Emerging Concepts in Neuropathic and Neurogenic Itch

Abstract

Chronic pruritus has multiple etiologies, ranging from inflammatory to metabolic and neuropathic processes. However, recent advances in itch biology have shed light on potential mechanisms that explain the molecular and cellular basis of these pathologies. Further, new understanding of neuroimmune itch circuits necessitates clarification of terminologies such as “neuropathic” and “neurogenic”. This review provides an overview of how new concepts may better explain the pathophysiology of a variety of chronic pruritic disorders and the rationale for directing emerging novel therapeutic strategies towards them.

Introduction

Itch sensation is a highly conserved, protective response across mammals to mechanically expel parasites and environmental irritants from the skin. However, upon becoming chronic, it is pathological and debilitating. Chronic pruritus, defined as itch lasting longer than 6 weeks, has a variety of etiologies including inflammatory (e.g., atopic dermatitis [AD]), metabolic (e.g., uremic and cholestatic pruritus), and neuropathic (e.g., brachioradial pruritus [BRP], notalgia paresthetica [NP], and scalp pruritus]). The latter is caused by direct damage to the nerve itself. Although specific itch conditions have predominant contributors to their pathogenesis, it is most likely that there are multiple etiologies. For example, in prurigo nodularis [PN], it is widely appreciated that spontaneous itch precedes the development of the fibrotic nodules that are highly inflamed.¹ Thus, therapies that simultaneously target neuropathic and inflammatory responses likely afford the most optimal clinical responses. Notwithstanding the complexity, understanding mechanisms that drive different forms of itch will likely inform drug development, treatment, and management of chronic pruritic disorders.

Clinical concepts in itch etiology preceded the modern advances of itch biology that firmly established the molecular and cellular specificity of itch. For example, the classical distinction between histaminergic and nonhistaminergic itch, although historical helpful, is largely an outdated concept. For example, it is well-established both clinically and scientifically that the vast majority of chronic itch disorders and itch pathways, respectively, are nonhistaminergic in nature. Thus, the utility of this distinction is increasingly unclear. Further, there is tremendous confusion about the distinction between “neuropathic” and “neurogenic” itch.^2,3 Although both imply itch that is triggered and/or perpetuated by itch sensory neurons (pruriceptors), these terms are often used interchangeably or defined in ways that could benefit from alignment with more recent advances in itch biology.

Herein, we give an overview of the latest molecular and cellular advances in itch biology and how they inform our understanding of traditional concepts of clinical itch. We summarize select itch conditions as paradigmatic examples of inflammatory and neuropathic itch, respectively, to shed light on mechanistic processes. To avoid confusion, we omit discussion of metabolic itch and refer the reader to the following review articles.^4–8 While early papers have referred to neurogenic itch in the context of post-stroke symptoms,^9,10 we propose that neurogenic itch should be used in a very specific manner to indicate itch that is triggered or propagated through a peripheral neuroinflammatory process. Finally, we invoke new knowledge about therapeutic efficacy of targeted agents and how they inform our understanding of the mechanistic basis of various chronic pruritic disorders.

Peripheral Itch Pathways

Peripheral mediators of itch

Itch is largely mediated by a subset of unmyelinated C fibers which are among the smallest in diameter and slowest in terms of transmitting action potentials. Classically, itch was divided into two categories: histamine-mediated (histaminergic) and non-histamine-mediated (nonhistaminergic). Histaminergic itch results from the direct action of the pruritogen histamine on its receptor (H1R) on sensory nerves to transmit itch signals. However, it is now well appreciated that most itch pathways function independently of histaminergic pathways (Figure 1). For example, the discovery of the Mas-related G protein-coupled receptor (Mrgpr) family of G protein-coupled receptors (GPCRs) demonstrated that deletion of these receptors have no effect on the ability of histamine to evoke itch.^11,12 Similarly, it is well-established that gastrin-releasing peptide receptor (GRPR) represents a critical histamine-independent itch circuit within the spinal cord.¹³ Finally, a number of cytokines that promote itch including IL-4, IL-13, and IL-31 are well-established to operate independently of the histamine pathways.^14–17 Although, the receptor for histamine (HR1) is co-expressed with other pruritogen receptors on pruriceptors, its utility as an itch therapeutic target is limited to certain inflammatory itch conditions such as urticaria.

