relevance, as confirmed by studies showing a point prevalence of around 15% in the European population.⁵^,⁶ Persistent pruritus is a hallmark symptom of several dermatological diseases and is closely associated with dysregulated skin inflammation. A common pruritic inflammatory skin disorder is atopic dermatitis (AD). However, it is essential to note that CP can also appear in non–skin-borne diseases, including metabolic, neurological or psychiatric disorders.⁴^,⁷

Chronic itch can have numerous adverse consequences for the patient. Mechanically induced skin damage, resulting from the scratching response, can lead to bacterial superinfections, pigmentation disorders, and scarring. Moreover, the steady desire to scratch can impede social activity, impair sleep quality, and increase the risk of suffering from mental health diseases such as depression.⁸^,⁹ Taken together, chronic itch significantly reduces the quality of life. Remarkably, CP reduces the quality of life to a similar extent as stroke.⁹ Considering these findings, examining this unpleasant sensation and its therapeutic options in more detail is worthwhile.

The first part of this review will provide an up-to-date overview of the anatomical and physiological basis of itch sensation and transmission. Here, we will focus on neuroimmune crosstalk, which helps us to elucidate the close relationship between pruritus and cutaneous inflammation. Itch-inducing molecules, or pruritogens, are a crucial part of this crosstalk and represent key drivers for CP. The second part of this review will focus on these endogenous pruritogens acting at the neurocutaneous interface and provide an up-to-date overview of their clinical relevance as targets in modern CP treatment.

II. Classification of acute itch by the mode of induction at steady state

At steady state, in the absence of chronic pathological processes, we can experience an acute itch sensation in response to mechanical or chemical stimuli that target the afferent nerves in our skin.

A. Mechanical itch

Mechanical itch is triggered by complex patterns of physical stimuli, including light touch, pressure, vibration, or stroking acting on the skin—for example, when a bug crawls on the skin. The crawling activates specialized mechanoreceptors, allowing sensory nerve fibers to encode and transmit the itch information to the brain for interpretation. The peripheral induction of mechanical itch is not well understood. Interestingly, recent mouse studies have demonstrated that Merkel cells and their mechanoreceptor Piezo2 play a crucial modulatory role in mechanical itch induction.¹⁰^,¹¹

B. Chemical itch

Chemical itch is triggered by specific exogenous or endogenous molecules, called pruritogens. These pruritogens target dedicated itch receptors, called pruriceptors, on somatosensory neurons in the skin. Histamine was one of the first identified pruritogens and served as a prototype itch-inducing molecule for decades of experimental studies.¹² Physiologically, granules in skin mast cells serve as an essential storage site for histamine. Mast cell degranulation, eg, after exposure to bee venom, causes a histamine-dependent itch and wheel reaction referred to as acute urticaria.¹³ Histamine signaling blockade effectively treats the itch sensation caused by bee stings. However, pruritus in other conditions, particularly in chronic diseases such as AD, is not well controlled by antihistamines. The existence of other, nonhistaminergic pruritogens explains this observation. Various nonhistaminergic pruritogens, including proteases, cytokines, biogenic amines, neuropeptides, opioids, and eicosanoids have been discovered over the last 2 decades.¹⁴ Many of these pruritogens are released during inflammation and represent interesting targets for treating antihistamine-refractory itch, as highlighted in more detail later in this review.

C. Contagious itch

Besides mechanically and chemically induced itch in the skin, contagious itch represents a third mode of action.¹⁵ Contagious itch describes the behavioral phenomenon in which humans start feeling itchy when they see or hear scratching behavior or content associated with itch or scratching.¹⁶ Evolutionarily, it may have been beneficial as an anticipatory behavior against contagious diseases in the social environment. Compared to mechanical or chemical itch, contagious itch does not originate in the skin and represents a behavioral phenomenon that relies on auditory and visual perception.¹⁵

Most pathological itch sensations originate in the skin and are commonly associated with skin inflammation. Dysregulated neuroimmune–epithelial circuits drive these pruritic inflammatory skin diseases, such as AD. Key players of these circuits are structural skin cells, skin-resident immune cell populations, and the peripheral somatosensory nervous system. In the following sections, we will first focus on these components individually and then examine their mutual relationships in the context of inflammatory pruritus.

III. Where itch begins: The skin as a sensory and immune interface

The skin is a sophisticated organ that serves as a physical barrier between the internal and external environment (Fig. 1). Despite its obvious barrier and protection function, the densely innervated skin enables the organism to sense its surroundings and initiate protective sensations, such as pain or itch.¹⁷ Moreover, the skin is critically engaged in pathogen defense and thermoregulation.¹⁸^,¹⁹ To fulfill all these demanding functions optimally, human skin is divided into 3 layers: (1) the epidermis, (2) the dermis, and (3) the subcutaneous tissue (Fig. 1).²⁰

When focusing on itch per se, the epidermis and the upper dermal compartment are of particular interest for 2 reasons: (1) the epidermis is the primary site where itch fibers terminate and are activated; and (2) the epidermis and dermis house various cell populations, including keratinocytes and different types of immune cells, which are critical sources for pruritogens and important drivers of pruritic inflammation.

A. The epidermis

The epidermis is the outermost layer of the skin, interacting directly with the environment. Inwardly, it is attached to the dermis via the basement membrane.²¹ Keratinocytes are the most abundant cell type in the epidermis.²² The epidermal compartment is self-renewing, and keratinocytes undergo a well organized differentiation process from the base to the surface. This epidermal differentiation is represented by different layers under the microscope: (1) the stratum basale, (2) the stratum spinosum, (3) the stratum granulosum, and (4) the stratum corneum.²³ Epidermal stem cells in the innermost stratum basale continually provide new keratinocytes.²⁴ The keratinocytes of the overlying stratum spinosum are interconnected by large protein complexes called desmosomes, which give them their characteristic spiny shape.²³ The stratum granulosum is characterized by keratinocytes synthesizing keratohyalin granules and lamellar bodies, which provide critical elements for the final cornification step in the overlying cell layer.²⁵ Importantly, as outlined in more detail later, murine studies have shown that well-characterized itch-mediating fibers terminate in the stratum granulosum.²⁶^,²⁷ The outermost layer of the epidermis is called the stratum corneum, and it provides a strong mechanical, water-impermeable barrier made of keratinocyte-derived avital corneocytes.²⁸ Notably, dysfunction of the stratum corneum is a key driver of dry skin (xerosis cutis), a common CP-associated skin disease in the elderly.²⁹

The epidermis additionally plays a role in triggering cutaneous immune responses. Keratinocytes act as early sensors for invading pathogens. Langerhans cells and CD8⁺ tissue-resident memory T cells patrol the epidermis and play crucial roles in initiating and exerting adaptive immune responses.30, 31, 32 Importantly, keratinocytes are also important players in itch circuits and a well known source of endogenous pruritogens, as outlined in detail later.

B. The dermis

The dermis represents a connective tissue and marks the middle layer of the skin. Based on its structural composition, it can be divided into a loosely arranged upper papillary layer and the deeper reticular layer.³³^,³⁴ The papillary dermis serves as a hub for itch fibers that breach into the epidermis,³⁴ but it also contains sensory nerve fiber endings that can initiate neurogenic inflammation. Notably, the dermis houses diverse populations of innate and adaptive immune cells. Many of them are packed with endogenous pruritogens, poised to drive acute and CP.³⁵ Cutaneous immune cells, including dermal macrophages, dermal dendritic cells (DCs), eosinophils, and innate lymphoid cells are key players in controlling invaders and in initiating the adaptive immune response.³⁶ Mast cells represent another essential immune cell player in the skin. Beyond its prominent role in IgE-dependent immune responses, mast cells also serve as crucial mediators linking sensory nerve fibers to skin immune cells. They are strategically positioned close to afferent nerve fibers in the dermis and are critically engaged in sensory nerve fiber-mediated skin inflammation,³⁷ as we detail later. All these resident skin immune cells form the backbone of a successful cutaneous immune response, which can be functionally classified into 3 different modules. The following section introduces these functional immune modules and discusses their relation to pruritus.

IV. Functional classification of skin immune responses and their relation to itch

Cutaneous immune responses are indispensable for host defense, providing broad protection against exogenous pathogens while eliminating endogenous threats such as mutated cells.³⁵ The plethora of different skin-resident immune cell populations reflects a threat-dependent specialization. From a functional perspective, 3 distinct immune response modules (types 1–3 immunity) can be distinguished, each specialized to target specific classes of threats according to their size and preferred habitat. The type 1 immune response module is mobilized to combat intracellular pathogens, such as viruses. In contrast, extracellular threats are addressed by either type 2 immunity (larger multicellular pathogens such as helminths) or type 3 immunity (microscopic threats such as bacteria and fungi). Each of these immune modules relies on distinct, yet partially overlapping, cellular and humoral effector pathways mediated by both innate and adaptive immune cells in the skin.³⁸ This functional framework is also helpful for phenotyping inflammatory skin diseases, enabling the identification of disease-driving cellular populations and mechanisms. Notably, pruritic inflammatory dermatoses are particularly associated with dysregulated type 2 immune responses, as discussed in the following section.

A. Type 2 inflammation and type 2-driven pruritic inflammatory skin diseases

Physiologically, humoral and cellular type 2 immune responses are not only crucial for clearing large, multicellular invaders, such as parasites, but also for neutralizing venoms and toxins.³⁹ Scratching is an essential behavioral effector mechanism employed by the type 2 immune module to repel large skin invaders or toxins. When facing a threat such as a parasite, the initial type 2 immune response is provided by innate immune cells, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells (ILC2s). Antigen-specific adaptive immune cells, including T helper cell 2 (Th2) and IgE-producing plasma cells, exert antigen-specific pathogen clearance at later stages.³⁸

Specific type 2 alarmins and cytokines mediate communication between the acting cell players.⁴⁰^,⁴¹ Intriguingly, several of these messenger molecules function as pruritogens by activating itch-mediating fibers.42, 43, 44 The type 2 alarmins interleukin IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are early inducers of the type 2 immune response. They are released when skin-resident cell populations, such as keratinocytes, sense pathogen-associated molecular patterns that require a type 2 immune response for optimal host defense.45, 46, 47 These alarmins license type 2 innate immune cells, in particular dermal ILC2s, to produce small amounts of the hallmark Th2 effector cytokines IL-4, IL-5, and IL-13.⁴¹ In parallel, eosinophils and basophils are recruited from the circulation into the skin to reinforce the response. Some alarmins, such as TSLP or IL-33, were identified as pruritogens in mouse studies.⁴⁸^,⁴⁹

The innate phase of the type 2 immune response keeps the invading parasite in check until the adaptive immune response is ready to clear it completely. Antigen-specific Th2 cells are recruited to the site of inflammation, where they produce locally high concentrations of type 2 effector cytokines, including IL-4, IL-5, IL-13, and IL-31. These cytokines initiate potent antiparasite effector mechanisms. Notably, the receptors for IL-4, IL-13, and IL-31 are expressed on itch-mediating nerve fibers, and their activation has been shown to drive CP in mice.⁴³^,⁴⁴ In addition, the humoral component of the adaptive type 2 immune response produces antigen-specific IgE, enabling mast cells and basophils to release toxic granules that target invading parasites.⁵⁰ These granules contain pruritogens such as histamine, serotonin, proteases, leukotrienes, and sphingosine-1-phosphate, which further drive pruritus in the context of type 2 inflammation.⁵¹^,⁵²

The type 2 immune module helps to clear parasite infections, for example, by inducing scratching. However, dysregulated type 2 immunity can cause inflammatory dermatoses such as AD.⁵³ AD is a chronic, noncontagious, and highly pruritic inflammatory skin disease that typically presents in early childhood with acute eczematous lesions. The global burden of AD is about 15%–20% among children and approximately 10% among adults, highlighting its high clinical relevance but also its decline with age.⁵⁴ The pathogenesis of AD is multifactorial and not yet fully understood. It is considered to involve elements of epidermal barrier dysfunction, alterations in the skin microbiome, and dysregulated type 2 and 3 immune responses.⁵⁵ Other human skin diseases showing a dysregulated type 2 immune phenotype include autoimmune blistering diseases such as bullous pemphigoid (BP), chronic urticaria, and even certain neoplastic disorders like the skin T cell lymphoma mycosis fungoides.56, 57, 58 Notably, all these primary skin-borne diseases feature pruritus as a hallmark symptom, stressing the strong mechanistic linkage between dysregulated type 2 inflammation and chronic itch.

B. Types 1 and 3 inflammation and type 1 and 3-driven pruritic inflammatory skin diseases

The type 1 immune response relies on cytotoxic T cells and macrophage-activating Th1 cells, and is specialized in clearing intracellular pathogens, such as viruses or mycobacteria. Moreover, it is crucial in detecting and eliminating mutant cells.⁵⁹^,⁶⁰ The type 3 immune response is orchestrated by Th17 cells and is dedicated to clearing small, extracellular pathogens, including bacteria and fungi.⁶¹ Generally speaking, itching and scratching are not typical behavioral components of type 1 or type 3 inflammation. However, this is not a universal statement, exemplified by the introduction of 2 inflammatory skin diseases in the next section.

Itch is a hallmark symptom of the inflammatory skin disease lichen planus (LP). LP is thought to arise from dysregulated type 1 and type 3 immune responses, culminating in T cell-mediated cytotoxicity that predominantly targets the basal keratinocyte layer of the epidermis.⁶² It is a chronic inflammatory skin condition that characteristically manifests as pruritic, purple, polygonal papules and frequently involves the mucous membranes. The mechanisms and molecules that induce itch in LP are not well understood.⁶³

Another prominent example is psoriasis, a prototypical type 3-driven inflammatory skin disease.⁶⁴ This chronic papulosquamous autoimmune disorder is critically mediated by the type 3 cytokines IL-23 and IL-17 and is frequently accompanied by CP.⁶⁵ Notably, a recent report studying murine psoriasis uncovered that the signature type 3 cytokine IL-17 exerts direct pruritogenic activity, providing important mechanistic insight into psoriatic itch.⁶⁶ However, in general, the pruritogens responsible for type 1- and type 3-driven pruritic dermatosis are not well defined.

From a physiological angle, it remains a fascinating question whether the host gains a selective advantage by coupling itch and scratching behavior to immune responses directed against microscopic threats. This topic will be revisited later when examining recent studies on the role of scratching in Staphylococcus aureus skin infection.² In sum, itch is a hallmark behavioral component of type 2 inflammation, which is critically engaged in parasite defense. Hallmark type 2 cytokines and alarmins have been characterized as pruritogens. This link is further supported by the observation that many pruritic inflammatory skin diseases share a dysregulated type 2 immune signature. However, CP is not restricted to type 2-driven diseases; certain type-1- or type-3-dominated skin diseases, such as LP, can also present with intense pruritus. Nevertheless, the driving pathogens in these diseases are less well defined.

Having outlined the interplay between pruritus and cutaneous inflammation, we now turn to the peripheral neurons that are activated by pruritogenic stimuli.

V. The peripheral neuronal itch pathway

The presence and activation of somatosensory neurons in the skin enable us to perceive sensations such as light touch, pressure, vibration, cold, warmth, pain, or itch. The cell bodies of these neurons are localized in ganglia far away from the skin; however, their pseudounipolar axons connect the skin to the central nervous system (CNS). Anatomically, somatosensory neurons in the dorsal root ganglia (DRGs), located adjacent to the spinal column, bridge the nonfacial skin regions to the spinal dorsal horn (Fig. 2, lower part). The facial skin represents an exception, as it is innervated by sensory neurons of the trigeminal ganglia, which project to the trigeminal sensory nuclei located in the midbrain, pons, and medulla.⁶⁷

Fig. 2 — Murine nonpeptidergic (NP) itch fibers. Schematic overview of itch-mediating murine NP subtypes (NP1, NP2, and NP3). The lower panel illustrates the anatomical localization and the peripheral-central pathway of each NP fiber class from the epidermis through the dorsal root ganglion (DRG) to their termination in Rexed lamina II of the spinal dorsal horn. The upper panels summarize pruriceptors expressed by each subtype, their known endogenous or exogenous ligands (pruritogens), and the downstream ion channels responsible for action potential initiation (light blue). Arrows indicate experimentally supported mechanistic coupling between receptors and downstream ion channels. Key literature references supporting each receptor-ligand-channel pathway are indicated. (BAM)8–22, bovine adrenal medulla peptide 8-22; Ca, calcium; Cl, chloride; Defb14, β-defensin 14; Na, sodium; PAR, proteinase-activated receptor; PIEZO1 & 2, Piezo-type mechanosensitive ion channel component 1 & 2; 5-HT1_x R, serotonin receptor x; S₁P, sphingosine-1-phosphate; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid 1. This figure was created with permission in BioRender: R. T. (2025) https://BioRender.com/687m8je.

Functionally, sensory nerve fibers can be classified based on their conduction velocity, which is determined by their axon diameter and degree of myelination. In 1937, Erlanger and Gasser⁶⁸ introduced a lettered nomenclature (A, B, and C) combining these morphological and functional aspects to categorize sensory and motor neurons (Table 1). This classification will help us to decipher which part of the somatosensory nervous system in the skin is responsible for itch transmission.

Table 1.

Classification of sensory and motor neurons introduced by Erlanger and Gasser, adapted to highlight the functions of nerve afferents in the skin⁶⁸

Fiber Type	Conduction Velocity	Diameter	Myelination Status	Afferent Function in the Skin
Aɑ	60–120 m/s	12–20 μm	Myelinated	N/A (proprioceptive; not cutaneous)
Aβ	30–70 m/s	5–12 μm	Myelinated	Touch and pressure. Potential role in mechanical itch under pathological conditions.
Aγ	15–30 m/s	3–6 μm	Myelinated	N/A (motor; muscle spindle efferents)
Aδ	12–-30 m/s	2–5 μm	Myelinated	Pain, temperature, pressure, and possible contribution to nonhistaminergic itch
B	3–15 m/s	<3 μm	Myelinated	N/A (autonomic efferents)
C	0.5–2 m/s	0.4–1.3 μm	Non-myelinated	Pain, temperature, well established role in chemical- and mechanical-induced itch

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A. Myelinated A fibers are potentially engaged in sensing itch

The fastest cutaneous sensory fiber class is Aβ fibers, which allow us to sense innocuous mechanical stimuli, including light touch, pressure, or vibration. To fulfill this role, Aβ fibers act as low-threshold mechanoreceptors, implying that they are activated by low-intensity tactile stimuli, such as an airflow. Considering the well established function of Aβ fibers in mechanical sensation, it is reasonable to consider that Aβ fibers may contribute to mechanical itch. Indeed, the mouse study by Pan et al⁶⁹ demonstrated that low-threshold toll-like receptor 5-positive Aβ mechanoreceptors provide peripheral input to spinal circuits signaling mechanical itch. At steady state, this input is largely suppressed by spinal inhibitory interneurons. However, under pathological conditions, central disinhibition allows Aβ mechanoreceptor input to promote mechanical itch. Together, these findings suggest that Aβ mechanoreceptors may contribute to mechanically induced CP following central disinhibition in pathological states. Nevertheless, a comprehensive picture, especially in humans, remains to be established.

Myelinated Aδ fibers show a smaller diameter than Aβ fibers and are functionally engaged in mechanical, temperature, and pain sensations.¹⁷ Aδ fibers are responsible for transducing acute, sharp, but not long-lasting pain. In addition to these well established findings, a study in humans using differential nerve block, a sequential block of different types of nerve fibers, concluded that nociceptive A fibers, likely Aδ fibers, may also be involved in nonhistaminergic itch signaling.⁷⁰ Nevertheless, a clearly defined physiological role for Aδ fibers in itch signaling is pending.

B. C fibers are established players in sensing itch in mice and humans

C fibers have the thinnest axons and are unmyelinated, resulting in the slowest conduction velocity among all fiber types. They are critically involved in pain or temperature sensation and play a crucial role in nerve fiber-induced (neurogenic) inflammation, as discussed in detail later. Notably, C fibers are well established as primary mediators of itch signaling in both mice and humans. There is ample evidence that subpopulations of C fibers are responsible for chemically mediated itch detection⁷¹ and increasing evidence that they are also engaged in mechanical itch signaling.¹¹^,⁷²^,⁷³

1. Nonpeptidergic (NP) C fibers signal itch in mice

Most C fibers are multimodal, implying they can respond to different stimuli, including pain, itch, or heat. Thus, subdividing C-fiber populations based on a unique physiological-perceptual function remains a challenge.⁷⁴ For this reason, molecular classification approaches in mice focused on categorizing functional units based on common protein expression characteristics. This molecular framework has recently been expanded through the advent of single-cell sequencing technologies, which have markedly increased the granularity of C-fiber classification. To contextualize the current nomenclature used for murine C-fiber subtypes, it is helpful to briefly recapitulate its historical development.