Figure 1.

Two modes of itch sensation: peripheral itch transmission may be mediated by histamine-dependent or histamine-independent mechanisms.

Peripheral itch-sensing neural circuits

Unbiased single cell RNA-sequencing (scRNA-seq) studies of dorsal root ganglia (DRG) in mice have revealed that there are at least three subsets of pruriceptors expressing dedicated pruritogen receptors.^18,19 These neurons are generally subdivided into NP1, NP2, and NP3 neurons based on their expression patterns. Cation channels TRPV1 and/or TRPA1 and Na_V1.7 and Na_V1.8, respectively, are required for downstream signaling of the itch receptors and are consistently expressed across subsets of these neurons.^15,20 Additionally, a variety of type 2 inflammation-associated cytokines including IL-4, IL-13, IL-31, IL-33, and TSLP have been implicated in promoting itch at the neuronal level, and some of these cytokines signal through downstream Janus kinase 1 (JAK1).²¹ Multiple itch-selective GPCRs (Hrh1, Cysltr2, Mrgprs), cytokine receptors (Il4r, Il31ra, Osmr), and neuropeptides (Nppb) converge upon the NP3 neuron.^22,23 In orthologous fashion, recent scRNA-seq studies in human DRG neurons have established the existence of pruriceptor populations that also express many of these same pruritogen receptors.²³ Indeed, blocking pruritogens from signaling on sensory neurons is now an important therapeutic strategy across multiple chronic itch conditions including AD, PN, and chronic spontaneous urticaria (CSU).²⁴

Aside from inflammatory mediators, it has long been appreciated that mu opioids (e.g., morphine) can trigger pruritus. Although, it is well-appreciated that mu opioids trigger itch, in part, within the central nervous system (CNS), scRNA-seq studies in both mice and humans demonstrate that mu opioid receptor (MOR) is abundantly expressed on pruriceptors.^25,26 Indeed, recent studies have demonstrated that mu opioids trigger itch by acting directly on TRPV1-expressing sensory neurons.²⁵ Thus, there appears to be a role for mu opioids acting as direct pruritogens (Figure 2). Collectively, recent advances in peripheral itch neurocircuitry have unveiled a broad array of nonhistaminergic pathways within the skin that can trigger various forms of itch.

Figure 2.

Schematic of peripheral itch-sensing neural circuits

Endogenous itch-suppressive pathways

Notwithstanding our increasing understanding of a highly sophisticated pruriceptive nervous system, it is important to note that there are endogenous pathways that serve to suppress itch both in the periphery as well as the CNS. It is well-known that mechanical stimuli (e.g., scratching) and pain serve to suppress itch. This is likely due, in part, to inhibitory pathways being triggered within the spinal cord. Additionally, endogenous kappa opioids, distinct from mu opioids, have been shown to suppress itch by their ability to act on sensory neurons, the spinal cord, and the brain.^26,27 Indeed, it is widely believed that activation of kappa opioid receptor (KOR) counterbalances the pruritogenic effect of MOR activation.¹⁸ However, the precise mechanisms by which KOR activation in the periphery suppresses itch remains unclear. Datasets of scRNA-seq on murine DRG neurons suggest that KOR is predominantly expressed on mechanosensory neurons (mechanoreceptors), rather than pruriceptors.²⁸ Thus, one possibility is that activation of KOR, rather than directly suppressing pruriceptor function, activates mechanoreceptors such that itch signals from pruriceptors are inhibited in the spinal cord (Figure 2). Indeed, multiple therapies for treating itch involve MOR antagonism and/or KOR agonism and include agents such as butophanol, nalbuphine, and nalfurafine (mixed KOR agonist/mu antagonist); difelikefalin (kappa agonist); naltrexone and naloxone (mu antagonist).²⁹