The first classification approaches in the 90s divided murine nociceptive C fibers into peptidergic and NP fibers.⁷⁵ At that time, peptidergic C fibers were named by their ability to produce the neuropeptides calcitonin gene-related peptide (CGRP) and Substance P, which are well known mediators of neurogenic inflammation.⁷⁶ NP fibers were demarcated by their inability to express neuropeptides such as CGRP or Substance P and by their reliance on distinct neurotrophic signaling pathways.⁷⁷

Importantly, the molecular characterization of pruritogens, murine knockout studies, and the emergence of single-cell sequencing technologies have provided compelling evidence that NP C fibers form the core of peripheral itch signaling in the mouse. Based on the landmark single-cell RNA sequencing studies published by Usoskin et al⁷⁸ in 2015, Zeisel et al⁷⁹ in 2018, and Sharma et al⁸⁰ in 2020, 3 molecularly distinct NP neuron populations (NP1–NP3) are now distinguished (Table 2),78, 79, 80, 81, 82, 83, 84 each implicated in the transmission of itch. These studies further revealed that NP neurons express multiple neuropeptides, including somatostatin (SST), neurotensin, brain natriuretic peptide (BNP), and CGRP.78, 79, 80 Hence, given the scientific progress, the term ‘NP’ C fibers is currently misleading and should be interpreted in a historical context. In addition, a recent comprehensive physiological characterization by Qi et al⁸⁵ demonstrated that all 3 NP subsets respond to mechanical and thermal stimuli, confirming their multimodal function.

Table 2.

Overview of key single-cell sequencing studies categorizing NP1-3 neurons in mice and putative correlates in NHP and human

	NP1 Neuron Cluster				Putative Cross-Species Cluster Equivalents
	Mouse				NHP	Humans
Study	Usoskin et al., 2015⁷⁸	Zeisel et al., 2018⁷⁹		Sharma et al., 2020⁸⁰	Kupari et al., 2021⁸¹	Nguyen et al., 2021⁸²	Tavares-Ferreira et al., 2022⁸³	Yu et al., 2024⁸⁴
Technology	RNA single-cell sequencing	RNA single-cell sequencing		RNA single-cell sequencing	RNA single-cell sequencing	Single-nucleus transcriptomic human DRG	Spatial transcriptomic analysis of human DRG	Whole-soma scRNA-seq of human DRG (neuronal somata microdissection by laser)
Input	Lumbar DRG (L-4-L6, 6-8 wk old, female + male). 622 neurons analyzed.	Cervical, thoracic & lumbar DRG (female & male). 2500 neurons analyzed.		Cervical, thoracic & lumbar DRG.	Macaque lumbar DRG (female & male). Two independent data sets with 2518 and 1038 neurons.	Human lumbar DRG L4 & L5 (female & male donors). Nuclei from 1837 neurons.	Human lumbar DRG L4 & L5 (female & male).	Human thoracic T11 & 12 and lumbar DRG L2 - L5 (male & female). 1,066 neurons were used for analysis
Cluster name in study (+ frequencies if applicable)	NP 1 Calculated Frequencies: 27,2% of all DRG neurons 73,96% of all NP neurons	PSNP 2	PSNP 3	MRGPRD⁺ polymodal Nociceptors Frequencies (RNA-FISH): 25% of cervical DRG neurons 23% of thoracic DRG neurons 24% of lumbar DRG neurons	NP 1 (cluster 8)	Cluster H10	No corresponding cluster suggested	Cluster 3: hNP1
Selection of enhanced transcripts	Mrgprd, Lpar3, P2rx3, Gfra2, Gfra1, Ret, Trpa1, P2rx3, Nmb				Gfra1, Gfra2, Mrgprd, Lpar3, P2rx3, P2Rx5, Ret (rather low), Mrgprx1, Mrgprx3, Mrgprx4, Adm, Il-31Ra, Sst, Osmr	Gfra2, MrgprX1, Osmr, IL-31Ra, Hrh1, Nppb, Piezo2, Prdm8, Rergl	N/A	Mrgprd (only a few NP1 neurons), MrgprX1, Hrh1, Gfra2, IL-31Ra,Lpar3, Piezo2, Trpv-1, F2rl1, CysLTR2, Osmr, Nppb, Ednra
Annotations	Zeisel et al. defined 2 NP1 subpopulations; it is unclear if this distinction is biologically relevant.				NP1 & NP2 fibers between the mouse and NHP are less conserved, in comparison to NP3.	H10 resembles murine NP1 in coclustering analyses, but H10 expresses murine NP2-related MRGPRX1, and murine NP3 restricts IL-31Ra. Expression of PIEZO2 suggests a role in mechanical itch.	Two clusters, H10 & H11, were associated with itch sensation; however, an allocation to murine or NHP NP1 fibers was not suggested.	Cell-type correlation analyses revealed good correspondence with Cluster H10 in the Nguyen et al. dataset. A cross-species comparison reveals a good correlation with mouse (Sharma et al.) and macaque NP1 (Kupari et al.).

	NP2 Neuron Cluster				Putative Cross-Species Cluster Equivalents
	Mouse				NHP	Human
Study	Usoskin et al., 2015⁷⁸	Zeisel et al., 2018⁷⁹		Sharma et al., 2020⁸⁰	Kupari et al., 2021⁸¹	Nguyen et al., 2021⁸²	Tavares-Ferreira et al., 2022⁸³	Yu et al., 2024⁸⁴
Technology	RNA single-cell sequencing	RNA single-cell sequencing		RNA single-cell sequencing	RNA single-cell sequencing	Single-nucleus transcriptomic human DRG	Spatial transcriptomic analysis of human DRG	Whole-soma scRNA-seq of human DRG (neuronal somata microdissection by laser)
Input	Lumbar DRG (L-4-L6, 6-8 wk old) (female + male). 622 neurons analyzed.	Cervical, thoracic & lumbar DRG (female & male). 2500 neurons analyzed.		Cervical, thoracic & lumbar DRG.	Macaque lumbar DRG (female & male). Two independent data sets with 2518 and 1038 neurons.	Human lumbar DRG L4 & L5 (female & male donors). Nuclei from 1837 neurons.	Human lumbar DRG L4 & L5 (male & female). 3952 barcodes overlapping with a single neuron	Human thoracic T11 & 12 and lumbar DRG L2 - L5 (male & female). 1,066 neurons were used for analysis
Cluster name in study (+ frequencies if applicable)	NP 2 Calculated Frequencies: 5,14 % of all DRG neurons 18,93 % of all NP neurons	PSNP 4	PSNP 5	CGRP θ Frequencies (RNA-FISH): 8% of cervical DRG neurons 8% of thoracic DRG neurons 8% of lumbar DRG neurons	NP 2 (cluster 9)	Partial coclustering with Cluster H10 & H11	No corresponding cluster suggested	Cluster 4: hNP2
Selection of enhanced transcripts	Mrgpra3, Trpa1, Trpv1 (for Zeisel data: PSNP5, but not PSNP4), Calca, Hrh1, P2rx3, Ret, Nmb, Osmr				Gfra1, Mrgprx1, Mrgprx3, Mrgprx4, Pnoc, Chrna3, Ephb1, Gabrg3, Tpcn1, Calca, Ret, Sst, Osmr, Il-31Ra	See Cluster H10 (human NP1 co-cluster) & Cluster H11 (human NP3 co-cluster)	N/A	Mrgprx4, MrgprX1, Hrh1, Hrh2, IL-31Ra, Trpv-1, CysLTR2, Osmr, Nppb
Annotations	Zeisel et al. defined 2 NP2 subpopulations, and it is unclear if functional differences exist.				NP1 & NP2 fibers between mouse and NHP were less conserved than NP3 between both species.	Coclustering analyses revealed relations to H10 (NP1 correlate) and Cluster H11 (NP3 correlate). The chloroquine-sensitive MRGPRX1, for example, is found on Cluster H10, the equivalent of murine NP1.	Two clusters, H10 and H11, were associated with itch sensation; however, an allocation/association between murine or NHP NP2 fibers was not suggested.	Cell type correlation analyses revealed no correspondence to any of the clusters in the Nguyen et al. dataset. A cross-species comparison reveals a good correlation with mouse (Sharma et al.) and macaque NP2 (Kupari et al.).

	NP3 Neuron Cluster			Putative Cross-Species Cluster Equivalents
	Mouse			NHP	Human
Study	Usoskin et al., 2015⁷⁸	Zeisel et al., 2018⁷⁹	Sharma et al., 2020⁸⁰	Kupari et al., 2021⁸¹	Nguyen et al., 2021⁸²	Tavares-Ferreira et al., 2022⁸³	Yu et al., 2024⁸⁴
Technology	RNA single-cell sequencing	RNA single-cell sequencing	RNA single-cell sequencing	RNA single-cell sequencing	Single-nucleus transcriptomic human DRG	Spatial transcriptomic analysis of human DRG	Whole-soma scRNA-seq of human DRG (neuronal somata microdissection by laser)
Input	Lumbar DRG (L-4-L6, 6-8 wk old) (female + male). 622 neurons analyzed.	Cervical, thoracic & lumbar DRG (female & male). 2500 neurons analyzed.	Cervical, thoracic & lumbar DRG.	Macaque lumbar DRG (female & male). Two independent data sets with 2518 and 1038 neurons.	Human lumbar DRG L4 & L5 (female & male donors). Nuclei from 1837 neurons.	Human lumbar DRG L4 & L5 (male & female). 3952 barcodes overlapping with a single neuron	Human thoracic T11 & 12 and lumbar DRG L2 - L5 (male & female). 1066 neurons were used for analysis
Cluster Name in study (+ frequencies if applicable)	NP 3 Calculated Frequencies: 1,92 % of all DRG neurons 7,1 % of all NP neurons	PSNP6	Sst Frequencies (RNA-FISH): 10 % of cervical DRG neurons 10 % of thoracic DRG neurons 9 % of lumbar DRG neurons	NP 7 (cluster 7)	Cluster H11	No corresponding cluster suggested	Cluster 5: hSST
Selection of enhanced transcripts	Il-31Ra, Sst, Nppb, Osmr, S1pr1, Cystlr2, Gfra3, Jak1, Hrh1, Htr1f, Trpv1, Trpa1, Nts, P2rx3, Ret, Nmb, Ptafr			Sst, Gfra3, Il-31Ra, Jak1, Osmr, S1pr1, App, Hrh1, Cxcr4, Tdrd1, Edn3, Gria1, Ret (rather low), Htr3b, Trpv-1 & Trpa1 (bot rather low)	Osmr, Il-31Ra, Hrh1, Nppb, Sst, Cck, Jak1, Calca, Gfra3, Htr3a, Trpv-1	N/A	Sst, IL-31Ra, Gfra3, Cck, Htr3a, Hrh1, Hrh2, Trpv-1, CysLTR2, Osmr, Nppb, Ednra
Annotations				NP3 neurons between mouse and NHP are better conserved compared to Np1 and Np2		Two clusters, H10 + H11, were associated with itch sensation; however, an allocation/association between murine or NHP NP3 fibers and these 2 clusters was not suggested.	Cell-type correlation analyses revealed good correspondence with Cluster H11 in the Nguyen et al. dataset. A cross-species comparison reveals good correlation with mouse (Sharma et al.) and macaque NP3 (Kupari et al.).

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Although the peptidergic versus NP classification is well established for murine C fibers, its applicability to human C fibers is an ongoing subject of debate.⁸³ To date, a widely accepted molecular-based taxonomy of human itch fibers has not been defined.

Over the past 2 decades, studies of murine NP neurons have yielded important mechanistic insights into how sensory neurons in the skin detect and encode pruritic stimuli. In the sections that follow, we synthesize these discoveries and emphasize their translational relevance to human itch biology. However, before turning to the individual NP subsets, we will briefly introduce the key receptor families that underlie peripheral itch signaling: the Mas-related G protein-coupled receptors (Mrgprs) and the transient receptor potential (TRP) and voltage-gated sodium (Na_V) ion channel families.

2. Mas-related G protein-coupled receptors (Mrgpr)

The family of Mrgprs was discovered in 2001 and has emerged since then as a key player in somatosensation, including peripheral itch induction.⁸⁶ The genes of this newly defined protein-coupled receptor family showed the highest similarity to the MAS1 proto-oncogene, resulting in the name Mrgpr.⁸⁷ In the mouse, different subfamilies of Mrgprs were defined based on sequence analyses, including MrgprA, MrgprB, and MrgprD. Individual members, such as neuronally expressed MrgprA3 and MrgprD, are well studied in murine itch pathways and represent hallmark markers for differentiating NP subsets.²⁶^,⁸⁸

Importantly, Mrgpr function extends beyond somatosensory neurons: For example, murine MrgprB2, or its human functional equivalent MrgprX2, is currently recognized as a key non-IgE-dependent mast cell activator.⁸⁹

As demonstrated by MrgprX2, Mrgprs also exist in humans. However, and interestingly, mice express significantly more intact Mrgpr members (n = 26) than do humans (n = 8). Some members (n = 4), such as MrgprD, are conserved between mice and humans.⁸⁷ Others lack direct orthologs but exhibit functional equivalents, such as human MrgprX1 (functionally analogous to mouse MrgprA3/MrgrC11) and human MrgprX2 (functionally analogous to mouse MrgprB2).⁸⁷

Several pruritogens activate neuronal Mrgprs to elicit itch signaling. Upon ligand binding, Mrgprs activate downstream intracellular cascades that converge on ionotropic channels, most prominently TRP channels. TRPs translate receptor activation into membrane depolarization and neuronal excitation, as discussed in the next section.

3. Transient receptor potential ion channels (TRP) and voltage-gated sodium channels (Na_V)

TRP ion channels comprise several families, including TRPA, TRPV, and TRPM, and are fundamental molecular transducers for somatosensory signaling in peripheral nerve fibers. Numerous chemical and physical stimuli can directly activate them, while intracellular signaling pathways (eg, initiated by Mrgprs) critically modulate their activity. Well studied TRP channels include TRPV1 and TRPA1, which have been characterized as important transducers in pain and heat signaling. TRPM8 is another prominent TRP engaged in cold detection.⁹⁰ In the context of neuronal itch signaling, TRPV1, TRPA1, and TRPV4 are considered critical downstream targets that promote itch.91, 92, 93, 94, 95, 96, 97, 98, 99 A detailed mechanistic connection illustrating which pruritogens target which TRPs in mice is shown in the upper panel of Fig. 2. Interestingly, TRPs are also expressed on nonneuronal cells, and epidermal TRPV3 and TRPV4 activation in particular has been linked to propagation of itch circuits in the skin, as outlined in detail later.100, 101, 102

Mechanistically, TRP channels are cation channels that allow positively charged ions, such as Ca²⁺ or Na⁺, to enter the cell. This depolarization in turn activates voltage-gated Na⁺-selective channels, such as Na_V1.7–1.9, which ultimately trigger an action potential. Na_V1.7–1.9 are broadly expressed across multiple sensory neuron subsets and have been shown to contribute to distinct sensory modalities. Notably, individuals carrying gain-of-function mutations in these channels experience recurrent episodes of pruritus, among other symptoms, underscoring their role in itch signaling.103, 104, 105

To explore this in more detail, Kühn et al¹⁰⁶ employed Na_V1.7-, Na_V1.8-, and Na_V1.9-deficient mice to systematically characterize the contribution of these sodium channels to acute itch signaling in vivo. They found that Na_V1.7 and Na_V1.9 are essential for the effective initiation and early phase of acute itch responses across multiple pruritogens. In contrast, Na_V1.8 contributed more selectively, mediating itch induced only by strong stimuli such as histamine.¹⁰⁶ These findings identify Na_V1.7 and Na_V1.9 as key determinants of acute itch signaling; whether they also represent principal drivers of CP remains to be investigated. TRP and Na_V channels are conserved in humans, making them attractive targets for antipruritic therapy. Although many ion channel-directed drugs have failed due to limited efficacy or tolerability, promising approaches exist, such as asivatrep. Asivatrep is a topical TRPV1 antagonist that recently demonstrated efficacy in a phase 3 trial for AD in South Korea¹⁰⁷; however, it has not yet received US Food and Drug Administration (FDA) approval.

Having introduced these backbone molecules of neuronal itch signaling, we now focus on murine NP1–3 neurons and their role in itch induction; translational human findings will be mentioned whenever possible. This section will close by presenting recent single-cell sequencing data on human DRGs, allowing us to discuss interspecies similarities as well as differences that need to be considered.

4. NP1 fibers

In mice, NP1 fibers terminate in the stratum granulosum of the epidermis and are not found in organs other than the skin (Fig. 2).²⁶ NP1 neurons represent 25%–30% of all DRG neurons⁷⁸^,⁸⁰^,¹⁰⁸ and constitute >90% of all NP C fibers.²⁶^,⁸³^,¹⁰⁹^,¹¹⁰ Specific expression of MrgprD is the hallmark marker for identifying NP1 fibers.⁷⁸ MrgprD not only serves to identify NP1 fibers, but also plays a functional role in NP1-mediated itch, supported by the observation that the natural MrgprD ligand β-alanine induces scratching behavior in mice after intradermal injection.¹¹¹ Moreover, Liu et al¹¹² demonstrated that β-alanine-induced itch is abrogated in MrgprD-deficient mice and that β-alanine can activate murine DRG neurons in a MrgprD-dependent manner. These findings indicate that β-alanine induces itch by activating MrgprD on NP1 neurons. However, the physiological relevance of endogenous MrgprD ligands remains elusive. As a translational finding, and in line with the conserved expression of MrgprD,⁸⁵ β-alanine can also induce pruritus in humans after intradermal injection.¹¹² Besides its role in pruriception, MrgprD was also shown to modulate responses to mechanical and thermal stimuli, highlighting the polymodal function of NP1 neurons.¹¹³

Regarding downstream TRP channels, it is worth noting that NP1 neurons do not express TRPV1, but they do express TRPA1. There is evidence that MrgprD activation targets and modulates TRPA1 activity, providing a mechanistic explanation for how NP1 neurons generate an itch-encoding action potential in response to β-alanine (see Fig. 2).¹¹⁴

So far, β-alanine is the only established pruritogen targeting murine NP1 neurons. However, single-cell sequencing data indicate that the lysophosphatidic acid receptor 3 is expressed on NP1 fibers in mice.⁷⁸ This observation raises the hypothesis that NP1 fibers may be involved in cholestatic pruritus, as the retention of lysophosphatidic acid is associated with cholestasis-associated pruritus.¹⁰⁸^,¹¹⁵ Importantly, murine NP1 neurons are not engaged in histamine-induced pruritus.¹¹²

5. NP2 fibers

The expression of MrgprA3 defines murine NP2 fibers, a sensory fiber class that has been associated with itch sensation since its discovery.²⁷ NP2 neurons represent approximately 4%–8% of total murine DRG neurons.⁸⁰^,⁸⁶^,¹⁰⁹^,¹¹⁶ Similar to NP1 fibers, NP2 fibers exclusively innervate the epidermis and terminate in the stratum granulosum (Fig. 2). In addition, NP2 fibers were found to wrap hair follicles.¹¹³ Studies employing the antimalarial drug chloroquine initially delineated the functional role of NP2 neurons in itch sensation. This early-generation antimalarial drug is notorious for causing severe pruritus in mice and also in susceptible humans.¹¹⁷^,¹¹⁸

a. Pruritogen detection and signal transduction in NP2 neurons

In 2009, Liu et al⁸⁸ found that MrgprA3 on NP2 neurons is responsible for chloroquine-induced itch in mice. Besides MrgprA3, NP2 neurons coexpress MrgprC11, another Mrgpr engaged in NP2 fiber-dependent itch sensation.¹⁰⁹ The peptides bovine adrenal medulla (BAM) 8-22 and SLIGR are well known ligands for MrgprC11 and exhibit high pruritic potential in mice. BAM8-22 is an endogenous peptide derived from proenkephalin A, a precursor for various endogenous opioid peptides. SLIGR is a synthetic peptide designed to mimic the activating part of the protease-activated receptor 2 (PAR2) G-protein receptor, a receptor targeted by various proteases discussed later in this review.⁸⁸ The physiological rationale for why these substances act as pruritogens is unknown. Humans express neither MrgprA3 nor MrgprC11, but rather the functional ortholog MrgprX1, explaining the mode of action by which chloroquine and BAM8-22 also induce itch in humans.⁸⁸^,¹¹⁹ Clinically, chloroquine-induced pruritus is frequently more severe and often generalized in individuals with black skin, whereas it is infrequently observed in white populations.¹¹⁸ This observation proposes a genetic contribution; however a mechanistic explanation, such as an MrgprX1 genetic polymorphism, has not yet been identified.

TRPA1-deficient mice show reduced scratching in response to chloroquine or BAM8-22, suggesting that MrgprA3 and MrgprC11 employ TRPA1 to generate the encoding action potential in NP2 neurons.¹²⁰ TRPV1 is another well known TRP protein expressed by a substantial fraction of NP2 neurons and is considered to be employed for neuronal signaling by various pruritogens acting on NP2 fibers.⁷⁸^,⁸⁰ Intriguingly, an elegant approach that limited TRPV1 expression to MrgprA3 neurons demonstrated that TRPV1 activation on NP2 fibers causes scratching but not pain behavior.²⁷ This finding supports the notion that NP2 neurons could represent dedicated itch fibers. Notably, single-cell sequencing data indicate that TRPV1 is not expressed on all NP2 fibers and can be utilized for a refined division of TRPV1-negative NP2.1 fibers and TRPV1-expressing NP2.2 fibers, which represent distinct clusters, for example, in the Zeisel single-sequencing data set.²^,⁷⁹

In addition to the pruritogens mentioned above, there is ample evidence that NP2 neurons are responsible for sensing various additional pruritogens, including the biogenic amines histamine and serotonin, the vasoconstricting peptide endothelin-1 (ET-1), or the antimicrobial β-defensin Defb14.²⁷^,¹²¹ These endogenous pruritogens will be introduced in greater detail in the second part of this review.

NP2 neurons are also thought to be engaged in mechanical itch sensation. Lu et al¹²² demonstrated that the mechanosensitive ion channel Piezo2 on NP2 fibers is crucial for sensing and initiating mechanically induced itch.

b. Itch selectivity versus polymodality in NP2 neurons

Together, these findings suggest a critical role for NP2 fibers in murine itch sensation, raising the question of whether NP2 neurons are completely dedicated to itch or also mediate other sensations. Several observations from the pioneering NP2 study by Han et al²⁷ support the former interpretation. Pain behavior was not altered in NP2-depleted mice, and TRPV1 activation, known to be important in pain signaling, caused pruritus when activated on NP2 fibers. Still, the same study, consistent with more recent findings by Qi et al,⁸⁵ also indicated that NP2 neurons can respond to heat and noxious mechanical stimuli; a finding proposing a degree of sensory polymodality.²⁷ Recently, Sharif et al¹²³ introduced a sophisticated mode of alternative receptor activation that explains the difference between pain and itch signaling in NP2 neurons. They demonstrated that pruritic substances like chloroquine employ metabotropic receptor activation to trigger itch behavior, whereas direct ionotropic activation of cation channels, eg, ATP acting on its ionotropic receptor P2RX3, induces NP2-fiber-mediated pain behavior. This concept proposes a molecular mechanism allowing NP2 neurons to discriminate between itch and pain stimuli. However, how NP2 fibers, like the other polymodal NP fiber classes, transmit distinct sensory modalities via the same axon to the CNS while preserving modality-specific information remains a fascinating question. Potential mechanisms include modality-specific action potential firing patterns of the responding neuron as well as complex integration and gating of diverse sensory inputs at the spinal level.⁷¹

6. NP3 fibers

NP3 fibers in mice are commonly identified by their expression of the IL-31 receptor⁷⁸ or the cysteinyl leukotriene receptor 2,⁵²^,¹²⁴ as well as the neuropeptides SST¹²⁵ and BNP.⁵¹ NP3 neurons represent approximately 1.8%–1.9% of all DRG neurons and are, at 7.1%, the smallest fraction of the NP neurons.⁷⁸^,¹²⁵

Somatostatin-driven visualization revealed a low NP3-fiber density in mouse skin.¹²⁵^,¹²⁶ NP3 neurons project along the dermal-epidermal interface and innervate a minority of hair follicles (Fig. 2).¹²⁵ Recent work by Qi et al⁸⁵ suggests that NP3 fibers can penetrate the epidermis; however, to the best of our knowledge, the precise epidermal termination layer remains uncharacterized.

Functional evidence for an itch-specific role of NP3 neurons comes from optogenetic activation, which induces robust scratching behavior in mice.¹²⁶ NP3 neurons respond to several pruritogens, one of the most prominent being the cytokine IL-31. IL-31 is associated with type 2 immune responses and is highly pruritogenic by engaging its receptor on murine NP3 neurons. Downstream, the IL-31 receptor utilizes TRPV1 and TRPA1, which are coexpressed on NP3 neurons, to transform the itch stimulus into action potentials.⁴³ Notably, IL-31 is pruritogenic in both mice and humans, highlighting cross-species conservation.¹²⁷ Other endogenous pruritogens, such as serotonin, leukotrienes, and sphingosine-1-phosphate (S1P), have been identified to activate NP3 fibers.⁵¹ Although histamine-induced itch is classically attributed to NP2 fibers, transcriptomic analyses reveal histamine 1 receptor (H1R) expression on NP3, raising the possibility that NP3 might be engaged in histaminergic itch.⁷⁸

The protease receptor PAR2, discussed in more detail later, is another potential pruritogen receptor expressed specifically on murine NP3 fibers.⁷⁹^,⁸⁰ Intriguingly, murine NP3 fibers might also be involved in mechanical itch. Hill et al⁷² recently showed that expression of Piezo1, a mechanosensitive ion channel, is responsible for mechanical itch sensation in mice. Importantly, their data demonstrate that Piezo1 is coexpressed in BNP-positive human DRGs, suggesting a cross-species conserved finding. Additional cross-species similarities and differences are the focus of the next section.

7. Are NP fibers conserved in primates and humans?

The last sections demonstrated that NP fibers play a fundamental role in the transmission of itch in mice. From a translational perspective, this finding raises the crucial question of whether this organization is preserved in primates and humans. This question is explored in the following 2 sections, which summarize recent single-cell sequencing findings from nonhuman primate (NHP) and human DRGs.

a. Nonhuman primate (NHP)

In 2021, Kupari et al⁸¹ conducted a high-quality single-cell RNA sequencing study of macaque DRGs (Table 2). This study proposed that a homologous organization also exists in NHPs, although some interspecies differences were noted. They defined NP1, NP2, and NP3 equivalent clusters in the macaque DRG. However, significant differences were also noted. For example, macaque NP1 neurons were shown to express itch receptors such as the IL-31 receptor and neuropeptides including SST, which are restricted to murine NP3 neurons.⁸¹ Moreover, expression profile analyses indicate that NP1 and NP2 neurons in NHPs may share similar functions, whereas these functions are strictly separated in mice. This statement is underscored, for example, by the finding that the chloroquine-responsive receptor MrgprA3 is selectively expressed in murine NP2 fibers, whereas its functional homolog MrgprX1 is expressed on both NP1 and NP2 fibers in NHP. Compared to NP1 and NP2 neurons, cross-species analyses revealed that NP3 neurons are particularly well conserved in NHPs. Similar to the mouse findings, NP3 neurons in NHPs were characterized by SST, IL-31 receptor A (IL-31RA), and S1P receptor 1 expression. However, significant qualitative differences were also apparent. Macaque NP3 neurons did not express BNP, the 5-hydroxytryptamine (5-HT) 1F receptor, or neurotensin, but instead expressed the neuropeptide cholecystokinin, which was barely detectable in murine NP3 neurons.⁸¹

b. Human

Transcriptomic studies relying on human DRGs are inconclusive about whether NP1–3 equivalents exist in humans (Table 2). A spatial transcriptomic study of human DRGs conducted by Tavares-Ferreira et al⁸³ did not define NP-equivalent populations in humans. In this study, 2 itch-related clusters were identified: cluster H10 and H11. Cluster H10 expressed the H1R and was related to mechanical itch, whereas cluster H11 expressed the NP3 characteristic neuropeptide natriuretic peptide B (BNP) and the pruritogen receptor IL-31RA. The authors observed broad expression of the peptidergic neuropeptides CGRP and tachykinin-1 (precursor protein for Substance P) in all small C-fiber clusters. Based on this observation, they concluded that the peptidergic/NP classification may not be transferable to humans. This conclusion could be the reason why no assignment of murine NP populations was proposed in this publication.⁸³

Relying on single-nucleus RNA sequencing, Nguyen et al⁸² identified 2 human DRG cell clusters that resemble features of murine NP populations. Cluster H10 was considered the human NP1 equivalent and cluster H11 the human NP3 equivalent. Still, and in line with the NHP dataset, the murine NP3-specific marker IL-31RA was also detected in the human NP1 equivalent. This finding highlights the existence of relevant interspecies differences between mice and humans. Notably, the mechanoreceptor Piezo2 was also identified in cluster H10, suggesting a potential role of human NP1 equivalents in the induction of mechanical itch.⁸² Cluster H11 (murine NP3 equivalent) expressed key murine NP3 markers, including IL-31RA, H1R, BNP, SST, and TRPV1. Cholecystokinin was also detected in this cluster, which aligns with the NHP data.⁸² A separate murine NP2 population was not defined in this study. In contrast, coclustering analysis by Nguyen et al⁸² revealed a partial overlap between the murine NP2 cluster and the 2 human itch clusters, H10 (the human equivalent of NP1) and H11 (the human equivalent of NP3). This finding suggests that human NP1 and NP3 equivalents have absorbed the properties of murine NP2 fibers.

The most recent human single-cell sequencing study, published by Yu et al⁸⁴ in 2024, employed a novel microdissection approach. This new technique enables the recovery of the entire neuronal soma from human DRG for sequencing, representing a technical advance compared to previous attempts. This single-soma RNA sequencing study generally concluded that murine NP1–3 equivalents also exist in humans. Cell-type correlation analysis revealed that the human NP1 cluster showed good correspondence with the human NP1 equivalent in Nguyen’s dataset, including expression of Piezo2 and IL-31RA.⁸⁴ Compared to the aforementioned human studies, Yu et al⁸⁴ also defined a distinct human NP2 equivalent. Cross-species analysis between mouse and human revealed that the NP2 population was well conserved. Human NP2 was characterized by MrgprX1 (human MrgprA3 equivalent); however, and in line with the NHP findings, it is worth noting that MrgprX1 was also detected in the human NP1 equivalent. It is possible that the new technical approach employed by Yu et al, which uses a laser to isolate neuronal somas for sequencing, enabled the recovery of human NP2 neurons, in contrast to previous human studies. Further studies are required to finally determine if an independent human NP2 equivalent exists or if human NP1 and or NP3 equivalents have incorporated functions of murine NP2 fibers. Yu et al also proposed a human NP3 equivalent, which showed a strong one-to-one match between Nguyen’s study and their human NP3 equivalent (cluster hSST).

In conclusion, although single-sequencing studies have assigned human NP equivalents, there is no final consensus on whether and to what extent the mouse itch fiber taxonomy is applicable to humans. The studies that advocate the existence of human NP equivalents diverged in particular on whether NP2 fibers are preserved as a distinct population in humans or are merged with the NP1 and NP3 populations. Aside from the general NP fiber organization, qualitative interspecies differences were apparent. A striking example is that specific murine NP3 markers, such as the IL-31 receptor or BNP, were also found in different itch-associated clusters in humans.⁸²

Further characterization studies are needed, and the field would greatly benefit from establishing a unified nomenclature for human itch fibers.

VI. Crosstalk at the neurocutaneous interface

A. Epithelial-neuroimmune circuits promote peripheral itch

In the aforementioned sections, key components engaged in peripheral itch induction were introduced: (1) the epidermis/dermis as structural compartments, (2) the cutaneous immune system, and (3) the sensory nerve fibers. So far, these components have been discussed separately to provide focused access. However, to understand the driving mechanisms and pathogenetic principles of pruritic inflammatory skin diseases, it is essential to explore their mutual interactions (Fig. 3).

Fig. 3 — Epithelial–neuroimmune circuits drive chronic pruritus in the skin. CP is driven by bidirectional interactions at the neurocutaneous interface involving keratinocytes, immune cells, and sensory neurons; as illustrated by solid arrows. Dotted arrows indicate modulatory influences of the CNS on these cutaneous interactions. The itch-scratch cycle is highlighted in red. HPA axis, hypothalamic-pituitary-adrenal axis; NGF, nerve growth factor; PAR, protease-activated receptor; SA axis, sympathetic–adrenal axis. This figure was created with permission in BioRender: R. T. (2025) https://BioRender.com/zx7jqs4.

1. Immune cells drive pruritic inflammation and neuronal remodeling

Immune cells, particularly those involved in type 2 inflammation including Th2 cells, ILC2s, eosinophils, basophils, and mast cells, are key sources of pruritogens that act on itch-mediating sensory nerve fibers (immune–neuronal axis). Many of these released pruritogens, such as the cytokines IL-31, IL-13, and IL-4, play crucial roles in orchestrating inflammation.⁴⁰^,⁴⁴^,¹²⁸^,¹²⁹ This dual inflammatory and pruritogenic activity illustrates the close functional coupling between inflammation and itch. In addition, findings by Feld et al¹³⁰ indicate that immune cells and their cytokines can exert neurotrophic functions. They demonstrated that the pruritic cytokine IL-31 induces nerve elongation and branching of small-diameter nerve fibers in vivo and in vitro. Given that pruritic skin diseases such as AD frequently show alterations in cutaneous innervation, IL-31-dependent remodeling of itch-mediating fibers could represent an important contributing mechanism for human CP.¹³¹

2. Keratinocytes as initiator and amplifier of inflammation and itch

Structural cells of the skin, and in particular keratinocytes, are also critically involved in skin inflammation and itch circuits. Given their strategic position at the interface with the external environment, keratinocytes serve as early sentinels for threats. Engagement of pathogen- or damage-recognition receptors triggers the release of alarmins to alert surrounding resident immune cells (epithelial–immune axis).¹³²

Notably, type 2 alarmins, such as TSLP and IL-33, have been shown to act as pruritogens in mice (epithelial–neuronal axis). Subsequent scratching behavior feeds back, targets, and disrupts the epidermal barrier (neuronal–epithelial axis). Persistent scratching provokes adaptive epidermal remodeling, including keratinocyte hyperproliferation and thickening of the epidermis, which manifests clinically as skin coarsening or lichenification. Mechanical injury to keratinocytes is thought to further promote the release of epithelial-derived pruritogens, thereby establishing a vicious itch-scratch cycle.¹³³ The itch-scratch cycle is clinically widely accepted as a driver of CP. However, robust functional evidence that keratinocyte-derived pruritogens, such as TSLP, indeed fuel this cycle is pending.

The relationship between epidermal barrier dysfunction and itch is also reflected by the close association between dry skin (xerosis cutis) and CP.²⁹ Dry skin itch is frequently observed in elderly patients and is considered a consequence of increased transepidermal water loss. Pathophysiological changes in the stratum corneum, reduced activity of cutaneous glands, and decreased estrogen levels are considered determinants resulting in impaired barrier function.¹³⁴ Importantly, xerotic itch generally presents without overt clinical signs of skin inflammation, suggesting that overt inflammation does not always accompany pruritic skin. The exact pathogenic mechanism underlying CP in dry skin remains poorly understood. Morphological studies have found increased intraepidermal nerve fiber density, suggesting that neurostructural changes may play an important role.¹³¹^,¹³⁵^,¹³⁶ Notably, keratinocytes are well known players in regulating epidermal nerve fiber density by releasing neurotrophic factors such as nerve growth factor.¹³⁷ Hence, keratinocyte-mediated neuronal remodeling, promoting the expansion of itch-mediating fibers in the epidermis, could represent a key pathogenic element of xerotic skin and CP more broadly.

Keratinocytes also contribute directly to pruritogen detection. Chen et al¹⁰² demonstrated that mice lacking TRPV4 specifically in keratinocytes show reduced scratching after intradermal pruritogen administration. This positions keratinocytes as nonneuronal detectors of itch stimuli. It remains exciting to see how keratinocytes mechanistically convey the TRPV4-dependent itch information to itch-mediating nerve fibers. Considering that most itch-mediating nerve fiber terminals end in the epidermis, a juxtracrine signaling pathway might be a possibility.

Aside from alarmins, keratinocyte-derived kallikreins, periostin, and β-defensins have also been identified as pruritogens.¹²¹^,¹³⁸^,¹³⁹ Interestingly, keratinocyte pruritogen release is triggered not only by environmental stimuli but also by immune cell-derived mediators, serving as an amplification loop for immune cell-mediated itch (immune–epithelial axis). A well studied pathway involves endogenous proteases such as tryptase acting on keratinocyte PAR2, initiating TRPV3-dependent pruritogen release including TSLP.¹⁴⁰ The immune–epithelial axis is also a critical driver of skin remodeling processes that frequently occur in pruritic inflammatory skin diseases. Specific morphological changes of the epidermis and dermis are closely linked to the type of inflammation prevailing in the skin. For example, hallmark cytokines of type 2 inflammation are well known to impair epidermal barrier integrity and promote dermal fibrosis.141, 142, 143

3. Neurogenic immunomodulation and itch

The neuronal–immune axis is characterized by neurons influencing immune cells to promote cutaneous inflammation. This can happen locally as well as systemically. The CNS employs the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenomedullary system to influence the cutaneous immune response during stress, as detailed at a later stage.¹⁴⁴ Direct neuroimmune interaction in the skin occurs during neurogenic inflammation, which describes the potential of sensory neurons to initiate cutaneous inflammation. Intriguingly, recent reports suggest that sensory nerve fibers also exert immunosuppressive effects on cutaneous immune cells.³⁷^,¹²⁹ This observation suggests that neurogenic immunomodulation is a more appropriate umbrella term. The following section will focus in more detail on the mechanisms of neurogenic immunomodulation and delineate connections to itch.

a. Neurogenic inflammation and itch

Sensory nerve fibers, particularly those involved in nociception, can initiate cutaneous inflammation by releasing small peptide fragments (neuropeptides) from their terminals. This phenomenon is termed neurogenic inflammation.⁷⁶ Various stimuli, including toxins, physical injury, and infections, trigger neurogenic inflammation. Pathogen recognition receptors, such as toll-like receptors and dectin-1, can be found in sensory neurons, proposing their active role in initiating immune responses.¹⁴⁵

Upon release, immunoreactive neuropeptides target various cutaneous cell populations to drive inflammation. In this context, mast cells are particularly important targets, as they can serve as an amplifier of neurogenic inflammation in the skin. This relationship is underscored by the observation that mast cells are in close proximity to sensory nerve fibers. Hence, they are optimally positioned to serve as bidirectional mediators between nerve fibers and other skin cells.¹⁴⁶ This neuron–mast cell axis is particularly interesting as a driver of CP, given that mast cells are rich in pruritogens, including histamine, serotonin, proteases, and ET-1.⁵¹

Neuropeptides are stored in dense core vesicles compared to classical neurotransmitters, which are released from small secretory vesicles. Exocytosis of neuropeptides is not bound to synaptic regions and does not depend on action potentials.¹⁴⁷^,¹⁴⁸ Mechanistically, neuropeptide release is initiated by an increase in cytosolic Ca²⁺, driven either by intracellular sources (eg, endoplasmic reticulum) or by cation-gated channels such as TRPV1 or TRPA1. Direct TRP activation (eg, TRPV1 by capsaicin), but also the activation of metabotropic receptors by immunoreactive molecules (eg, histamine) or proteases (eg, tryptase), are well known upstream triggers of the neuropeptide release.¹⁴⁹

Several neuropeptides have been identified; CGRP and Substance P are the best-studied ones. After release, both neuropeptides mediate immediate vascular effects promoting the recruitment of immune cells. CGRP overtakes a dominant role in promoting vasodilation¹⁵⁰; Substance P increases vascular permeability and upregulates adhesion molecules on the endothelial cells.151, 152, 153 Aside from mediating these acute inflammatory effects, both neuropeptides also target various immune cell populations. CGRP was characterized to promote Th2 responses by acting on antigen-presenting Langerhans cells¹⁵⁴ and is an essential player in antifungal clearance by inducing IL-23 production in dermal DCs.¹⁵⁵ Interestingly, another study reported that CGRP suppresses neutrophil recruitment, thereby facilitating Streptococcus skin infection.¹⁵⁶ Hence, these findings underscore that the immunological role of CGRP in the skin is likely context-dependent.

Substance P has been associated with promoting dermal DC migration and is engaged in initiating allergic type 2 immune responses.¹⁵⁷ Substance P can also activate mast cells by targeting MrgprB2 (or in humans, MrgprX2).⁸⁹ This is of particular interest, as we learn later that MrgprX2-blocking agents are currently being tested in clinical trials for pruritic inflammatory skin diseases.

b. Itch-mediating NP fibers: Rising players in neurogenic immunomodulation

In mice, peptidergic C fibers are traditionally thought to be the primary driver of neurogenic inflammation. Interestingly, recent findings indicate that, contrary to their name, NP fibers also shape the cutaneous immune environment through neuropeptide release. For example, itch-mediating murine NP3 fibers have been described to release proinflammatory BNP in an IL-31-dependent manner; a mechanism proposed to contribute to human AD.¹²⁸ Interestingly, emerging evidence suggests that NP fibers can also overtake a counterregulatory part and act immunosuppressive. It has been demonstrated that NP1 fibers have the immunoregulatory capacity to suppress cutaneous mast cell function in a glutamate-dependent manner.³⁷ In addition, Fassett et al¹²⁹ showed that IL-31-dependent CGRP release from NP3 fibers suppresses type 2 inflammation. The observation that IL-31, as a potent pruritogen, also exerts neuropeptide-releasing properties suggests a close connection between neurogenic immunomodulation and pruritus.

c. Neurogenic inflammation in human disease

The phenomenon of neurogenic inflammation is also well known in humans, exemplified by local capsaicin application. Growing evidence suggests that neurogenic inflammation is a crucial driver of inflammatory skin diseases associated with CP, such as AD or psoriasis. The significance of neurogenic inflammation is demonstrated by observations indicating complete remission of skin diseases at sites that became de-innervated due to an acquired neural damage.¹⁵⁸ All these findings indicate that neurogenic inflammation, itch, and scratching are closely intertwined. The following section will exemplify how these elements interact in the context of microbial encounters, when pathogens exploit the itch-scratching response.

B. Itch, pathogens, and neurogenic inflammation

Recent findings studying bacterial skin infection with S. aureus provided fascinating insights into how itch and scratching are intertwined in pathogen-neuroimmune crosstalk. Deng et al¹⁵⁹ found that S. aureus secretes the protease V8 to induce itch during epicutaneous infection (Fig. 4, left panel). Mechanistically, it was shown that V8 targets PAR1 on murine NP2 fibers to initiate scratching behavior.²^,¹⁵⁹ A simple explanation for why S. aureus produces this itchy molecule is that it hijacks the scratching reflex to promote its spreading to uninfected skin sites. This idea aligns with the clinical disease impetigo contagiosa, a highly contagious skin infection caused by S. aureus or Streptococcus pyogenes in children. Impetigo contagiosa typically manifests as honey-colored, crusted lesions and is frequently accompanied by itching, which is considered to promote the spread of bacteria on the skin.