The neuro-immune itch circuit

Given the discovery of a variety of immune cell-derived factors in activating the itch-sensory circuit, a major area of inquiry is understanding precise immune cell-neuron synapses. For example, it is well-appreciated that mast cells trigger both histaminergic itch and nonhistaminergic itch via leukotriene C4 (LTC4), while T cells promote itch via IL-31.^14,15 More recently, we uncovered that activated basophils can also employ LTC4 to elicit acute itch flares in the setting of AD.³⁰ Thus, understanding the precise identity and function of immune cells in relation to pruriceptors may inform which molecular triggers of itch are relevant across various disease contexts.

However, beyond being a mere conduit for itch, sensory neurons also have the capacity to promote inflammation through the release of various neuropeptides including calcitonin gene-related peptide (CGRP) and substance P.^31–33 The ability of sensory neurons to activate inflammation via the release of such neuropeptides is referred to as neurogenic inflammation or neuroinflammation.³⁴ Indeed, in recent years, the concept of neuroinflammation has only become increasingly solidified through the discovery of MRGPRX2 as the primary receptor for substance P on mast cells.³⁵ Thus, it is well-established now that there is a clear neuron-substance P-mast cell circuit to induce inflammation and itch (Figure 3). Importantly, this process does not require IgE crosslinking and hypothetically can be triggered by protease allergens directly stimulating sensory neurons such as house dust mite (HDM) antigen. These major conceptual advances are redefining how we view the pathophysiology of a variety of inflammatory and pruritic disorders.

Figure 3.

Neuropathic vs. neurogenic itch pathways mediate pruritus through distinct neuro-immune circuits

Neuropathic versus neurogenic itch

As neurogenic and neuropathic itch are the most commonly confused terminologies of itch, we aim clarify this terminology. Herein, we discuss neuropathic and neurogenic itch definitions, respectively, and highlight the best-known itch conditions that exemplify these distinct processes.

Neuropathic itch

Neuropathic itch refers to a group of disorders characterized by chronic itching caused by dysfunction or damage to pruriceptors. In these conditions, itch sensation is not triggered by external stimuli, such as irritants or allergens, but rather arises spontaneously. Neuropathic itch can occur due to nerve damage that may be caused by mechanical, metabolic, inflammatory, or cytopathic injury.³⁶ As a result, it is often companied by overall neural hypersensitivity that can manifest as alloknesis in response to innocuous mechanical stimuli.³⁷ The key defining features of neuropathic itch are that it occurs spontaneously and transmits signals toward the brain exclusively, can display neural hypersensitivity, and does not require an inflammatory or other stimulus (Figure 3). Another possible mechanism underlying neuropathic itch is damage to mechanoreceptors in the periphery that serve to suppress itch signal via pruriceptors (Figure 2). In this context, pruriceptive C fibers may fire spontaneously uninhibited by mechanoreceptors.

Itch neural hypersensitivity is exhibited in the following common neuropathic itch conditions. BRP is characterized by itching on the arms bilaterally. It is often associated with compression or irritation of the nerves of the cervical spine.³⁸ NP is a common chronic itch condition characterized by localized itching or burning sensation in the subscapular region. It is thought to be caused by thoracic nerve damage or irritation in the affected area.³⁹ Postherpetic pruritus is a complication of herpes zoster (shingles). After nerve viral reactivation has resolved, some individuals may experience persistent itching in the affected area due to nerve damage caused by viral cytopathic changes.⁴⁰ Finally, scalp pruritus is neuropathic when it occurs independently of any observable rash (e.g., seborrheic dermatitis). It is believed that the occipital nerves from the cervical spine are damaged to result in scalp pruritus.⁴¹ In general, for neuropathic itch conditions, neuromodulatory agents are the mainstay rather than anti-inflammatory agents such topical capsaicin, oral gabapentin or pregabalin, or the opioid modulators (see above).