Fig. 4 — Scratching induced by *S. aureus* infection boosts the cutaneous immune response. The left panel illustrates a mechanism by which Staphylococcus aureus infection induces scratching behavior in mice. The right part depicts a recently identified neuroimmune feedback loop where scratching enhances the antibacterial immune response of the host. IgE, immunoglobulin E; NP2, nonpeptidergic type 2 fiber; PAR1, protease-activated receptor 1; Staph. Aureus, *Staphylococcus aureus*; TNFɑ, tumor necrosis factor ɑ. This figure was created with permission in BioRender: R. T. (2025) https://BioRender.com/o9o1x2a.

Intriguingly, a recent study has identified a mechanism allowing the host to exploit scratching to its own advantage during S. aureus infection. It was demonstrated that the scratching act activates pain neurons to release Substance P, which synergistically enhances the mast cell-dependent IgE response against S. aureus, a mechanism that promotes bacterial clearance (Fig. 4, right panel).² Notably, these findings introduce a novel concept: Scratching is not only a mechanical act to repel threats, but also a feedback mechanism that boosts the cutaneous immune response.²

Collectively, these observations illustrate how S. aureus and the host have coevolved strategies to employ itch and scratching for survival. Beyond this specific interaction, 16S rRNA sequencing and culturomics approaches revealed that scratching directly affects the cutaneous microbiome within 24 hours.² Moreover, emerging evidence suggests that microbial dysbiosis has a crucial role in CP,¹⁶⁰ altogether highlighting the cutaneous microbiome as a potential therapeutic target in future.

Having outlined the mutual interaction between key players involved in peripheral itch induction, the next section will now focus on how the itch signal is processed in the CNS.

VII. Central conductivity and processing of itch

The pseudounipolar axons of itch fibers serve as conduit to carry itch-encoding action potentials to the CNS. Itch fibers innervating nonfacial skin regions project their axons to the posterior gray column of the spinal cord, where the incoming information is processed by interneurons and subsequently relayed to higher brain centers.

A. Itch circuits at the spinal level

NP itch fibers project to the superficial dorsal horn of the spinal gray matter. A traditional approach to categorize areas of the spinal gray matter is the Rexed lamina classification, which uses cytoarchitectural features to define 10 different laminae, beginning with lamina I at the most dorsal part of the gray matter.¹⁶¹ NP axons terminate and engage the second neuron of the itch pathway in the lamina II, also termed the substantia gelatinosa of Rolando (Fig. 5).⁷¹^,¹⁰⁹ All NP fiber classes, similar to nociceptive fibers, primarily employ the neurotransmitter glutamate to communicate with the second spinal neuron. Notably, combinatorial knockout of glutamate signaling in NP itch fibers and peptidergic nociceptors led to enhanced itch transmission, challenging the presumed essential role of glutamate at the first synapse of the itch pathway.¹⁶² This finding may be explained by the idea that nociceptors employ glutamate to inhibit spinal itch signaling circuits under steady-state conditions. In contrast, a more selective approach by Cui et al¹⁶³ revealed that glutamate release from NP2 neurons is indeed crucial for spinal itch transmission. This study further demonstrated that the neuropeptide neuromedin B can act as a synaptic cofactor to enhance glutamate-mediated itch transmission.¹⁶³

Fig. 5 — Spinal circuity of chemical and mechanical itch. On the left, schematic overview of the spinal cord with projection of primary sensory afferents from the dorsal root ganglion (DRG) into the dorsal horn. Middle and right panels show enlarged views of the superficial dorsal horn (Rexed laminae I-IV). The middle panel illustrates the spinal processing of chemical itch; while the right panel thematizes the spinal circuits of mechanical itch conduction. Spinal interneurons are illustrated in black. Excitatory synaptic connections are indicated by green plus symbols, whereas inhibitory connections are marked by red minus symbols. Bhlhb5, basic helix-loop-helix domain containing class B 5; Calcrl, calcitonin receptor-like; NK1R, neurokinin 1 receptor; NMB, neuromedin B; NP, nonpeptidergic; NPR1, natriuretic peptide receptor A; NPY, neuropeptide Y; PIEZO1 & 2, Piezo-type mechanosensitive ion channel component 1 & 2; SP, substance P; TLR5, Toll-like receptor 5; UCN3, urocortin 3. This figure was created with permission in BioRender: R. T. (2025) https://BioRender.com/njolxgv.

1. Gastrin-related peptide (GRP) and spinal excitatory interneurons mediate chemical itch

GRP is another neuropeptide and is considered a central molecule for chemical-induced itch signaling at the spinal level by targeting its receptor GRPR. Liu et al¹⁶⁴ demonstrated that GRPR-mutant mice show reduced scratching responses to pruritogens activating NP2 or NP3 nerve fibers. Importantly other sensory qualities such as pain were unaffected in GRPR-deficient mice. Consistent with these findings, injection of a GRPR antagonist into the cerebrospinal fluid inhibited scratching behavior.¹⁶⁴ Single-cell sequencing data do not support GRP expression in peripheral DRG neurons,⁷⁹^,⁸⁰ proposing that GRP is predominantly produced by spinal excitatory interneurons. Mishra et al¹⁶⁵ demonstrated that the neuropeptide BNP promotes GRP-dependent circuits upstream of GRP signaling, which is consistent with increased systemic BNP levels detected in CP patients.¹⁶⁶ In addition, BNP is increased in sensory neurons of mice and NHP subjected to chronic itch models,¹⁶⁷ suggesting that NP itch neurons may utilize BNP in addition to glutamate release for activating GRP-excitatory interneurons (Fig. 5). However, given that BNP expression is restricted to NP3 neurons at steady state,⁷⁸ this mode of action would be only valid for this itch fiber subclass. NP1 or NP2 itch fibers likely employ other neuropeptides besides glutamate for activating GRP-expressing interneurons.⁷⁸ GRP-releasing excitatory interneurons activate GRPR-expressing interneurons in the Rexed lamina I, which in turn activate projection neurons relaying the itch signals to higher brain regions such as the thalamus and the parabrachial nucleus in the pons. In the mouse, these projection neurons express the Substance P receptor neurokinin-1 receptor (NK1R), and their depletion ameliorated scratching in a murine model of AD.¹⁶⁸

2. Inhibitory interneurons shape chemical itch transmission

Interneurons modulate the spinal pathway that conducts chemical itch information. Ross et al. demonstrated that the transiently expressed transcription factor Bhlhb5 is crucial for the development of itch-inhibiting GABAergic interneurons located in Rexed lamina I-II. Mice lacking Bhlhb5 expression in the dorsal horn did not develop this particular interneuron population and showed self-inflicted skin lesions and enhanced responses to pruritogens.¹⁶⁹ A follow-up study confirmed that this phenotype is restorable by spinal cord transplantation of inhibitory interneuron precursors.¹⁷⁰ It is well known that itch and pain sensations mutually influence each other; for example, scratching-induced pain can alleviate the itch sensation (“scratching an itch”). Moreover, activation of cold-sensitive fibers, whether through cold exposure or menthol-induced TRPM8 stimulation, suppresses itch signaling and can be utilized locally as therapeutic strategy for CP.¹⁷¹ The existence of Bhlhb5-expressing inhibitory interneurons can explain these phenomena. Kardon et al¹⁷² demonstrated that a subset of Bhlhb5-expressing interneurons receives input from menthol- (cold detection) and capsaicin- (pain) sensitive fibers, which triggers the release of the κ-opioid dynorphin to inhibit GRP-mediated itch signaling. Another study found that glycinergic interneurons also inhibit chemical itch signaling at the spinal level.¹⁷³ Interestingly, these glycinergic interneurons are innervated by Aβ-mechanosensitive neurons, suggesting a dedicated pathway allowing tactile stimuli to limit itch sensation.¹⁷³ The neuropeptide SST represents another modulatory player in spinal itch circuits. Huang et al¹²⁶ demonstrated that SST enhances spinal itch transmission by inhibiting dynorphin-expressing inhibitory interneurons. Because NP3 fibers express SST, spinal release of this neuropeptide may promote NP3-mediated itch signaling. The spinal itch pathways delineated here were all described in the context of chemically induced itch, in which NP2 or NP3 fibers were stimulated with specific pruritogens.

3. Mechanical itch signaling

The spinal pathway of mechanical itch is less well characterized (Fig. 5, right panel). Available data suggest that mechanical-induced itch transmission neither employs spinal GRP signaling nor the modifying influence of Bhlhb5 interneurons. Neuropeptide urocortin 3-positive excitatory interneurons were recently identified to promote mechanical itch signaling on the spinal level.⁶⁹ These interneurons receive input from Aβ low-threshold mechanoreceptors,⁶⁹ so another primary neuron source besides Piezo2-expressing NP2 fibers and Piezo1-expressing NP3 fibers, which is associated with mechanical itch induction in the periphery.⁷² Urocortin 3-positive excitatory interneurons receive inhibitory input from neuropeptide Y-expressing interneurons.¹⁷⁴ The spinal projection neurons involved in mechanical itch sensation also appear distinct from those expressing NK1R, which are involved in chemical itch. Instead of NK1R-neurons, Ren et al¹⁷⁵ identified that calcitonin-receptor-like receptor-expressing projection neurons are critical for mechanical itch transmission to the brain.

B. Itch processing in the brain and descending brain-spinal modulation of itch

Elegant tracing studies revealed that NK1R-expressing projection neurons are connected to the somatosensory thalamus and the lateral parabrachial nucleus in the pons.¹⁶⁸ Both regions serve as relay stations for the spinal projection neurons, bridging to higher subcortical and cortical areas.

The spinothalamic tract is generally considered the pathway for the conscious perception of sensations and is thereby responsible for sensory discrimination. Thalamic neurons project itch information to the primary somatosensory cortex 1 (S1). Functional studies using positron emission tomography or functional magnetic resonance imaging suggest that itch is topographically and intensity coded in S1.¹⁷⁶^,¹⁷⁷ Interestingly, the response patterns of spinothalamic neurons demonstrated that histamine and the nonhistaminergic pruritogen cowhage (a PAR2 agonist) activate distinct neuronal populations.¹⁷⁸ This finding indicates that histaminergic and nonhistaminergic itch are processed through partially separated central pathways. Supporting this notion, functional magnetic resonance imaging studies showed that slightly distinct neuronal networks are involved in the processing of histamine- and cowhage-induced itch.¹⁷⁹ The spinoparabrachial pathway is essential for motivational, aversive, and motor components of itch responses.¹⁸⁰ Sun et al¹⁸¹ demonstrated that optogenetic suppression of spinal axon projections in the parabrachial nucleus markedly reduced chloroquine- or histamine-induced scratching responses. Similar to the thalamus, the nucleus parabrachialis serves as a relay. It is connected to other subcortical nuclei, including the thalamus, hypothalamus, limbic system, basal ganglia, and reticular formation. Complex networks involving the limbic system allow the processing of motivational and emotional components of itch. Networks connecting the motor-associated regions, such as the basal ganglia or the reticular formation, are involved in planning and executing the scratching response.¹⁸⁰ The brain-wide neural dynamics of itch were recently intensively mapped by Chen et al,¹⁸² who characterized histamine- and chloroquine-induced response patterns across 126 distinct murine brain areas.

The itch signaling pathway is not a one-way route. Descending pathways from higher brain areas set the tone for itch signaling at the spinal level. Tachykinin 1 (precursor for Substance P)-expressing glutamatergic neurons located in the periaqueductal gray¹⁸³ or serotonergic neurons in the brainstem¹⁸⁴ form descending pathways to enhance itch sensation by promoting spinal GRP signaling. Conversely, noradrenergic neurons in the locus coeruleus were identified to suppress acute and chronic itch signaling at the spinal level.¹⁸⁵ These supraspinal, descending pathways complicate the comprehension of spinal itch processing but offer interesting approaches to therapeutically target and modify the incoming itch signal.

C. Glia cells and their role in itch transmission

Neurons critically depend on glial cells for proper function. Macroglia, such as Schwann cells in the peripheral nervous system or oligodendrocytes and astrocytes in the CNS, are critical players in maintaining neuronal function. They provide the myelin sheath, structural support, and nutrients to neurons. Microglia, the resident macrophages of the CNS, are responsible for eliminating pathogens and engulfing dead neurons.¹⁸⁶ Given the close relationship between proper neuronal function and glia, it is evident that glia could play a fundamental role in itch signaling and CP development.

1. Peripheral glia and itch

A potential contribution of peripheral glia to pruritus was first highlighted in patients receiving hydroxyethyl starch (HES) plasma expansion therapy. While HES accumulates in several nonneuronal tissues, patients who developed pruritus showed additional HES deposits specifically within glial cells of peripheral nerve fibers.¹⁸⁷^,¹⁸⁸ This finding indicates a role of peripheral glia in HES-induced pruritus; however, a mechanistic explanation is pending. Another study found that peripheral glial cells are activated by lysophosphatidic acid, which is considered a relevant pruritogen in cholestatic pruritus.¹⁸⁹ This finding supports the hypothesis that glial dysfunction might be involved in cholestatic pruritus.

2. Central glia and itch

Central glia cells have also been suggested to propagate itch. In particular, astrocyte activation, or astrogliosis, has been linked to CP. Shiratori-Hayashi et al¹⁹⁰ found that spinal segments innervating pruritic inflammatory skin lesions exhibited astrogliosis. Astrocyte-specific deletion of signal transducer and activator of transcription 3 (STAT3) significantly reduced CP development, identifying astrocytic STAT3 signaling as a key driver of central itch sensitization. Downstream analyses revealed that lipocalin-2, a modulator of neuronal excitability in the CNS, is a critical effector in this pathway. Other reports indicated that the pathogen recognition receptor TLR4,¹⁹¹ the IL-33 cytokine receptor ST2,¹⁹² or the chemokine receptor CXCR3¹⁹³ could mediate chronic itch through astrocyte activation. Microglia were also reported to be activated by itch-inducing substances¹⁹⁴ and in a psoriasis-related CP mouse model¹⁹⁵; however, the mechanistic relationship to persistent itch still needs to be defined.

Together, these observations underscore the role of glial cells as relevant players in CP pathogenesis. We are just beginning to understand the glial-neuron crosstalk in the context of itch, but the identification of potential targets, such as lipocalin-2, should encourage future research.

D. Mental status and itch—Stress and the skin immune response

So far, we have focused on the mechanisms of peripheral itch generation and the neuronal structures involved in itch transmission. However, the final interpretation of an itch stimulus is strongly shaped by psychological factors, including emotional state and cognitive appraisal. CP is frequently accompanied by psychiatric disorders, in particular, affective disorders such as depression or anxiety disorders.¹⁹⁶ Mental disorders and CP are etiologically intertwined and can mutually promote each other: On the one hand, the psychological burden imposed by persistent itch and its underlying diseases can trigger the development of mental disorders such as depression. On the other hand, psychopathological changes associated with mental disorders can alter the perception and accentuate the subjective CP burden or even drive itch perception in the absence of a clear somatic reason, called psychogenic CP.¹⁹⁶^,¹⁹⁷ A chronic stress reaction is the result.

Notably, the stress reaction itself can induce biological changes that further fuel CP by acting on peripheral players such as the cutaneous immune system. Psychological stress impacts the cutaneous immune system through the sympathetic adrenomedullary axis, the HPA axis, and the release of neuropeptides.¹⁴⁴ Persistent dysregulation of the central HPA axis is a recognized driver of inflammatory pruritic skin diseases, such as AD.¹⁹⁸ Key central HPA axis hormones, such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone, are also expressed in the skin and link distress to local cutaneous inflammation and pruritus. CRH, for example, targets the mast cell–neuron unit to induce and amplify skin inflammation.¹⁹⁹ CRH is a potent mast cell activator, leading to increased skin levels of immunoreactive mediators, including histamine and proteases. These mediators target sensory nerve fibers to drive itch and to release Substance P and CGRP, thereby promoting neurogenic inflammation.¹⁹⁹

Hence, the close relationship between our mental health and CP is obvious. The interdisciplinary field of psychoneuroimmunology aims to decipher this bidirectional crosstalk between psychological processes, the nervous system, and the immune system.²⁰⁰ This integrative research approach loops psychological factors into biological models of diseases, allowing us to understand all facets of CP.

After detailing the anatomical and physiological bases of itch signaling, the next part of this review will address its clinical manifestations and implications.

VIII. Chronic itch from a clinical perspective

Unlike acute itch, which is common and often a harmless sensation in everyday life, CP is typically associated with persistent dysfunction of at least one organ system and occurs in a wide range of disease entities. These include primary skin-borne diseases, as well as systemic (eg, metabolic), neurological, and psychiatric diseases. The excessive presence and action of pruritogens, neuronal damage, or psychopathological processes cause chronic itch in these diseases.⁴ The umbrella term itch sensitization, including its subtypes hyperknesis and alloknesis, describes an altered sensory state which is considered an important driver for chronic itch, focused in the next section.

A. Itch sensitization: Hyperknesis and alloknesis

Chronic activation of itch-conducting pathways can lead to itch sensitization. This concept describes adaptive changes within the nervous system that result in exaggerated itch perception in response to weakly pruritic or even nonpruritic stimuli.²⁰¹ A similar concept is well established for chronic pain.²⁰² These adaptive processes can involve altered peripheral signal responsiveness, changes in signal conduction, and modification of central itch processing. Underlying neuroplastic changes might be visible at the microscopic level, such as differences in cutaneous nerve fiber density; but they also affect the molecular equipment of neurons, including altered expression and function of signaling receptors and associated molecules.⁴⁴^,²⁰³^,²⁰⁴ In summary, these changes lead to an abnormal sensory state that promotes itch sensation.

The clinical term hyperknesis describes the phenomenon in which CP patients experience an enhanced and/or prolonged itch perception when exposed to the same pruritic stimulus as healthy subjects.²⁰⁴ Adaptive processes can also render stimuli pruritogenic that ordinarily do not induce itch; this phenomenon is clinically termed alloknesis.²⁰⁵ An example of alloknesis is the itch-inducing potential of rubbing clothes on AD skin. Alloknesis can also be observed in the periphery of histamine-exposed skin, indicating a close relationship between chemical-induced itch and alloknesis.²⁰⁶ Mechanistically, Lu et al¹²² recently demonstrated that NP2 fibers are engaged in mediating pruritogen-induced alloknesis. They demonstrated that histamine injection sensitized the activity of the mechanosensitive channel Piezo2 in NP2 neurons, allowing it to mediate mechanically induced itch after histamine pre-treatment. Other studies suggest that changes in spinal circuits⁶⁹^,²⁰⁷ and the loss of Merkel cells¹¹ also represent critical factors that promote alloknesis.

Importantly, itch sensitization, hyperknesis, and alloknesis are key concepts to understand the chronicity of itch.

B. Etiology and clinical classification of CP

Many different disease entities can cause CP (Table 3). For this reason, a precise classification of the etiology is crucial to initiate an effective and specific treatment for CP patients. The goal should be to treat the underlying disease specifically by targeting disease- and itch-driving mechanism selectively, which may include the neutralization of relevant pruritogens. Symptomatic and nonspecific itch-relieving approaches, such as topical anesthetics, might be considered supportive. The International Forum for the Study of Itch provides a practical diagnostic concept that helps narrow down the etiology of CP.⁴ First, a careful anamnesis and physical examination should determine if visible skin lesions accompany CP.⁴

Table 3.