Neurogenic itch

In contrast to neuropathic itch, the term neurogenic is a more general term that encompasses a pathologic process arising from the nerve. In other words, tumors of the nerve or pathologies that have nothing to do with sensation or afferent transmission can still be referred to as neurogenic. However, it is well understood now that sensory nerves can promote neuroinflammation, namely inflammation in tissues via the efferent release of neuropeptides (Figure 3).³⁵ Thus, there are two ways in which sensory neurons can be the source of itch. The first is neuropathic itch, where neuropathology directly promotes excessive afferent itch transmission towards the CNS. The second, is a neuroinflammatory process whereby sensory neurons activate an immune cell (or other cell) intermediate to trigger the itch. The latter is an indirect itch process. The clearest example of this is the release of substance P by sensory neurons, its binding to MRGPRX2 on mast cells, and the release of a variety of pruritogenic factors like histamine and LTC4 by mast cells (Figure 3).³⁵

The best example of a neurogenic itch process would be chronic inducible urticaria (CIndU). This is a condition in which numerous neurologic triggers including thermal (heat, cold), mechanical (friction, pressure, vibration), and autonomic (acetylcholine) stimuli promote the formation of hives and associated itch. Thus, CIndU is likely the clearest example of neurogenic itch, whereby in the absence of any clinically defined neuropathic itch, itch can still be initiated by the nervous system, presumably through the activation of intermediate mast cells.^42,43 Additionally, it is widely believed that PN also has underlying neurogenic itch processes that trigger the formation of nodules. To what extent such neurogenic processes underlie other pruritic disorders is an active area of investigation.

Integrating inflammatory, neuropathic, and neurogenic processes

Although we clinically define conditions based on their predominant etiology, in reality, there are likely multiple processes underlying different conditions. For example, while AD is largely inflammatory in nature, resulting in secondary itch, there may be neuropathic or neurogenic processes also at play. Thus, although potent anti-inflammatory agents are capable of controlling AD-associated itch, there is likely benefit to having additional neuromodulatory mechanisms of action as evidenced by the effective agents that target neuronal cytokine receptors (dupilumab, lebrkizumab, nemolizumab, tralokinumab) and JAK1-targeting agents (abrocitinib, baricitinib, upadacitinib, ruxolitinib).^44–51 Even blocking physiological levels of IL-4 and IL-13 may be effective in alleviating itch due to the fact that these cytokines are known to promote neural hypersensitivity to a variety of pruritogens.¹⁶ Indeed, this may be why agents like dupilumab demonstrate broad efficacy across a number of conditions with variable elevations in IL-4 and/or IL-13 including PN and CPUO.^52,53 These clinical trials have significantly accelerated interest in neuromodulation even within inflammatory itch conditions.

Neuromodulatory agents such as difelikefalin which stimulate the KOR pathway, although clearly efficacious in neuropathic itch conditions such as NP, have also exhibited efficacy in AD.^27,54 Lastly, conditions such CIndU, due to their dependence on mast cells within the neuroimmune circuit, despite being neurogenic can benefit tremendously from mast cell-targeted immunomodulatory therapies as evidenced by recent clinical trials with c-Kit antagonists.⁵⁵ Collectively, these clinical advances coupled to new understanding of neuroimmune biology underscore the importance of understanding processes and circuits within diseases rather than mere classification.

Chronic pruritus of unknown origin (CPUO) is an example of a disease that is difficult to classify within one category. These patients are generally elderly, have widespread pruritus, and typically lack a rash.⁵⁶ It has been reported that these patients exhibit immune dysregulation possibly secondary to immunosenescence.⁵⁷ On the one hand, it is widely believed that there is also generalized neuropathic itch processes underlying these patients as well.⁵⁸ Indeed, dupilumab is now in phase 3 clinical trials for CPUO based on the rationale that blockade of IL-4Rα may limit multiple inflammatory and neural itch pathways.^52,59

PN may be the clearest example of a disease that is uniquely challenging to classify within one simple category. Although its origin is thought to be rooted in pruritus in the absence of a rash (i.e., neuropathic process), mechanical trauma from scratching results in inflamed, hyperkeratotic papulonodules (i.e., inflammatory process).¹ Further, the fact that so many other pruritic conditions do not result in such dramatic lesions induced by mechanical stimulation, there is a strong suggestion that there may be a neurogenic process at play that makes PN skin uniquely susceptible to the formation of papulonodules.⁶⁰ Indeed, it is likely that the efficacy of agents such as dupilumab and nemolizumab for PN derive from their ability to modulate multiple processes simultaneously.^53,61,62 Thus, understanding the various processes underlying such conditions, rather than focusing on classification of the disease itself is likely much more informative in guiding both the development and application of various therapies (Table 1).

Table 1.

Anti-itch therapies

Target	Medication	Disease	Stage
IL-4R	dupilumab	AD, PN	approved
		CSU, CICU, CIndU CPUO	phase 3
IL-13	lebrikizumab	AD	phase 3
	tralokinumab	AD	approved
IL-31RA	nemolizumab	AD, PN	phase 3
JAK	abrocitinib	AD	approved
		PN, CPUO	phase 2
	baricitinib	AD	pending approval
	ruxolitinib	AD	approved
		PN	phase 3
	upadacitinib	AD	approved
OPRK1	difelikefalin	AD	phase 3
		NP	phase 2
c-Kit	barzolvolimab	CSU, CIndU	phase 2
		PN	phase 1
Siglec-8	lirentelimab	CSU	phase 2
IgE	omalizumab	CSU, AD	approved (CSU)

Conclusion

Terms like neuropathic, neurogenic, and neuroinflammatory have been used for decades to describe different clinical entities ranging from pain and itch to tumors and autoimmune (e.g., multiple sclerosis) conditions within the CNS. However, major advances in basic sensory biology and peripheral neuroimmunology, coupled to therapeutic innovations, necessitate clarifying such terminology to align more clearly with current concepts in itch biology. Key discoveries, including the importance of neuropeptides from sensory neurons, canonical neuropeptide receptors on immune cells like mast cells, and therapeutics that disrupt neuroimmune axes have clearly established that understanding mechanistic processes embolden the development of new treatments for neuropathic and neurogenic itch disorders and beyond.

Key Messages:

• New understanding of molecular and cellular itch pathways have advanced new concepts in neuroimmune itch biology.

• Terminologies such as “neuropathic” and “neurogenic” itch require clarification that aligns with new biological discoveries such as the role of neuropeptides and novel GPCRs on mast cells.

• Understanding processes based on basic science will inform drug development and therapeutic rationale better than traditional clinical classifications.

• Simultaneously targeting neural and inflammatory processes may offer the most effective clinical outcomes in managing chronic pruritic disorders.

Abbreviations/Acronyms:

AD

atopic dermatitis

BRP

brachioradial pruritus

NP

notalgia paresthetica

PN

prurigo nodularis

Mrgpr

mas-related G protein-coupled receptor

GRPR

gastrin-releasing peptide receptor

GPCR

G protein-coupled receptor

CNS

centra nervous system

MOR

mu opioid receptor

KOR

kappa opioid receptor

DRG

dorsal root ganglia

LTC4

leukotriene C4

HDM

human dust mite

CSU

chronic spontaneous urticarial

CIndU

chronic inducible urticarial

CPUO

chronic pruritus of unknown origin

BAM (8–22)

bovine adrenal medulla 8–22