The etiology of chronic itch. Adapted version of the classification by the International Forum for the Study of Itch⁴

Etiology of Chronic Pruritus (a classification suggested by the International Forum for the Study of Itch⁴, here slightly modified)
Dermatological Diseases	Systemic Diseases	Neurological Diseases	Psychiatric Diseases
Inflammatory skin diseases: Infectious skin diseases: Viral infection (HIV/AIDS), ectoparasitoses (scabies, oxyuriasis, pediculosis) Autoimmune skin diseases: Autoimmune blistering diseases (AIBD) such as dermatitis herpetiformis or bullous pemphigoid, dermatomyositis. Other: Atopic dermatitis, lichen planus, psoriasis, chronic urticaria, seborrheic eczema, allergic contact dermatitis, cutaneous amyloidosis, pityriasis lichenoides chronica, xerosis cutis.	Endocrinopathies: Hyperparathyroidism, hyperthyroidism, hypothyroidism, perimenopausal pruritus.	Disorders of the peripheral nervous system: Brachioradial pruritus, Chronic sensory neuropathy (Notalgia paresthetica). Post-herpetic neuralgia, Vulvar dysesthesia	Schizophrenia, schizotypal, and delusional disorders (ICD F2): Schizophrenia Tactile hallucinosis
	Infectious diseases: Parasitosis (for example lambliasis, ascariasis, schistosomiasis), Viral infection (HIV/AIDS)		Affective disorders (ICD F3): Depression
Hereditary skin diseases (genodermatoses): Darier disease, Hailey-Hailey disease, and different varieties of ichthyosis. Netherton syndrome.	Metabolic diseases: Iron deficiency, chronic kidney failure, cholestasis with and without hepatopathies, diabetes mellitus (neuropathia)		Neurotic, stress-related, and somatoform disorders (ICD F4): Anxiety disorders Obsessive-compulsive disorders
Pregnancy-related skin diseases: Pemphigoid gestations (AIBD), Pruritic urticarial papules and plaques of pregnancy (PUPPP)	Neoplastic diseases: Solid tumors (prostate, cervix, or colon carcinoma), polycythemia vera, myelodysplastic syndromes, Hodgkin disease, plasmacytoma, neuroendocrine tumors (NET)	Disorders of the CNS: Multiple sclerosis Neoplasms (glioblastoma), Abscesses Cerebral or spinal infarcts	Behavioral syndromes associated with physiological disturbances and physical factors (ICD F5): Anorexia nervosa
Skin-borne malignancies: Cutaneous B or T cell lymphoma, mastocytosis	Drug-induced pruritus: Selection of potential drugs: Opioids, ACE inhibitors, ß-blockers, chloroquine

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1. CP without skin lesions: Hallmark of systemic, neurological, and psychiatric diseases

Chronic itch without visible skin lesions is a typical constellation for CP in systemic, neurological, or psychiatric diseases. Systemic diseases associated with CP include endocrinopathies (eg, hyperthyroidism), malignancies and lymphoproliferative disorders (eg, polycythemia vera [PV], a rare blood cancer), infectious diseases (parasite infections), or metabolic disorders (eg, chronic kidney failure or cholestasis secondary to liver diseases).⁴ The pathophysiological mechanisms underlying CP in most of these conditions are not well characterized, but the systemic presence of pruritogens acting on itch-mediating fibers in the skin is considered to play a significant role. Itch in neurological diseases is caused by damaged or dysfunctional neuronal itch pathways (eg, multiple sclerosis or small-fiber neuropathy) and is also referred to as neuropathic itch.⁴ CP linked with psychiatric and psychosomatic diseases (like depression or tactile hallucinosis) is the result of altered awareness and perception driven by complex psychopathological changes.⁴

2. CP accompanied by skin lesions

CP associated with lesioned skin requires the differentiation between whether the skin changes are caused secondarily by scratching-dependent behavior or represent characteristic skin lesions of primary skin-borne diseases (dermatoses) (Fig. 6, middle and right panels).⁷ Dermatoses associated with chronic itch as a hallmark symptom include infectious dermatoses (eg, scabies mite infestation or impetigo contagiosa, an itchy and highly contagious bacterial skin infection in children), autoimmune dermatoses (eg, BP, a skin blistering disease triggered by autoantibodies against the basement membrane), other noncontagious inflammatory dermatoses (eg, AD), hereditary dermatosis (Darier’s disease, a congenital epidermal differentiation disorder), or cutaneous neoplasms (eg, cutaneous T cell lymphoma such as mycosis fungoides).⁴ Dysregulated cutaneous immune responses and the resulting pruritogen-enriched environment are major drivers of CP in most of these dermatoses. Importantly, secondary skin lesions caused by scratching can coexist with primary skin-borne diseases and also appear in systemic, neurological, and psychiatric diseases.⁴ For this reason, identifying or excluding characteristic skin lesions associated with a dermatological disease is essential for guiding the diagnostic workflow and engaging other medical fields in determining the underlying etiology of CP.

Fig. 6 — CP and skin status. Chronic itch may manifest in the absence of skin lesions, which is characteristic of CP driven by systemic diseases (left panel). Skin lesions may arise either from primary skin-borne diseases (dermatoses) or secondarily as a consequence of scratching behavior. The middle panel summarizes common dermatoses frequently associated with CP and their typical clinical presentation. The right panel illustrates characteristic skin lesions resulting from chronic scratching. Secondary skin lesions can therefore occur both in primary dermatologic diseases causing CP and in systemic diseases associated with CP. This figure was created with permission in BioRender. R, T. (2025) Created in BioRender. R. T. (2025) https://BioRender.com/vbainmb.

IX. Endogenous pruritogens, their clinical relevance, and therapeutic use as target

Pruritogens are molecules that directly activate itch-mediating nerve fibers at the neurocutaneous interface to elicit pruritus. Exogenous pruritogens, such as allergens or environmental irritants, can provoke acute itch and, with persistent exposure may also contribute to chronic itch states. However, the principal drivers of CP are endogenous pruritogens acting at the neurocutaneous interface, making them particularly attractive therapeutic targets.

As outlined in the first part of this review, many of these endogenous pruritogens are released by immune cells and also mediate essential functions in orchestrating skin inflammation, in particular in the context of type 2 inflammation. The existence of numerous pruritic inflammatory skin diseases underscores the close relationship between cutaneous inflammation and itch. Accordingly, it is not surprising that immunoreactive cytokines, alarmins, leukotrienes, or neuropeptides also function as pruritogens.⁴⁴^,²⁰⁸^,²⁰⁹

Notably, endogenous pruritogens are also considered to mediate CP at the neurocutaneous interface in systemic diseases. For example, CP arising in conditions with reduced organ clearance, such as cholestasis or chronic kidney failure, is considered to result from the accumulation of metabolic products that also act as pruritogens in the skin.²¹⁰ These systemic forms of CP typically occur without overt skin inflammation and therefore represent a mechanistically distinct, largely inflammation-independent condition.

The following section provides a translational overview of endogenous pruritogens that act at the neurocutaneous interface. We will summarize their physiological roles, link their itch-driving properties to human disease, and discuss their therapeutic relevance for the treatment of CP (Table 4).²¹¹

Table 4.

Therapeutic landscape of targeted therapies for treating itch

	Pharmacological Target	Role of the target	Generic Drug Name	Clinical status
	Pharmacological Target	Role of the target	Generic Drug Name	FDA Approvals for CP-Associated Diseases	Stage of Clinical Investigation if not Approved
Cytokines	IL-31	Type 2 immune cytokine, predominantly produced by activated Th2 cells. Potent pruritogen.	BMS-981164 (antibody) IL-31 inhibitor s.c. and i.v.	-	Completed Phase 1 study in healthy volunteers and adults with AD; no results posted (NCT01614756)
	IL-31RA	Specific receptor subunit for IL-31. Pruriceptor.	Nemolizumab (antibody) IL-31RA inhibitor s.c.	1. PGN (adults, 08/2024) 2. Moderate-to-severe AD (12 y or older, 12/2024)
	OSMRß	Part of the IL-31 receptor, as well as the OSM receptor. OSM is for examples produced by activated T cells and macrophages and promotes inflammation and tissue remodeling.	Vixarelimab (antibody) OSMRß inhibitor s.c.	-	Positive Phase 2a/b results in PGN (NCT03816891)
	IL-4RA	IL-4RA is the shared receptor subunit for IL-4 and IL-13 signaling. IL-4 and IL-13 drive type 2 inflammation. Neuronal expression is engaged in chronic itch sensitization in mice. Potential pruriceptor.	Dupilumab (antibody) IL-4RA inhibitor s.c.	1. Moderate-to-severe AD (adults, 03/2017; 12-17 y 03/2019; 6-11 y 05/2020; 0,5-5 y, 06/2022) 2. PGN (adults, 09/2022) 3. CSU (12 y or older, 04/2025) 4. Bullous pemphigoid (adults, 06/2025)	-
	IL-13	Hallmark type 2 cytokine, predominantly produced by Th2 cells. Engaged in murine chronic itch sensitization.	Lebrikizumab (antibody) IL-13 inhibitor s.c.	Moderate-to-severe AD (12 y or older, 09/2024)	-
	IL-13		Tralokinumab (antibody) IL-13 inhibitor s.c.	Moderate-to-severe AD (adults 12/2021; 12 y or older 12/2023)	-
	IL-17A	Hallmark type 3 immune cytokine. Predominantly produced by Th17 cells. Pruritogen in murine psoriasis.	Ixekizumab (antibody) IL-17A inhibitor s.c.	Moderate-to-severe plaque psoriasis (adults 03/2016; 6 y or older 03/2020)	-
	IL-17A		Secukinumab (antibody) IL-17A inhibitor s.c.	Moderate-to-severe plaque psoriasis (adults since 01/2015; 6 y or older 06/2021)	-
	IL-17RA	Part of IL17 receptor. Neuronal expression mediates IL17-induced psoriatic itch in mice.	Brodalilumab (antibody) IL-17RA inhibitor s.c.	Moderate-to-severe plaque psoriasis (adults, 02/2017)	-
Alarmins	TSLP	Alarmin of type 2 immune response. TSLP induces scratching behavior in mice and activates sensory nerve fibers. Potential pruritogen in human?	Tezepelumab (antibody) TSLP inhibitor s.c.	-	Across 2 Phase 2 studies in moderate-severe AD tezepelumab failed to demonstrate statistically significant efficacy over placebo. (NCT02525094 & NCT03809663)
	IL-33	Alarmin of type 2 immune response. Pruritogen in mice.	Etokimab (antibody) IL-33 inhibitor s.c.	-	Did not meet the primary end point vs. placebo in Clinical Phase 2 study in moderate-to-severe AD (NCT03533751)
	ST2	Targeted receptor by IL-33. Neuronal activation promotes inflammatory itch in mice.	Astegolimab (antibody) ST2 inhibitor s.c.	-	Did not meet the primary end point vs. placebo in Clinical Phase 2 study in moderate-to-severe AD (NCT03747575)
Biogenic amines	Histamine 1 receptor	H1 Receptor targeted by the pruritogen histamine, which is, for example, released from mast cells in allergic reactions. Found on murine and human nerve fibers. Pruriceptor. H1R is considered to play an essential role in acute allergic reactions such as urticaria.	Diverse H1R antagonists are available. (small molecule) First-generation H1R antihistamines come with sedative side effects (such as diphenhydramine). Second plus-generation antihistamines are non-drowsy and are nowadays the standard (such as loratadine, levocetirizine fexofenadine) oral	Chronic idiopathic urticaria (e. g. loratadine, levocetirizine fexofenadine; FDA-approved ages vary by drug, indication, and formulation.)	-
	Histamine 4 receptor	The H4 Receptor represents another target of the pruritogen histamine. It is found on sensory nerve fibers and preclinical studies indicate a role in chronic pruritic skin diseases.	Izuforant (small molecule) H4 receptor blocker oral	-	Did not meet the primary end points vs. placebo in Clinical Phase 2 study in cholinergic urticaria (NCT04853992) and AD (NCT05117060)
	Histamine 4 receptor		Adriforant (small molecule) H4 receptor blocker oral	-	Improved some clinical measures (e. g. inflammatory skin severity), but did not meet pre-specified efficacy endpoints (improvement in itch) in Clinical Phase 2 study in AD (NCT02424253)
	Serotonin Transporter (SERT)	Regulates the uptake of serotonin. Serotonin is involved in both central and peripheral itch pathways. For example, serotonin receptors are expressed on murine itch-mediating nerve fibers, and descending serotonergic neurons in the brainstem promote itch signaling at the spinal level.	Paroxetine Fluvoxamine (small molecule) selective serotonin reuptake inhibitor (SSRI) oral	-	Both drugs showed efficacy in a proof-of-principle study in pruritic patients, with the best response for pruritus in the context of AD, lymphoma and solid carcinoma²¹¹
.Neuropeptides	NK1 receptor	G protein receptor targeted by the neuropeptide Substance P. NK1R-expressing projection neurons have a crucial role in central itch pathways, whereas NK1R expression on peripheral neurons was not found to be engaged in Substance P-mediated itch in mice.	Aprepitant (small molecule) NK1 receptor blocker oral & gel	-	Oral aprepitant reduced itch intensity in a Phase 2 pilot study of pruritus induced by biological anticancer therapies (NCT01683552) Oral aprepitant did not show a significant antipruritic effect in a randomized Phase 2 trial of chronic PGN (DRKS00005594). Aprepitant gel application did not meet the primary endpoint (itch intensity) in Phase 2 study in PGN (NCT01963793).
			Serlopitant (small molecule) NK1 receptor blocker oral	-	Did not meet the primary end point vs. placebo in Clinical Phase 2 study in Epidermolysis Bullosa (NCT03836001) and AD (NCT02975206) Showed efficacy in Clinical Phase 2 study in Psoriasis (NCT03343639) and chronic pruritus of unknown origin (NCT03841331) and PGN (NCT02196324) However, failed to meet the primary end point vs. placebo in Phase 3 studies in PGN (NCT03677401 & NCT03546816)
			Tradipitant (small molecule) NK1 receptor blocker oral	-	Did not meet the primary endpoint (reduction in worst itch) in Clinical Phase 3 study in AD (NCT03568331)
Mrgprs	MrgprX2	Human G protein receptor expressed on mast cells and sensory neurons. (Functional equivalent for murine MrgprB2). Neuropeptides including Substance P, antimicrobial peptides, and certain drugs are well known ligands. MRGPRX2 is a key driver of IgE-independent mast cell activation and is considered an important mediator of mast cell-dependent, IgE-independent itch.	EVO756 (small molecule) Mrgprx2 receptor blocker oral	-	Ongoing Clinical Phase 2b study in moderate-to-Severe CSU (NCT06873516) and AD (NCT07150845)
	MrgprX2		EP262 (small molecule) Mrgprx2 receptor blocker oral	-	Terminated Clinical Phase 2 study in Severe Chronic Spontaneous Urticaria (NCT06077773): because of toxicological findings in preclinical studies, no official results have been posted yet.
	MrgprX4	Human G protein receptor expressed in human sensory neurons. It is activated by bile acids and bilirubin and is considered a potential mediator of cholestatic itch.	EP547 (small molecule) Mrgprx4 receptor blocker oral	-	Studied in Phase 2 study in Cholestatic Pruritus (due to Primary Biliary Cholangitis or Primary Sclerosing Cholangitis). Unpublished results. The owning company has discontinued this drug from its pipeline. (NCT05525520)
Antibody	IgE	IgE is an antibody subclass that plays a key role in antiparasite immunity and allergic reactions. It binds to a high-affinity receptor (FcεRI) on mast cells and mediates allergic mast cell activation, leading to the release of pruritogens such as histamine.	Omalizumab (antibody) anti-IgE s.c.	Chronic spontaneous urticaria (12 y or older, 03/2014)	-
Leukotrienes	CysltR1	Receptor for cysteinyl leukotrienes (LT) such as LTC4. LTC4 is a pruritogen in murine chronic dermatitis; however, it signals predominantly through CysltR2 rather than CysltR1.	Montelukast (small molecule) CysltR1-specific inhibitor oral	-	Did not convince (global disease severity) in a Phase 4 clinical trial (already approved for other diseases) in AD (NCT00557284), although a statistically significant reduction in pruritus vs placebo was reported .
Tyrosine kinseases (in mast cells)	KIT (CD117)	KIT is a receptor tyrosine kinase expressed on mast cells that is essential for their development, survival, and activation through the binding of stem cell factor (SCF). By regulating mast cell number and function, KIT is considered to indirectly contribute to itch, particularly in mast cell-dependent inflammatory and allergic conditions.	Barzolvolimab (antibody) KIT inhibitor s.c.	-	Ongoing Phase 3 trial in CSU (NCT06455202) Phase 2 study in Cold Urticaria and Symptomatic Dermographism met end points (NCT05405660). Phase 3 study starts 01/2026. Ongoing Phase 2 trial in PGN (NCT06366750) and AD (NCT06727552)
	KIT (CD117)		Briquilimab (antibody) KIT inhibitor s.c.	-	Ongoing clinical Phase 1b/2a studies for CSU (NCT06162728) and Chronic Inducible Urticaria (NCT06353971)
	BTK (Bruton's tyrosine kinase)	BTK is a tyrosine kinase expressed in mast cells that is critical for signaling downstream of FcεRI and other activating receptors. By promoting mast cell activation and degranulation, BTK contributes to the release of pruritogenic mediators and thus plays an important role in allergic and inflammatory itch.	Remibrutinib (small molecule) BTK inhibitor oral	Chronic spontaneous urticaria (adults, 09/2025)	-
	BTK (Bruton's tyrosine kinase)		Rilzabrutinib (small molecule) BTK inhibitor oral	-	Met the primary endpoint in clinical Phase 2 study in CSU (NCT05107115)
Signal transduction molecules	Janus kinases : JAK1,2,3, & TYK2	Signal transducing molecules. The JAK-STAT signaling pathway is employed by several cytokine receptors, including those engaged in itch signaling, such as IL-4RA, IL-13RA1 or IL-31RA. JAK1 in particular plays an essential role as a downstream target in pruritic type 2 inflammation. Murine JAK1 gain-of-function mutation causes pruritic dermatitis.	Upacitinib (small molecule) JAK1 inhibitor oral	Moderate-to-severe AD (12 y or older, 01/2022)	Ongoing clinical Phase 4 study for PGN (NCT06773403)
			Abrocitinib (small molecule) JAK1 inhibitor oral	Moderate-to-severe AD (adults 01/22, 12 y or older 02/2023)	-
			Povorcitinib (small molecule) JAK1 inhibitor oral	-	Clinical Phase 2 study in CSU met primary end point (NCT05936567) Ongoing clinical Phase 3 study in PGN (NCT06516965)
			Ruxolitnib (small molecule) JAK1 & 2 inhibitor cream	Mild to moderate AD (12 y and older 09/2021, 2 y and older 09/2025)	Ongoing clinical Phase 3 study for PGN (NCT05764161)
			Delgocitinib (small molecule) pan JAK inhibitor cream	Moderate-to-severe chronic hand eczema (adults, 07/2025)	-
Opioid receptor signaling	μ-Opioid receptor (MOR) & κ-Opioid receptor (KOR)	Opioid receptors are broadly expressed in the peripheral and central nervous system. Endogenous endorphins activate MORs to alleviate pain signaling but to promote itch signaling. Endogenous dynorphins activate KORs to suppress both pain and itch.	Difelikefalin (synthetic peptide) Peripheral KOR agonist i.v. & oral	Moderate-to-severe pruritus in CKD patients undergoing hemodialysis (i.v. adults, 08/2021)	Did not meet the primary endpoint (itch) in the Phase 2 study (oral) in AD (NCT04018027) Terminated Clinical Phase 2 study (oral) in Primary Biliary Cholangitis and Moderate-to-Severe Pruritus (NCT03995212). Unpublished results.
			Nalfurafine (small molecule) KOR agonist (acts also centrally) oral	-	Showed efficiency in phase 3 study in Pruritus in Patients receiving hemodialysis, but not FDA-approved over concerns for side effects (NCT01513161). Approved in Japan.
			Nalbuphine (small molecule) KOR agonist/MOR antagonist oral	-	Phase 2 study in PGN: signals of itch reduction but failed to meet the primary endpoint of a statistically significant ≥30% improvement in worst-itch (NCT02174419) Met the primary endpoint in Phase 2 study in uremic pruritus in hemodialysis patients on itch outcomes (NCT02143648) Unknown status of Phase 2 study in Adding Nalbuphine for Control of Intrathecal Morphine Pruritus (NCT04589429)
Ionotropic receptors	TRPV1	TRPV1 is a TRP ion channel expressed on sensory neurons. It transduces sensory stimuli, including itch, into neuronal depolarization and action potential firing.	Asivatrep (small molecule) TRPV1 antagonist cream	-	Phase 3 clinical trial met the primary endpoint for topical treatment of AD in Korea. No FDA approval.

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A. Type 2 cytokines

1. IL-31

The interleukin IL-31 was discovered in 2004 and represents the prototype pruritogen of the type 2 immune response. It is a well established concept that Th2 cells release IL-31, which is engaged in acute and CP in mice and humans.²⁰⁸^,²¹²^,²¹³ In addition to Th2 cells, a variety of other cell types have been described as alternative sources of IL-31, including macrophages,²¹⁴ DCs,²¹⁵ eosinophil granulocytes,²¹⁶ and mast cells.²¹⁷

a. IL-31 signaling

IL-31 targets a heterodimeric receptor complex comprising the oncostatin M receptor subunit β (OSMRβ) and the IL-31 receptor A (IL-31RA) (Fig. 7).²⁰⁸ The specific binding of IL-31 to the IL-31RA chain enables the IL-31 receptor complex to activate the JAK-STAT cascade, a common intracellular signaling pathway used by various cytokines. In detail, the IL-31-dependent activation enables the recruitment of JAK1 and JAK2 to intracellular domains of the IL-31 receptor.²¹⁸ The resulting spatial proximity allows JAK1 and JAK2 to activate each other. Activated JAKs recruit and subsequently activate STAT proteins that ultimately modulate gene expression in the nucleus.²⁰⁸^,²¹⁹ Neuronal STAT3 has been identified in mice as a key mediator of IL-31-dependent itch.²²⁰ The PI3 kinase-PDK1-Akt pathway or the Ras-Raf-MEK-ERK pathway represent alternative signaling cascades activated by IL-31.²¹⁹^,²²¹ Downstream, the IL-31 receptor targets the TRP channels TRPV1 and TRPA1 for itch signaling.⁴³

The IL-31 receptor is expressed on various cell populations, including neurons,⁴³ keratinocytes,²²²^,²²³ and immune cells, such as DCs and monocytes.²¹⁸ In mice, IL-31RA is expressed on NP3 neurons, which mediate IL-31-dependent itch.⁴³^,⁷⁸ The IL-31 receptor is also expressed in human sensory nerve fibers. Single-cell sequencing analysis of human DRG revealed IL-31RA expression in distinct itch-associated cell clusters, suggesting a broader expression profile than in mice, which selectively express IL-31RA in NP3 fibers.⁸²^,⁸³

The pioneering work from 2004 stressed the pruritic potential of IL-31. At that time, Dillon et al²⁰⁸ generated an IL-31-overexpressing mouse line, which is characterized by excessive scratching behavior, AD-like skin lesions, and alopecia.

b. IL-31 in human pruritic diseases

The following translational studies showed that the IL-31 axis is dysregulated in many human CP-related diseases. Several reports have indicated that IL-31 is increased in the skin of patients suffering from AD.²¹²^,224, 225, 226, 227 Moreover, enhanced IL-31 levels were also detected in other dermatological diseases, including chronic spontaneous urticaria (CSU),²²⁸^,²²⁹ mastocytosis,²³⁰ cutaneous T-cell lymphoma²³¹^,²³² or the autoimmune blistering disease BP.²¹⁶^,²³³

Notably, IL-31 levels are markedly elevated in prurigo nodularis (PGN) lesions, and IL-31 is presently considered a crucial driver of this highly pruritic skin disease.234, 235, 236 PGN is a chronic inflammatory skin disease characterized by highly pruritic, round nodules on the skin and a strong desire of the patient to scratch off these formations for relief. Because persistent scratching is required for nodule formation, PGN lesions appear only at skin sites the patient can reach. Importantly, PGN is currently regarded as a distinct reaction pattern to chronic scratching, independent of the underlying cause of CP. Lesions show elements of neurogenic inflammation, type 2 inflammation, dermal fibrosis, changes in nerve fiber density, and epidermal hyperplasia.²³⁷^,²³⁸ However, the exact pathophysiology remains to be characterized.

All of the aforementioned diseases are associated with increased IL-31 levels and show an increased type 2 immune response. Still, enhanced action of the IL-31 axis was also described in CP-associated disease without a prominent type 2 immune signature, such as uremic pruritus,²³⁹^,²⁴⁰ cholestatic pruritus,²⁴¹ or psoriasis.²²⁹^,²⁴² Additionally, mouse data suggest that IL-31 is responsible for itch during wound healing.²¹⁵ These findings indicate that IL-31 fulfills roles beyond type 2 inflammation and should also be considered a therapeutic target for CP in these conditions.

c. IL-31 beyond pruritus and type 2 Inflammation

Although IL-31 is considered a typical Th2 cytokine, like IL-4, IL-5, or IL-13, its functional role in type 2 inflammation remains debatable. Reports suggest that IL-31 promotes type 2 inflammation by releasing the proinflammatory neuropeptide BNP from NP3 fibers in the murine AD model.¹²⁸ On the other hand, a recent report showed that IL-31 can suppress the type 2 immune response by releasing the neuropeptide CGRP from NP3 neurons.¹²⁹ These findings indicate a complex role of IL-31 in neurogenic inflammation. Beyond its pruritic and inflammatory role, IL-31 was also associated with structural and regenerative processes, such as epidermal differentiation²⁴³^,²⁴⁴ or nerve growth.¹³⁰ These additional hints suggest that IL-31 has a broader physiological function than simply serving as an itch mediator during type 2 inflammation.

Taken together, the IL-31 pathway poses an attractive target for treating chronic itch in pruritic inflammatory skin diseases, and maybe beyond. To date, therapeutic strategies have primarily focused on the IL-31 receptor subunits and the cytokine IL-31 itself.

d. IL-31RA blockade

Nemolizumab is a monoclonal, humanized IgG₂ antibody that inhibits IL-31 signaling by binding to the IL-31RA chain.²⁴⁵ An IgG₂F_c region was chosen for this therapeutic antibody to minimize the potential of activating the complement system or antibody-dependent cell-mediated cytotoxicity. This constitution allows nemolizumab to interfere with receptor signaling without inducing cell death in IL-31RA-expressing cells. The FDA approved nemolizumab for the treatment of moderate-to-severe PGN and AD in adolescents and adults in 2024. Approval for PGN was granted after the phase 3 clinical trial OLYMPIA 2 demonstrated that nemolizumab met both primary and all 5 secondary endpoints. The primary endpoint included a significant reduction in itch burden (56.3% with nemolizumab vs 20.9% with placebo) and a response in disease activity (37.7% with nemolizumab vs 11.0% with placebo) after a 16-week treatment period.²³⁶ In addition to the IL-4-Rɑ antibody dupilumab, nemolizumab was the second drug approved for PGN, expanding the therapeutic toolbox for this highly chronic skin disease. The approval of nemolizumab for treatment of AD was granted after the 2 successful phase 3 studies, ARCADIA 1 and 2, demonstrated that adding nemolizumab to topical corticosteroids significantly reduces itch and skin lesions in adults with AD.²⁴⁶ This approval offers a valuable option for treating therapy-resistant itch in AD.

e. OSMRβ blockade

Vixarelimab is a human monoclonal antibody that targets the OSMRB chain of the IL-31 receptor. Compared to the IL-31RA chain, OSMRB is not specific for the IL-31 receptor. OSMRB can also assemble with the glycoprotein 130 to form the oncostatin M (OSM) type II receptor, which is targeted by the cytokine OSM.²⁴⁷ OSM is considered to promote skin inflammation. Given this dual role of OSMRB, vixarelimab was developed to treat itch and inflammation associated with PGN. A phase 2 clinical study published in 2023 demonstrated that vixarelimab reduced pruritus and the extent of PGN skin lesions, with no severe side effects evident.²⁴⁷ A subsequent phase 3 study needs to clarify whether vixarelimab could serve as an alternative treatment for PGN.

f. IL-31 cytokine blockade

Lokivetimab is an IL-31-neutralizing antibody approved for treating canine AD and is particularly effective at reducing pruritus symptoms in dogs.²⁴⁸^,²⁴⁹ It is specific for canine IL-31 and does not bind mouse or human IL-31. For humans, the anti-IL-31 monoclonal antibody BMS-981164 has been developed. This antibody was tested in a phase 1 clinical trial between 2012 and 2015; however, no results were published. Given the resounding success of blocking the IL-31 receptor, neutralizing the cytokine itself probably takes a back seat.

2. IL-4 and IL-13

a. Receptor architecture and signal transduction

IL-4 and IL-13 are structurally related cytokines that signal through 2 distinct receptor complexes, both of which share the IL-4 receptor A (IL-4RA) chain. The type I receptor complex consists of the IL-4RA chain and the common gamma chain and is selectively activated by IL-4. The type II receptor is formed by the encounter of the IL-4RA with the IL-13RA1 chain and is activated by both cytokines (Fig. 7).²⁵⁰ Similar to the IL-31 receptor, activation of both receptors results in the recruitment of Janus kinases: the type I receptor recruits JAK1 and JAK3; whereas the type II receptor recruits JAK1, JAK2, or tyrosine kinase 2.251, 252, 253 Downstream of the Janus kinases, the formation of STAT6 homodimers represents a key step in mediating the intracellular effects of IL-4 and IL-13.²⁵¹ Neuronal TRPV1 has been identified as a relevant downstream transducer conveying neuronal IL-4 and IL-13 signaling.⁴⁴ In addition to JAK-STAT signaling, the IRS pathway²⁵⁴^,²⁵⁵ and the SHP-1/SHP-2/SHIP pathway²⁵⁶ represent alternative signaling pathways.

b. Neuronal actions of IL-4 and IL-13 in CP

IL-4 and IL-13 share many effector functions but also exhibit unique properties. IL-4 is involved in priming Th2 cells and inducing the switch to the IgE antibody class.²⁵⁷ Hence, IL-4 is critical in orchestrating the adaptive type 2 immune cell response. IL-13 integrates non-hematopoietic cells into the type 2 immune response by stimulating epithelial mucus production, smooth muscle contractility, or tissue fibrosis.²⁵⁸ Despite their well known role in type 2 inflammation, there is evidence that IL-4 and IL-13 directly act on sensory neurons to promote chronic itch. Oetjen et al⁸⁰ identified the expression of IL-4RA and IL-13RA1 on murine NP itch fibers. Single-sequence data indicate broad expression of IL-4RA and IL-13RA1 on all NP subsets, with IL-13RA1 appearing particularly enriched in NP3 fibers. Functionally, in vitro experiments demonstrated that most IL-4/IL-13-responsive cells were also activated by IL-31, suggesting that IL-4 and IL-13 primarily activate IL-31RA-positive NP3 itch fibers.⁴⁴ Oetjen et al⁴⁴ found that the injection of IL-4 and IL-13 did not induce acute scratching behavior; however, itch fibers become sensitized to respond more strongly to other pruritogens. The clinical relevance of this finding was demonstrated by studying mice deficient in neuronal IL-4RA-signaling, which showed reduced scratching behavior in a murine model of AD. Remarkably, the deletion of neuronal IL-4RA was more effective in ameliorating CP than the global knockout of the IL-31 receptor.⁴⁴ Two years later and in contrast to the study by Oetjen et al, Campion et al⁴² reported that IL-4 and IL-13 indeed cause acute scratching behavior in mice after injection. They hypothesized that variations in the cytokine doses used across studies may account for the observed differences.⁴² Although the role of both cytokines as acute pruritogens remains debated, there is substantial evidence that IL-4 and IL-13 are involved in CP by sensitizing itch-specific nerve fibers.

Given the crucial roles of IL-4 and IL-13 in type 2 inflammation and chronic itch, numerous efforts have been made to therapeutically interfere with their signaling. Duplilumab, lebrikizumab, and tralokinumab are 3 FDA-approved biologicals targeting the IL-4/IL-13 network.

c. IL-4RA blockade

Dupilumab is a fully human IgG₄ antibody that targets the IL-4RA subunit and blocks signaling of IL-13 and IL-4.²⁵⁹ It is therapeutically used for type 2 immune diseases, such as eosinophilic esophagitis or asthma.²⁶⁰^,²⁶¹ The FDA approval for AD and PGN is especially notable in the context of CP. Dupilumab was approved in 2017 for the treatment of moderate-to-severe AD, following the pivotal phase 3 clinical studies SOLO 1 and SOLO 2, which demonstrated significantly improved skin status compared with placebo within 16 weeks.²⁶² Importantly, pruritus intensity (a secondary endpoint) decreased substantially in the dupilumab-treated arm from week 2 after treatment initiation.²⁶² Moreover, dupilumab gained considerable attention in 2022 as the first approved drug for PGN. The phase 3 clinical trials, LIBERTY-PN PRIME and PRIME2, demonstrated that dupilumab significantly reduced pruritus in PGN at 12 and 24 weeks. In addition, the secondary endpoints also highlighted a reduction of PGN-lesioned skin.²⁶³

In June 2025, the indication for dupilumab was extended to include the most common autoimmune blistering disease BP. BP is a chronic inflammatory skin characterized by macroscopic blister formation on the skin, which is the result of autoantibodies attacking the basement membrane. BP is frequently accompanied by severe pruritus. The approval of dupilumab for BP was based on pivotal data from the ADEPT clinical phase 2/3 study. Aside from convincing in the primary endpoint “disease remission“, this study also indicates a clinically meaningful itch reduction (measured as a secondary endpoint).²⁶⁴

Although it is generally well tolerated, it is worth noting that dupilumab-induced conjunctivitis is a characteristic side effect of the treatment. Mechanistically, Thyssen hypothesized in a comment that an increased number of Demodex mites might drive type-17-driven inflammation, triggering a rosacea-like condition.²⁶⁵ In addition, a histological study found that dupilumab reduced the number of goblet cells, suggesting that a reduced mucin production might drive this common adverse effect.²⁶⁶ Last but not least, a recent study relying on tear fluid analyses proposes that dupilumab-related conjunctivitis is accompanied by a shift from Th2/Th17 toward Th1/Th17 inflammation.²⁶⁷ In conclusion, some directions are available; however, the exact mechanism for this hallmark side effect is pending.

d. Specific IL-13-signaling blockade

Tralokinumab and lebrikizumab are monoclonal, fully human IgG₄ antibodies that bind and functionally neutralize the cytokine IL-13.²⁶⁸^,²⁶⁹ The FDA approved both antibodies for treating moderate-to-severe AD (tralokinumab in 2021, lebrikizumab in 2024) after studies successfully demonstrated their clinical efficacy in ameliorating skin disease as well as meaningful reduction in pruritus burden.²⁷⁰^,²⁷¹

e. Janus kinase inhibitors (JAKi)

The inhibition of Janus kinases (JAKs), which are employed for downstream signaling by all known type 2 pruritogens, currently represents another essential therapeutic concept for CP and type 2 inflammation.

JAKs are crucial members of the JAK-STAT signaling pathway, which mediates signal transduction for a broad range of interleukins, interferons, and growth factors.²⁸⁴ Named after the Roman double-headed gateway god Janus, receptor-associated JAKs comprise 4 subtypes: JAK1, JAK2, JAK3, and tyrosine kinase 2.²⁸⁵ Depending on the signaling receptor, activated JAK proteins form homo- or heterodimers for selective STAT activation.²⁸⁶ Given that different interleukins converge on the same JAK family members for downstream signaling, JAKs represent an attractive and powerful therapeutic target for broad but predictable suppression of disease-relevant immune signaling pathways. Beginning with ruxolitinib in the early 2010s, several small-molecule JAKis with specificity for one or more JAK proteins have been developed for oral application. Nowadays, JAKis are approved and commonly used in inflammatory diseases such as alopecia areata,²⁸⁷ rheumatoid arthritis,²⁸⁸ but also hematological diseases.²⁸⁹

As already highlighted, pruritic type 2 cytokines such as IL-31, IL-4 or IL-13 employ the JAK-STAT pathway for intracellular signal transduction (Fig. 7). Mouse studies have confirmed the critical role of JAK molecules in CP. Oetjen et al⁴⁴ showed that IL-4RA on afferent itch fibers utilizes JAK1 to promote chronic itch in a murine dermatitis model. In particular, specific JAK1 inhibitors exhibit an interesting profile in the context of pruritic inflammatory skin diseases, as most pruritic type 2 cytokines (IL-31, IL-4, IL-13) target JAK1. This is supported by the observation that mice with a JAK1 gain-of-function mutation are prone to develop spontaneous pruritic dermatitis.²⁹⁰

Upadacitinib and abrocitinib are selective JAK1is. Both drugs received FDA approval for AD after demonstrating significant amelioration of skin lesions (primary endpoint) and reduction of pruritus (secondary endpoint) in clinical studies.²⁹¹^,²⁹² In addition to these systemic approaches, the FDA approved the JAK1 and 2 inhibitor ruxolitinib in 2021 for the topical treatment of mild to moderate AD.²⁹³ The cream application of a JAKi represents an attractive development because it could minimize rare but severe systemic side effects, such as thrombotic complications, which have raised safety concerns in the context of systemic JAKi treatment.²⁹⁴ JAKis are also an interesting therapeutic option for pruritic inflammatory diseases other than AD. The pan-JAKi delgocitinib is another cream formulation recently approved by the FDA for chronic hand eczema, a polyetiological chronic inflammation of the hand palms frequently accompanied by severe pruritus.²⁹⁵ In addition, oral and topical JAK inhibitors are currently being investigated in PGN.²⁹⁶

3. IL-33

IL-33 represents a crucial type 2 immune alarmin that signals through the ST2 receptor, which pairs with the IL1RAcP to form a functional receptor. This receptor complex recruits the adaptor protein MyD88 to initiate a pathway ultimately leading to the activation of NF-κB proteins and MAP kinases.²⁷² Epidermal-derived IL-33 targets different type 2 immune cell populations, including ILC2s, mast cells, Th2 cells, eosinophils, and basophils and is a well established early driver of type 2 skin inflammation.²⁷²^,²⁷³ Interestingly, there is evidence that IL-33 directly activates itch-sensing fibers, thereby representing a bona fide pruritogen in mice. Liu et al²⁷⁴ demonstrated that ST2 is expressed on small-to-medium-sized DRG neurons, and that silencing neuronal ST2 expression through intrathecal siRNA injection ameliorates pruritus in a murine model of inflammatory skin. TRP-channel blocking experiments further indicated that both TRPV1 and TRPA1 serve as key downstream targets of neuronal IL-33 signaling. Consistently, another study indicated that neuronal IL-33 signaling mediates itch in a chronic dry skin disease model.⁴⁸

These findings suggest that IL-33 signaling may be a suitable target for treating chronic itch in type 2 inflammation. Phase 2 clinical trials explored the therapeutic benefit of IL-33 neutralization (etokimab)²⁷⁵ and ST2-receptor blockade (astegolimab)²⁷⁶ in AD. Unfortunately, the results did not meet expectations, showing neither a beneficial effect on skin lesion improvement (the primary endpoint) nor itch reduction (the secondary endpoint) compared to the placebo,²⁷⁶^,²⁷⁷ representing a significant setback for the field.

4. Thymic stromal lymphopoietin (TSLP)

TSLP is an interleukin 7-like cytokine that targets a heterodimeric receptor, consisting of the IL-7 receptor α chain (IL-7Rα) and the TSLP receptor.²⁷⁸^,²⁷⁹ TSLP receptor signaling employs JAK1 and JAK2 to activate the STAT proteins STAT1, STAT3, and particularly STAT5.²⁸⁰ Epidermal TSLP drives type 2 inflammation and AD-like skin disease, as demonstrated in transgenic mice overexpressing TSLP in keratinocytes.²⁸¹ Importantly, these mice exhibit increased scratching behavior,²⁸¹ indicating that TSLP is engaged in itch pathways. Wilson et al⁴⁹ confirmed that TSLP induces acute scratching behavior in mice and showed that TSLP activates a small proportion of mouse sensory neurons in a TRPA1-dependent manner in vitro. Most TSLP-responsive neurons were not activated by other pruritogens such as histamine, chloroquine, or BAM8-22. Hence, the exact neuronal population targeted by TSLP remains elusive. Together, these findings suggest that TSLP acts as a pruritogen in mice and may also represent an interesting target for treating CP in humans.

a. TSLP blockade

Tezepelumab is a fully human IgG2λ monoclonal antibody that prevents TSLP from binding to its receptor. The FDA has approved it to treat asthma bronchiale.²⁸² Tezepelumab also reached the phase 2 clinical stage for AD; however it could not convince.²⁸³ Hence, despite compelling preclinical evidence, clinical trials to date suggest that type 2 alarmins such as IL-33 or TSLP may be insufficient for treating chronic pruritic inflammatory disease, particularly AD.

B. Other cytokines

Pruritic properties are not restricted to type 2 cytokines. Recent findings indicate that the hallmark type 3 cytokine IL-17A also exerts pruritogenic effects, offering mechanistic insights into conditions such as psoriatic itch.

1. IL-17A

IL-17A was the first member of the IL-17 cytokine family discovered and represents the hallmark cytokine of type 3 inflammation.²⁹⁷ Produced primarily by Th17 cells, IL-17A is critically involved in host defense against fungal and bacterial invaders.²⁹⁸ IL-17A binds its specific receptor, which is formed by the engagement of 2 subchains: IL-17RA and IL-17RC. This receptor complex is for example present on immune cells and keratinocytes and initiates IL-17A-mediated production of inflammatory molecules, chemokines, and antimicrobial peptides. Dysregulated type 3 inflammation, driven by excessive IL-17A signaling, is a crucial driver of several inflammatory skin diseases, such as psoriasis. Psoriasis is a chronic autoimmune disease characterized by abnormal epidermal turnover, leading to scaly patches, and is frequently accompanied by itch. Intriguingly, a recent report studying a murine psoriasis model showed that IL-17, by acting on IL-17 receptor-expressing neurons, mediates itch in mice. Mechanistically, IL-17-induced itch depends on TRPV4 expression.⁶⁶ These findings align with clinical observations that blocking the IL-17 axis ameliorates psoriatic itch.

a. Anti-IL-17 blockade

Several biologicals targeting the IL-17 axis are now available that effectively treat moderate-to-severe psoriasis. Secukinumab and ixekizumab are monoclonal antibodies that neutralize IL-17A, whereas brodalumab inhibits IL-17 signaling by directly blocking the IL-17RA receptor subunit. All 3 drugs are FDA-approved for the treatment of human psoriasis and have been proven in clinical studies to alleviate psoriatic itch.299, 300, 301

C. Biogenic amines

Biogenic amines are derivatives of decarboxylated amino acids. Many endogenous amines, such as the catecholamines adrenaline and norepinephrine, act as hormones or neurotransmitters.³⁰² Histamine and serotonin are additional key members of this class and notable for their involvement in itch pathways.

1. Histamine

Histamine is one of the best-characterized pruritogens. It is derived from the amino acid histidine and functions as an essential tissue hormone at epithelial sites, but also as neurotransmitter in the CNS.³⁰³ In the skin, mast cells are the principal source of histamine,¹² but it is also produced by keratinocytes³⁰⁴ or basophils.³⁰⁵

a. Mast cell activation pathways

Mast cells store histamine and other inflammatory mediators in cytoplasmatic granules, which can be released through 2 mechanisms: The first and most well known mechanism is the antigen-dependent cross-linking of membrane-bound IgE.³⁰⁶ This mechanism is a crucial part of the adaptive type 2 immune response, for example against invading parasites. However, when activated inappropriately, it can also cause allergic reactions. The term "allergic reaction" describes an abnormal immune response to otherwise harmless environmental agents, such as innocuous animal proteins. Especially acute allergic reactions, which manifest quickly after antigen exposure, rely on the IgE-mast cell axis. In 2015, McNeil and colleagues discovered an IgE-independent pathway of mast cell activation, mediated by MrgprB2 in mice or its functional equivalent MrgprX2 in humans. A wide range of substances, including endogenous neuropeptides and exogenous cationic compounds, were shown to activate these receptors.⁸⁹ This important discovery was crucial in explaining the mechanism of IgE-independent yet allergic-like skin reactions. Such pseudoallergic reactions can occur, for example, after the intake of certain drugs like vancomycin or muscle relaxants, which have the capacity to directly activate MrgprX2.³⁰⁷

b. Cutaneous effects of histamine and urticaria

Intradermal injection of histamine elicits acute itch in both mice and humans, but it also exerts additional biological effects. Histamine induces vasodilation and endothelial activation, facilitating plasma exudation and enhanced immune cell recruitment to the skin, highlighting its role in orchestrating allergic inflammation.³⁰⁸ Clinically, histamine’s biological effects result in a typical skin reaction pattern combining erythema, wheal, and pruritus. These symptoms are summarized as urticaria. Urticarial skin lesions are highly dynamic and generally do not persist longer than 24 hours at a location.³⁰⁹ Urticaria can be triggered physiologically in the context of an appropriate type 2 immune response against invading pathogens. However, it frequently occurs in the absence of threats and is then triggered by a plethora of chemical and physical stimuli, leading to inappropriate mast cell activation. The incidence of acute urticaria is pretty high, but mainly self-limiting. In contrast, chronic urticaria is defined by the daily appearance of wheals and pruritus for longer than 6 weeks and needs a careful examination to exclude driving co-diseases.³¹⁰

c. Histamine receptors and neuronal itch signaling

Histamine exerts its biological functions by targeting 4 different G protein-coupled histamine receptors (H1R–4R). H1R and H4R are considered fundamental for histamine’s effects on the skin, particularly in inducing itch.³¹¹ H1R couples to the Gαq/11 protein, an activator of phospholipase C, which ultimately leads to the accumulation of the second messengers inositol triphosphate, diacylglycerol, and Ca²⁺ ions.³¹² H1R is ubiquitously expressed in the skin, including immune cells, as well as structural cells such as blood vessel cells. H1R1 was considered for a long time to be the primary driver of histamine-dependent allergic skin inflammation.³¹³ However, with the discovery of H4R,³¹⁴^,³¹⁵ several studies pointed out that this subtype represents another crucial player in allergic skin diseases.316, 317, 318, 319 H4R couples to inhibitory Gα proteins, which modulate the concentration of the second messenger cAMP by inhibiting adenylyl cyclase. Various immune cell populations, including mast cells, granulocytes, and T cells express H4R.³¹² Importantly, there is evidence that both receptors are present on sensory neurons, supporting the concept that direct histamine-neuron interactions mediate histamine-induced itch. H1R was found on the murine NP2 and NP3 itch fibers,⁷⁸ and H4 mRNA was detected in rodent and human sensory neurons. In addition, pharmacologic blockade of H1R or H4R abrogated histamine-triggered scratching behavior in mice.³²⁰ Mechanistically, murine studies showed that H1R-mediated itch requires both TRPV1 and TRPA1, whereas H4R-induced itch depends on TRPA1 but not TRPV1.³²¹

d. Antihistamines

Antihistamines, particularly those that block the H1R, have a long history in itch treatment. In the early 1940s, phenbenzamine was the first clinically used H1R blocker to treat urticaria and serum sickness.³²² For structural and pharmacodynamic reasons, antihistamines are classified as first- and second-generation. First-generation antihistamines, such as diphenhydramine, share the ability to cross the blood-brain barrier and induce sedation by interfering with histamine’s function in maintaining wakefulness. Additionally, first-generation compounds are not specific for the H1R and can interfere with other receptors, including muscarinic receptors, leading to undesired side effects, such as decreased saliva production. Because of their poor tolerability, first-generation H1R antihistamines are rarely used but gain attention in situations where a sedative effect is desired. The second generation of antihistamines, such as loratadine or cetirizine, was marketed in the 1980s and outperformed the first generation by not penetrating the blood-brain barrier and showing H1R-specific effects. In the 2000s, newly developed antihistamines such as desloratadine were sold as the third generation of antihistamines. They share the same safety profile as members of the second generation but show a longer duration of action and a higher potency. Second- and third-generation antihistamines are the preferred choice for treating allergic pruritus due to their safety profile. Besides antagonizing the itchy potential of histamine itself, studies have shown that antihistamines also reduce the itch-inducing potential of other pruritogens, including prostaglandin E2 and Substance P.³²² This indicates that histamine may also sensitize itch-dedicated fibers to other pruritogens.

H1R antihistamines are a fundamental tool for treating pruritus in acute or chronic urticaria, but frequently fail to reduce itch in other forms of CP, such as AD.³⁰⁹^,³²²^,³²³ One possible conclusion is that the presence of other relevant pruritogens, such as IL-31, may outcompete histamine's role in inducing itch in these conditions. On the other hand, recent evidence suggests that histamine-related itch in non-urticaria conditions might be mediated by H4R signaling, explaining the frequently observed inefficiency of currently used antihistamines, which only block the H1R. Preclinical models of AD have indicated that specific H4R blockade significantly ameliorates the inflammation and pruritus burden.³¹⁹^,³²⁴^,³²⁵ Moreover, there is evidence that combining H1R and H4R blockade efficiently reduces pruritus in murine chronic dermatitis.³²⁵^,³²⁶ However, the FDA has not approved any H4R-targeting antihistamines to date. Substances tested so far in clinical phase 2 studies have failed either due to severe side effects or a lack of clinical efficacy.³²⁷^,³²⁸

2. Serotonin

Serotonin, or 5-HT, is an endogenous biogenic amine derived from the amino acid tryptophan.³²⁹ As a neurotransmitter in the CNS, serotonin is critical in regulating behavioral, vegetative, and motor functions. Dysregulation of the central serotonergic system is closely tied to different psychiatric conditions, such as depression or anxiety disorders. Hence, serotonin represents a crucial therapeutic target in these diseases.³³⁰ In addition, serotonergic neurons in the brainstem form descending pathways to enhance itch sensation at the spinal level, as already discussed.¹⁸⁴ Interestingly, most serotonin in our body is outside the CNS. Peripherally, serotonin is critically engaged in many physiological processes, including digestion, sexual function, and blood circulation.³³¹ There are 7 different classes of serotonin receptors (5-HT1–7) and at least 15 different receptor subtypes, which makes it challenging to dissect receptor subtype-specific effects. Most serotonin receptors are G protein-coupled; only the 5-HT3A and 5-HT3B subtypes are ionotropic receptors.³³² In the skin, serotonin is found in mast cell granules, platelets, endothelial cells, or keratinocytes. It is released during inflammation, but its functional role remains incompletely characterized.³³³ Studies have demonstrated that serotonin injections can cause pain,³³⁰ as well as acute itch behavior in mice²⁷^,³³⁴ and humans.³³⁵^,³³⁶ These results suggest that serotonin can act as a pruritogen. Consistently, single sequencing data indicate the presence of serotonin receptors on itch-mediating fibers in mice: 5-HT1F and 5-HT3A RNA were found in NP2 fibers, and 5-HT1F and 5-HT2A transcripts were detected in NP3 fibers.78, 79, 80 In addition, Morita et al⁹³ found the HTR7 receptor on murine small-diameter skin fibers and demonstrated that serotonin-mediated HTR7 activation promotes chronic itch in a murine model of AD in a TRPA1 dependent manner. The 5-HT3A and 5-HT7 receptors were also found in human DRG.⁸²^,⁹³ Besides its potential role as a pruritogen in skin inflammation, several reports have also suggested that serotonin is involved in mediating cholestatic itch.³³⁷^,³³⁸ Taken together, serotonin promotes both peripheral and central itch transmission, making it an interesting target for the treatment of chronic itch.

Currently, no drugs interfering with serotonin pathways are specifically approved for treating CP. However, some clinical trials have indicated that selective serotonin reuptake inhibitors (SSRIs) could have a positive influence on chronic itch, for example, in AD or chronic liver disease.²¹¹^,³³⁹^,³⁴⁰ SSRIs, which are FDA-approved for treating depression, enhance the extracellular serotonin level by inhibiting the serotonin uptake into cells. Regarding CP treatment, this seems counterintuitive when considering serotonin's peripheral and central pro-pruritic role. The exact mechanism is unclear, but adaptive processes in response to enhanced serotonin signaling, such as downregulation of 5-HT3 receptors, were considered to explain SSRIs’ antipruritic effects.³⁴¹ In line with this idea, some reports have proposed that 5-HT3-receptor blockade may be beneficial in treating CP in chronic kidney failure and uremia.³⁴² However, convincing clinical trials are yet to be conducted.

D. Neuropeptides

1. Substance P

Substance P belongs to the tachykinin peptides and serves as a neurotransmitter in the CNS. It is also a crucial player in neurogenic inflammation at the neurocutaneous interface.³⁴³ Historically, the neurokinin receptor neurokinin 1 receptor (NK1R) was considered the predominant target of Substance P; however, recent findings have shown that Substance P also interacts with members of the MRGPR family, such as MrgprB2 and MrgprA1 in mice, or the functional equivalent MrgprX2 in humans.³⁴⁴

NK1R exhibits a broad expression profile. In addition to its expression on neurons, NK1R was also found in various skin cell populations.³⁴⁵ Central neuronal NK1R signaling is critically involved in chemotherapy-related nausea and postoperative nausea and vomiting, explaining the clinical success of NK1R-blocking agents in these conditions.³⁴⁶^,³⁴⁷ Regarding itch, spinal NK1R-expressing projection neurons play a crucial role in central itch pathways, and their deletion alleviates both acute and chronic itch behavior in mice.¹⁶⁸^,³⁴⁸ These findings underscore that the Substance P–NK1R pathway is crucial in spinal itch transmission. In mice and humans, Substance P induces itch after intradermal injection, and NK1R is expressed in peripheral sensory nerve fibers. However, recent murine findings suggest that NK1R is not essential for mediating peripheral-induced itch by Substance P.³⁴⁹ Instead, Azimi and colleagues proved that Substance P induces itch by targeting the Mrgpr MRGPRA1 on afferent nerve fibers rather than NK1R.³⁴⁴^,³⁴⁹ Importantly, Substance P-induced itch in mice is considered independent of mast cell degranulation, a significant observation given that Substance P is a potent activator of mast cell degranulation in a MrgprB2-dependent manner.³⁵⁰ Humans do not express MrgprA1 or MrgprB2; instead the human functional equivalent MrgprX2 interacts with Substance P.⁸⁹ MrgprX2 is predominantly present on human mast cells and has also been reported in human DRG.⁸⁹^,³⁵¹ It remains unclear how Substance P induces peripheral itch in humans. However, a MrgprX2-dependant pathway, either involving mast cell activation or directly via nerve fibers, seems likely.⁷¹^,³⁵²

a. NK1R blockade

Several NK1R-blocking agents, such as the orally applied aprepitant, are available. The FDA has approved aprepitant for the treatment of chemotherapy-induced nausea and vomiting.³⁵³ NK1R-antagonists showed promising results in treating itch and inflammation in murine dermatitis models.³⁵⁴ However, human clinical studies were somewhat disappointing, as they did not convincingly alleviate inflammation and showed mixed effects on pruritus burden. Clinical trials in AD patients demonstrated that the NK1R antagonists aprepitant, serlopitant, and tradipitant did not significantly improve either skin disease severity or pruritus burden compared to placebo.³⁵²^,³⁵⁵ Serlopitant, another NK1R blocker, initially showed encouraging results in phase 2 studies for PGN,³⁵⁶ psoriasis,³⁵⁷ and therapy-resistant CP of various origins.³⁵⁸ However, subsequent phase 3 clinical studies of serolpitant in PGN failed to meet their primary endpoint (NCT03677401 and NCT03546816). In conclusion, despite substantial clinical efforts, NK1R blockade has not emerged as an effective therapy for CP.

A potential explanation for the mouse-human discrepancy could be that studied NK1R-blocking agents also antagonize murine MrgprA1 and MrgprB2 but not their functional human ortholog MrgprX2.³⁴⁴

b. MrgprX2 inhibitors

As already outlined above, MrgprX2 expression on mast cells and/or sensory nerve fibers may be crucial for mediating Substance P-dependent itch in humans. In addition, MrgprX2 is also activated by several other endogenous ligands and can be considered a crucial hub of IgE-independent mast cell activation. Given these properties, MrgprX2 represents a highly attractive therapeutic target to interfere with mast-cell-driven itch and inflammation. Several small-molecule MrgprX2 antagonists have been recently described.³⁵⁹ The first-in-class agent EP262 demonstrated proof-of-mechanism in a phase 1 clinical study for chronic urticaria. Unfortunately, the subsequent phase 2 study was terminated in January 2025 due to toxicological findings in preclinical in vivo experiments.³⁶⁰ EVO756 represents another promising MrgprX2 inhibitor, currently being tested in clinical phase 2 studies for AD and CSU. It will be exciting to see if this substance expands our therapeutic armamentarium in the future.

c. Tyrosine kinases KIT and BTK as targets to block mast cell activation

Mast cells play a crucial role in releasing histamine and other nonhistaminergic pruritogens during allergic inflammation. Targeting the Substance P–MrgprX2 axis could be one strategy to modulate mast cell-dependent itch. Another promising strategy is to target tyrosine kinases such as KIT and Bruton’s tyrosine kinase (BTK), which regulate mast cell differentiation and function.

The receptor tyrosine kinase KIT is a crucial regulator of mast cell maturation, differentiation, proliferation, survival, and activation. KIT is activated by mesenchymal cell-derived stem cell factor.³⁶¹^,³⁶² Disturbed KIT signaling in mice results in mast cell deficiency.³⁶³ The key role of KIT in mast cell biology makes it a promising target for treating mast-cell-dependent pruritus. Recently, monoclonal antibodies and small molecules have been introduced that specifically target KIT.³⁶⁴ The humanized antibody barzolvolimab is one of these promising new candidates and is currently being tested in a phase 3 clinical trial for CSU.

BTK is another tyrosine kinase expressed on mast cells and other immune cells, such as B cells.³⁶⁵^,³⁶⁶ It is engaged in diverse signaling pathways, including BCR signaling in B cells.³⁶⁷ BTK is thought to promote mast cell activation by integrating signals from the cell surface, such as FcϵRI receptor binding.³⁶⁸ Facing this central role in regulating mast cell biology, BTK inhibition represents an interesting therapeutic target for mast cell-driven CP. Small-molecule BTK inhibitors were first approved for myeloproliferative diseases but are now also being investigated for inflammatory diseases. Notably, in October 2025, the small-molecule BTK inhibitor remibrutinib was approved by the FDA for the treatment of CSU following convincing results from a phase 3 clinical trial. Itch severity was assessed as a secondary endpoint and alleviated by remibrutinib treatment.³⁶⁹ Together, these findings highlight KIT and BTK inhibition as promising therapeutic approaches to attenuate mast cell–driven CP and inflammation.

D. Endothelin-1

Various cell populations, including endothelial cells, keratinocytes, and immune cells, produce the peptide ET-1. This peptide exerts its biological effects by targeting the G protein-coupled receptors endothelin receptor A (ETRA) and B (ETRB).370, 371, 372 ET-1 is a potent vasoconstrictor, and bosentan, a dual endothelin receptor antagonist, is approved to treat pulmonary arterial hypertension.³⁷³ Besides its vasoregulatory function, ET-1 is also considered to play a role in various biological processes, including epidermal proliferation and leukocyte migration.³⁷⁴^,³⁷⁵ Importantly, ET-1 was described as a pruritogen in mice³⁷⁶ and humans.³⁷⁷ Clinical studies have shown that ET-1 plasma levels correlate with itch intensity in AD patients³⁷⁸ and have demonstrated that ET-1 is enriched in the skin of patients with PGN.³⁷⁷ These observations suggest a role of ET-1 in CP-associated diseases. Functional studies indicated that the ETRA receptor, whose RNA was detected in murine NP2 and NP3 fibers,⁸⁰ is crucial for ET-1-related itch induction.³⁷⁹^,³⁸⁰ ETRA receptor activation employs the MAP kinase pathway to culminate in ERK1/2 activation. Kido-Nakahara et al³⁷⁷ determined that the neural endothelin-converting enzyme 1 (ECE-1) is a critical suppressor of ET-1-induced neural signaling and itch. ECE-1 physiologically limits ET-1-initiated ETRA receptor signaling in the endosomes of DRG neurons and promotes the recycling of the receptor to the cell surface. Inhibition of ECE-1 aggravated neuronal ERK-1/2 activation and increased chronic scratching behavior in a murine dermatitis model.³⁷⁷ These observations indicate that ET-1, ETRA, or the negative regulator ECE-1 could represent interesting therapeutic targets for CP. Because the dual ETR antagonist bosentan is already established for treating pulmonary hypertension, it might represent an attractive candidate. In a preclinical AD model, topical bosentan alleviated skin inflammation, pruritus, and neurite elongation.³⁸¹ However, more basic research and clinical trials are warranted to define the relevance of ET-1 as a therapeutic target in human CP.

E. Proteases and PAR receptors

The exogenous protease mucunain, the pruritogenic component of cowhage, is long known as an inducer of nonhistaminergic itch.³⁸² PARs are the key biological responders through which proteases mediate pruritic responses. Four PAR family members (PAR1–4) have been identified; PAR1 and PAR2 in particular have been associated with mediating protease-driven itch.383, 384, 385, 386 Mechanistically, proteases cleave the extracellular N-terminal part of PARs, thereby exposing a conserved tethered ligand that subsequently auto-activates the receptor. PARs show a broad expression profile including keratinocytes, immune cells and sensory nerve fibers, underscoring their diverse biological functions. Importantly, proteases do not derive solely from external sources such as plants and microbes; endogenous proteases, including tryptase or chymotrypsin, play key roles in inflammation and itch circuits.³⁸⁵ In the skin, PAR-expressing keratinocytes are a crucial target for proteases, fueling itch and inflammatory cascades through the release of proinflammatory mediators and pruritogens.³⁸⁵ This circuit is an indirect route of how PAR activation propagates itch in the skin. Given that PARs are also expressed on neurons, it is an important and exciting question whether they can also function as direct pruritogens.

1. PAR1

Deng et al¹⁵⁹ recently illuminated this question. They demonstrated that the protease V8 released by S. aureus induces scratching behavior in mice by targeting the PAR1 receptor. The broad cell expression pattern of PAR1 includes itch-mediating NP2 fibers in the mouse. Notably, PAR1 knockdown in sensory neurons inhibits V8-induced itch, demonstrating that V8 is a bona fide pruritogen that acts directly on neuronal PAR1. The authors could also demonstrate that PAR1 is expressed in human DRG and that V8 activates human DRG neurons in vitro. However, if S. aureus and the V8 axis also induces itch in humans remains to be explored.¹⁵⁹

2. PAR2

PAR2 is another well studied receptor in the context of itch. It is well established that several PAR2-activating proteases, such as mucunain, induce nonhistaminergic itch in humans.³⁸⁷ In mice, PAR2 RNA is expressed in NP3 itch fibers, providing a hint that proteases could target itch-mediating fibers via PAR2 activation.⁷⁸

However, the concept that PAR2 mediates itch was challenged by studies on SLIGRL, a ligand that resembles the PAR2 activating tethered ligand. As already outlined in the NP2 fiber section, SLIGRL not only promotes PAR2 activation but also activates MrgprC11 on NP2 fibers. Importantly, scratching behavior in response to SLIGRL injection was abrogated in Mrgpr cluster (including MrgprC11)-deficient but PAR2-competent mice.³⁸⁴ This observation suggests that MrgprC11 activation, rather than PAR2, is crucial in mediating SLIGRL-induced itch. Other publications have proposed a relevant role for PAR2 in inducing an itch response.³⁸⁵ Hence, whether PAR2 mediates itch induction remains an active field of research.

Endogenous and exogenous proteases are abundant in inflamed skin, and targeting the protease-PAR axis could be an interesting approach to alleviate pruritus and inflammation. Two general concepts might be successful: (1) inhibiting the proteolytic activity of CP-driving proteases; and (2) antagonizing PAR signaling.³⁸⁸ To our knowledge, promising clinical trials targeting this axis for CP-associated diseases are not available yet.

F. Arachidonic acid derivatives: Prostaglandins, thromboxane, and leukotrienes

Leukotrienes and prostanoids are 2 groups of lipid mediators derived from arachidonic acid (AA), a polyunsaturated ω-6 fatty acid released from membrane lipoproteins. Importantly, various members of both groups are considered potential pruritogens (Fig. 8).

Fig. 8 — Synthesis of various prostaglandins and leukotrienes and their relation to itch. The synthesis of prostaglandins and leukotrienes relies on the release of arachidonic acid (AA, *yellow*) from membrane lipoproteins. The enzyme phospholipase A2 controls this release. Further processing of AA by the enzyme cyclooxygenase determines the prostaglandin pathway *(blue)*, whereas the enzyme lipoxygenase initiates the leukotriene *(green)* fate. Specific enzymes *(italics)* are responsible for generating the different prostaglandin and leukotriene molecules. Some AA derivatives were reported to induce itch or were even characterized as bona fide pruritogens, highlighted in red. This figure was created with permission in BioRender. R. T. (2025) https://biorender.com/g4nc6gy.

The enzyme phospholipase A2 tightly controls the release of AA.³⁸⁹ The processing of AA by cyclooxygenases determines the prostanoid pathways, ultimately leading to the formation of either prostaglandins (PGE2, PGF2α, PGI2, and PGD2) or thromboxane A2 (TXA2) (Fig. 8).³⁹⁰^,³⁹¹ Prostanoids regulate many physiological processes but are also induced during inflammation. Prostaglandins are critically engaged in pain sensation, explaining the therapeutic action of painkillers such as aspirin, which target the cyclooxygenase.³⁹² Alternatively to the prostanoid pathway, the enzyme arachidonate 5-lipoxygenase can convert AA into 5-hydroxyeicosatetraenoic acid. This acid serves as a precursor for all leukotrienes (LTA4, LTB4, LTC4, LTD4, and LTE4), representing another family of lipophilic, inflammatory mediators.³⁹³

1. Prostaglandin E2

Physiologically, PGE2 is a crucial molecule in pregnancy. It keeps the ductus arteriosus in the unborn fetus open and promotes the maturation of the cervix shortly before birth. Moreover, PGE2 is induced by different cell types, including immune cells, during inflammation and promotes fever, edema, and leukocyte infiltration.³⁹⁴ Intriguingly, studies have shown that PGE2 can elicit acute itch in humans after intradermal injection,³⁹⁵^,³⁹⁶ but not in mice.³⁹⁷ PGE2 targets 4 different G protein-coupled prostaglandin receptors EP1–EP4; whether one of those plays a leading role in pruritus induction remains unclear.³⁹⁸ Notably, some reports suggested that PGE2 might provoke pruritus in the blood disease PV.³³⁵ PV is a myeloproliferative disorder that causes increased red blood cell numbers. The typical clinical presentation of PV includes a characteristic pruritus that is triggered by water exposure to the skin, which is referred to as ‘aquagenic pruritus.’³⁹⁹ The exact pathogenesis of aquagenic pruritus in PV is poorly understood. Still, reports suggest that aspirin or SSRIs can alleviate the symptoms, suggesting that AA derivatives and serotonin might play a key role in the pathophysiology.³³⁵^,³⁹⁹

2. Thromboxane A2

TXA2 is enriched in thrombocytes and promotes thrombocyte aggregation via the thromboxane A2 receptor (TXA2R). Andoh et al. demonstrated that activating the TXA2R in mice resulted in scratching behavior, which was successfully abrogated after administration of a selective TXA2R antagonist. Moreover, the TX receptor was detected on afferent nerve fibers, suggesting that keratinocyte-released TXA2 induces itch by acting on these nerve fibers.⁴⁰⁰ In NC/Nga mice, a genetic AD mouse model, TXA2R blockade reduced spontaneous scratching.⁴⁰¹ Mechanistically, it was suggested that keratinocyte-released TXA2, induced by PAR2 activation or alternatively by IL-31 receptor activation, might be relevant for TXA2-induced itch.⁴⁰¹^,⁴⁰² In addition, a mouse model of chronic kidney failure proposed the involvement of TXA2 in chronic renal failure-associated pruritus.⁴⁰³ The clinical and therapeutic relevance of these findings for human diseases needs to be determined.

3. Leukotriene B4

Leukotriene B4 (LTB4) is induced and released during inflammation. It facilitates the recruitment and activation of leucocytes, such as neutrophils, by acting on the leukotriene B4 receptors 1 (BLT1) and 2 (BLT2).⁴⁰⁴^,⁴⁰⁵ LTB4 can elicit scratching behavior in mice, and it was reported to induce persistent itch in humans after intradermal administration.³⁹⁷^,⁴⁰⁶ In a preclinical mouse model, blocking the leukotriene B4 receptor ameliorated chronic spontaneous itch.⁴⁰⁷ Mechanistically, it was proposed that IL-31 can mediate the release of LTB4 from keratinocytes in mice.⁴⁰⁸ Available single-cell sequencing data indicated that BLT1 and BLT2 are expressed on murine unmyelinated mechanoreceptors and peptidergic subsets, but not on the itch-detecting NP1-3 neurons.⁸⁰ Hence, it is unclear if LTB4 induces itch in mice by directly activating itch-mediating neurons.¹²⁴ In humans, LTB4 was found to be enriched in different CP-associated diseases, such as psoriasis⁴⁰⁹^,⁴¹⁰ or AD.⁴¹⁰^,⁴¹¹ However, the clinical relevance of this finding remains to be characterized.

4. Leukotriene C4

Besides LTB4, Leukotriene C4 (LTC4) is another leukotriene produced during inflammatory processes.³⁹³ After release into the extracellular space, LTC4 can act directly as a lipid mediator or serve as a precursor for LTD4 and LTE4. LTC4 and its derivatives are commonly summarized as cysteinyl leukotrienes (CysLTs). LTC4 exerts its biological effects by targeting the G protein-coupled receptors Cystlr1 or Cystlr2. During inflammation, LTC4 is released by various immune cells, such as mast cells.⁴¹² LTC4 and its derivatives are considered to play a disease-promoting role in allergic inflammation, especially in asthma bronchiale, where anti-Cystlr1 antagonists, such as montelukast, are established as a treatment option for children.⁴¹³

Recently, Voisin et al. demonstrated that LTC4 induces itch in mice but not its derivatives, LTD4 and LTE4. LTC4-induced itch was shown to be dependent on the Cysltr2 receptor, which is highly expressed on murine NP3 neurons. From a translational perspective, expression of Cysltr2 was also confirmed in human DRG.¹²⁴ Moreover, it was demonstrated that LTC4-induced itch contributes to chronic itch in murine dermatitis.¹²⁴ Around the same time, Wang et al. showed that LTC4 plays a crucial role in acute itch flares in a chronic AD mouse model. Mechanistically, they demonstrated that IgE-mediated activation of basophils causes the release of LTC4, which mediates acute allergen-dependent itch flares by acting on Cysltr2-expressing neurons.⁵² Both reports indicate that LTC4 could have a crucial role in human CP and that its receptor, Cystlr2, might be an attractive therapeutic target in the future.

G. Sphingosine-1-phosphate (S1P)

S1P represents another lipid mediator derived from membrane sphingolipids. S1P targets 5 classes of G protein-coupled S1P receptors (S1PR1-5).⁴¹⁴ Physiologically, S1P signaling is involved in various processes, including lymphocyte trafficking⁴¹⁵ and epidermal differentiation.⁴¹⁶ Several studies have demonstrated that S1P plays a role in the induction and modulation of pain.417, 418, 419, 420 Recently, Hill et al⁴²¹ demonstrated that S1P can trigger both pain- and itch-associated behavior in mice, and that lower doses of S1P specifically elicit scratching behavior. They found that S1P-related scratching behavior was dependent on S1PR3, which is expressed on murine NP2 and NP3 fibers. Enhanced levels of S1P have been detected in human CP-associated diseases, such as psoriasis.⁴²² Although functional evidence for driving CP is pending, it is worth considering that S1PR3 blockade may be a helpful strategy for treating CP in the future.

H. The matrix protein periostin

Periostin is an extracellular matrix protein that can communicate with cells by binding to integrin receptors.⁴²³ In healthy skin, periostin is found in the papillary dermis and is considered to play a role in tissue development and repair.⁴²⁴ In type 2 inflammation, it is markedly produced by keratinocytes and deposited throughout the dermis, promoting chronic skin inflammation.⁴²⁵^,⁴²⁶ Translational studies suggest that periostin deposition in the skin correlates with pruritus burden in type 2 inflammatory diseases.⁴²⁷^,⁴²⁸ Intradermal injection of periostin causes acute itch behavior in mice and nonhuman primates.¹³⁹ As a mechanism, it was suggested that periostin could indirectly induce itch by releasing pruritogens from immune cells, eg, IL-31 from polarized M2 macrophages.⁴²⁹ Moreover, Mishra et al¹³⁹ also proposed that periostin can directly activate itch-conducting fibers by binding to the integrin αVβ3. This suggestion is based on the finding that inhibiting neuronal αVβ3 integrin ameliorates periostin-induced scratching behavior in mice. Nevertheless, the exact type of itch fiber involved in periostin-induced itch remains to be determined.

From a clinical perspective, enhanced periostin production has been reported in several skin diseases associated with CP, such as AD,⁴³⁰ PGN,⁴²⁸ BP⁴²⁷ or cutaneous T-cell lymphoma.⁴³¹ For this reason, periostin may be an attractive therapeutic target for treating CP in dysregulated type 2 inflammation.

Most of the pruritogens discussed so far are closely linked to ongoing cutaneous immune responses, highlighting the strong link between CP and inflammatory processes. The closing part of this review will now focus on 2 systemic diseases in which CP occurs independently of primary skin inflammation: cholestasis and chronic kidney failure. Both disease entities are characterized by systemic accumulation of endogenous and exogenous substances that are not properly cleared from the body, raising the question of whether some of these substances act as pruritogens at the neurocutaneous interface.

I. Pruritogens involved in cholestasis-associated itch

Cholestasis refers to the reduced flow of bile, which can result from various pathological processes, including liver diseases. It is characterized by the systemic accumulation of substances, such as bile acids or the yellow erythrocyte breakdown product bilirubin, which are usually eliminated by the biliary system and the gut. Clinically, cholestasis is accompanied by jaundice due to yellow bilirubin deposits in the tissue, and importantly by pruritus.432, 433, 434 Cholestasis-associated CP typically does not show specific skin lesions and usually presents at the soles and palms, but can also manifest systemically.⁴³⁵ A simple explanation for the association of CP and cholestasis is that accumulating substances behave as pruritogens, activating itch fibers in the skin.

1. Bile acids as pruritogens in cholestasis

Bile acids produced by hepatocytes, such as deoxycholic acid, are a crucial components of the bile fluid and accumulate systemically during cholestasis. Intriguingly, experimental studies have suggested that bile salts exert pruritic effects in mice and humans when exposed to cutaneous itch fibers.⁴³⁶^,⁴³⁷ TGR5 is a bile acid receptor on murine sensory nerve fibers. It has been implicated in mediating bile acid-induced itch in mice.⁴³⁸ However, TGR5 was not found in human DRGs, and TGR5 agonists did not cause itch in clinical studies, which raises doubts about the translational relevance of this mouse finding.⁴³⁹^,⁴⁴⁰ Meixong et al⁴⁴¹ identified MrgprX4, a human Mas-related G protein receptor targeted by various bile acids. Their elegant experimental approach demonstrated that MrgprX4 mediates bile acid-induced itch when expressed selectively in murine NP2 itch fibers. Interestingly, the erythrocyte degradation product bilirubin was also shown to activate MrgprX4 in vitro.²¹⁰ However, from a clinical perspective, it is unlikely that bilirubin plays a significant role as a pruritogen because hereditary syndromes, including specific defects in bilirubin elimination, do not develop substantial pruritus symptoms.⁴⁴² Taken together, regardless of bilirubin’s role, MrgprX4 was considered an attractive target for treating cholestatic pruritus. EP547 was developed as a specific antagonist of MrgprX4 and was studied in a phase 2 clinical trial. Unfortunately, in November 2024, the stakeholder dropped EP547, stating that the data did not support further development.³⁶⁰

2. The ATX–LPA axis in cholestatic pruritus

Lysophosphatidic acid (LPA) was recently proposed as another potential pruritogen accumulating in cholestasis.⁴⁴³ LPA signals through 6 different G protein-coupled LPAR receptors (LPA1–6). Single-cell sequencing data indicate that LPAR1 is highly enriched in NP3 neurons and lysophosphatidic acid receptor 3 in NP1 neurons,⁸⁰ indicating a relation to itch sensation. Significantly, LPA can induce scratching behavior in mice when injected intradermally.⁴⁴⁴ The circulating lysophospholipase D autotaxin (ATX) generates LPA, and ATX is the first biomarker which concentration was shown to correlate with itch intensity in cholestasis patients.⁴⁴³^,⁴⁴⁵ Thus, the ATX–LPA axis may be an important mediator of cholestatic itch, and targeting LPAR receptors could represent a promising therapy strategy in the future.

In conclusion, several potential pruritic substances in cholestasis have been identified. However, a key CP-driving substance has not yet been established. Refined characterization of the pruritic potential of accumulating substances and the identification of essential CP-driving molecules could revolutionize the treatment of cholestatic itch.

J. Pruritogens involved in chronic kidney disease (CKD)-associated itch

Chronic itch is a very common symptom in patients with chronic kidney disease (CKD).⁴⁴⁶^,⁴⁴⁷ CKD-associated itch has a complex pathogenesis. Notably, the kidney's inability to eliminate unwanted metabolites can lead to the accumulation of toxic substances, which may act as pruritogens targeting itch fibers in the skin. A metabolic profiling approach identified a couple of metabolites, such as kynurenic acid or hypotaurine, which could serve as biomarkers associated with CP in kidney failure.⁴⁴⁸ However, whether these molecules act biologically as pruritogens or serve as a surrogate marker remains elusive. Other studies suggest that CP in CKD may also be mediated by a dysregulated immune response, including enhanced IL-31 production.²⁴⁰^,⁴⁴⁹

1. Opioid receptor signaling in CP

CKD-associated CP⁴⁵⁰ as well as CP occurring in other disease entities⁴⁵¹ has been linked with an imbalance in opioid receptor signaling. In particular, alterations in the activity of the G protein-coupled μ-opioid receptor (MOR) and the κ-opioid receptor (KOR) have been implicated to influence itch pathways.452, 453, 454, 455 Physiologically, endorphins activate MOR to alleviate pain signaling, but simultaneously also promote itch signaling.⁴⁵³ KOR activation by endogenous dynorphins does not show this dissociative effect; instead, both pain and itch are suppressed.⁴⁵⁴ Opioid receptors are broadly expressed in the peripheral and CNS, suggesting a complex mode of action that is not yet fully characterized. Relying on the aforementioned observations, MOR-antagonism or KOR-agonism represents a logical therapeutic strategy to alleviate itch. Several agents targeting these pathways have been developed, with the FDA-approved KOR agonist difelikefalin representing the most successful to date.

2. κ-Opioid receptor agonist

The mouse finding that peripheral κ-opioid receptor activation inhibits itch was translated into successful clinical studies relying on patients suffering from uremic pruritus. The synthetic peptide difelikefalin represents a selective KOR agonist and is the only FDA-approved drug for moderate-to-severe pruritus in hemodialysis patients.⁴⁵⁶ Difelikefalin’s hydrophilic feature prevents it from crossing the blood-brain barrier and restricts its function to peripheral KORs present on immune cells and peripheral neurons.⁴⁵⁷ Difelikefalin was approved in 2021 after demonstrating clinical efficiency by significantly reducing patients’ worst itch experiences (primary endpoint) and enhancing their itch-related quality of life.⁴⁵⁷ Currently, this intravenously applied drug represents a key treatment option for CP in hemodialysis patients and exemplifies the successful translation of targeted therapies for CP in systemic diseases.

VI. Concluding remarks and future perspective

Intensive research over the last 2 decades has significantly enhanced our understanding of the physiological mechanisms of itch, culminating recently in specific therapeutic concepts for treating CP. Strikingly, the identification of various nonhistaminergic pruritogens and their receptors revolutionized and expanded our view on how chemical itch is initiated in the skin. The fact that many of these pruritogens are key mediators engaged in type 2 inflammation underscores the strong connection between itch and type 2 immune responses. On the other hand, it is still not well understood how mechanical itch is generated in the periphery. The fact that alloknesis is a crucial driver of CP can serve as motivating factor to focus on the mechanisms involved in mechanical itch induction.

Functional mouse studies in combination with modern molecular biological technologies, such as RNA single-sequencing studies, provided a detailed picture of which part of the murine afferent nervous system is responsible for transmitting the sensation of itch. These findings also led to a generally accepted taxonomical classification, including the different itch-transmitting NP fibers. From a translational perspective, the scientific community would also greatly benefit from a generally accepted taxonomy of afferent nerve fibers in humans, including the allocation of itch-mediating subpopulations.

From a clinical angle, many pruritogens have been identified that play a relevant role in prevalent skin diseases associated with CP, such as AD. Most of these acting pruritogens also play critical roles in orchestrating the immune response and promoting inflammation. Molecules showing this dual character are optimal targets for the treatment of pruritic inflammatory skin diseases. The identification and functional characterization of pruritic cytokines such as IL-4, IL-13, IL-31, but also IL-17 were fundamental in developing modern, molecular targeted therapies. In the context of pruritic inflammatory skin diseases, these new therapies mark a shift from broad immunosuppressive strategies to highly specific approaches targeting disease-relevant axes. This shift enables high therapeutic efficiency and reduces the risk of off-target effects and undesired side effects. In particular, the multimorbid patient is profiting from this shift. However, plenty more relevant pruritogens likely exist and await characterization. Interestingly, a recent study defined transcriptomic differences between itch and non-itchy skin sites in AD and psoriasis. This study represents an elegant approach to narrow down potential new pruritogen candidates that could serve as therapeutic targets in the future.⁴⁵⁸

Another focus should be to characterize the relevant pruritogens in disease-specific contexts. We already have a good understanding of which pruritogens act in well studied skin diseases, such as AD. However, various dermatoses, such as LP, remain for which the relevant pruritogens are poorly characterized.

In addition, we are just starting to understand the CP-driving mechanism in systemic diseases such as CKD or cholestasis. Considering the high clinical relevance of those conditions, it is desirable to elucidate the pathophysiological mechanism in more detail, which requires interdisciplinary strategies. A detailed picture of which pruritogens are relevant drivers in certain diseases will allow a highly targeted therapy, maybe by simply expanding the usage of already approved drugs. Of note, also not a focus in this review, but the pathophysiological mechanism driving CP in neurological and psychiatric condition also require attention.

Emerging technologies, including spatial transcriptomics, in vivo Ca²⁺ imaging, and organoid models will shape future scientific progress and will support our efforts to decipher the sensation itch. Artificial intelligence will be a helpful tool for data analysis, e.g., allowing standardized quantification of murine scratching behavior. Given the subjective nature of itch, it is crucial to keep in mind that the interpretation of a defined itch stimulus depends heavily on emotional, cognitive, and stress circuits. This fact should be considered when conducting research on itch, and particularly when treating CP patients. Itch research exemplifies neuroimmune-sensory integration and relies heavily on collaborative efforts across fields including dermatology, internal medicine, neuroscience, immunology, and psychobiology. Integrative approaches, such as psychoneuroimmunology, will be key to a thorough understanding of the driving mechanisms engaged in CP.

Conflict of interest

D.H.K. is a paid consultant for AbbVie Inc, Beiersdorf AG, Janssen Research and Development LLC, Merck and Aditum Bio. D.H.K. has a sponsored research agreement with Almirall S.A. and Galderma Laboratories, Lp.

Acknowledgments

Financial support

The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (RA 4013/1-1 708228 809907) and the NIH (R01 AR071720) supported this work.

Data availability

There are no datasets presented in this paper.

CRediT authorship contribution statement

Torben Ramcke: Writing – original draft, Writing – review and editing. Daniel H. Kaplan: Writing – original draft, Writing – review and editing.

Declaration of AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used Grammarly to proofread the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Associate Editor: Francesca Levi-Schaffer

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Associated Data

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Data Availability Statement

There are no datasets presented in this paper.

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PERMALINK

From neuroimmune circuits to targeted therapy of chronic pruritus

Torben Ramcke

Daniel H Kaplan

Abstract

Significance Statement

I. Introduction

II. Classification of acute itch by the mode of induction at steady state

A. Mechanical itch

B. Chemical itch

C. Contagious itch

III. Where itch begins: The skin as a sensory and immune interface

Fig. 1.

A. The epidermis

B. The dermis

IV. Functional classification of skin immune responses and their relation to itch

A. Type 2 inflammation and type 2-driven pruritic inflammatory skin diseases

B. Types 1 and 3 inflammation and type 1 and 3-driven pruritic inflammatory skin diseases

V. The peripheral neuronal itch pathway

Fig. 2.

Table 1.

A. Myelinated A fibers are potentially engaged in sensing itch

B. C fibers are established players in sensing itch in mice and humans

1. Nonpeptidergic (NP) C fibers signal itch in mice

Table 2.

2. Mas-related G protein-coupled receptors (Mrgpr)

3. Transient receptor potential ion channels (TRP) and voltage-gated sodium channels (NaV)

4. NP1 fibers

5. NP2 fibers

a. Pruritogen detection and signal transduction in NP2 neurons

b. Itch selectivity versus polymodality in NP2 neurons

6. NP3 fibers

7. Are NP fibers conserved in primates and humans?

a. Nonhuman primate (NHP)

b. Human

VI. Crosstalk at the neurocutaneous interface

A. Epithelial-neuroimmune circuits promote peripheral itch

Fig. 3.

1. Immune cells drive pruritic inflammation and neuronal remodeling

2. Keratinocytes as initiator and amplifier of inflammation and itch

3. Neurogenic immunomodulation and itch

a. Neurogenic inflammation and itch

b. Itch-mediating NP fibers: Rising players in neurogenic immunomodulation

c. Neurogenic inflammation in human disease

B. Itch, pathogens, and neurogenic inflammation

Fig. 4.

VII. Central conductivity and processing of itch

A. Itch circuits at the spinal level

Fig. 5.

1. Gastrin-related peptide (GRP) and spinal excitatory interneurons mediate chemical itch

2. Inhibitory interneurons shape chemical itch transmission

3. Mechanical itch signaling

B. Itch processing in the brain and descending brain-spinal modulation of itch

C. Glia cells and their role in itch transmission

1. Peripheral glia and itch

2. Central glia and itch

D. Mental status and itch—Stress and the skin immune response

VIII. Chronic itch from a clinical perspective

A. Itch sensitization: Hyperknesis and alloknesis

B. Etiology and clinical classification of CP

Table 3.

1. CP without skin lesions: Hallmark of systemic, neurological, and psychiatric diseases

2. CP accompanied by skin lesions

Fig. 6.

IX. Endogenous pruritogens, their clinical relevance, and therapeutic use as target

Table 4.

A. Type 2 cytokines

1. IL-31

a. IL-31 signaling

Fig. 7.

b. IL-31 in human pruritic diseases

c. IL-31 beyond pruritus and type 2 Inflammation

d. IL-31RA blockade

e. OSMRβ blockade

f. IL-31 cytokine blockade

2. IL-4 and IL-13

a. Receptor architecture and signal transduction

b. Neuronal actions of IL-4 and IL-13 in CP

c. IL-4RA blockade

d. Specific IL-13-signaling blockade

3. Transient receptor potential ion channels (TRP) and voltage-gated sodium channels (Na_V)