Molecular and cellular mechanisms of itch sensation and the anti-itch drug targets

Abstract

Itch is an uncomfortable feeling that evokes a desire to scratch. This protective reflex can effectively eliminate parasites that invade the skin. When itchy skin becomes severe or lasts for more than six weeks, it has deleterious effects on both quality of life and productivity. Despite decades of research, the complete molecular and cellular coding of chronic itch remains elusive. This persistent condition often defies treatment, including with antihistamines, and poses a significant societal challenge. Obtaining pathophysiological insights into the generation of chronic itch is essential for understanding its mechanisms and the development of innovative anti-itch medications. In this review we provide a systematic overview of the recent advancement in itch research, alongside the progress made in drug discovery within this field. We have examined the diversity and complexity of the classification and mechanisms underlying the complex sensation of itch. We have also delved into recent advancements in the field of itch mechanism research and how these findings hold potential for the development of new itch treatment medications. But the treatment of clinical itch symptoms still faces significant challenges. Future research needs to continue to delve deeper, not only to discover more itch-related pathways but also to explore how to improve treatment efficacy through multitarget or combination therapy.

Introduction

Pruritus (itchy skin) is a debilitating sensation that makes you keep scratching. Although previous elegant studies revealed distinct signalling pathways involved in the development of both acute and chronic itch, druggable targets can be counted on one’s fingers. Moreover, while histamine and histamine receptors are critically involved in acute allergic itch, antihistamines are ineffective in various chronic itch disorders. Thus, establishing a comprehensive understanding of the pathogenesis of chronic itching and identifying potential drug targets are crucial for drug screening and treating this somatosensory disorder.

With over 7 million outpatient visits annually in the United States, itch is among the 50 most common diseases [1]. The occurrence of itching is notably heightened among elderly people, mainly due to age-related declines in sebum function, which lead to atrophy, dryness, and desquamation [2]. Specifically, pruritus affects approximately 64%–89% of patients with psoriasis [3], while it is reported to have a 100% incidence rate in patients with atopic dermatitis (AD) and urticaria [4, 5]. Chronic pruritus is often accompanied by many other systemic conditions. For example, approximately 20%-27.5% of diabetic patients experience chronic pruritus [6], and more than 40% of patients undergoing haemodialysis suffer from itchy skin [7]. Notably, as China is a major country with a high incidence of liver disease, more than 15% of patients with specific liver disorders in China suffer from chronic itching problems [4]. In addition to disrupting one’s quality of life, itching also results in heavy economic burdens, including direct medical costs and loss of productivity. With the increasing prevalence and attention given to pruritus worldwide, the market for pruritus drugs is also showing a steady growth trend. The global itch treatment market size was estimated at $8.39 billion in 2022 and is expected to grow at a compound annual growth rate of 4.0% from 2023 to 2030. The increasing prevalence of itch-related diseases such as AD, urticaria and psoriasis will be high-impact drivers on the market. Although the market demand is significant, effective clinical treatments for chronic itching are virtually nonexistent. The main reason for this situation is the complexity of the mechanisms underlying chronic itching, coupled with a severe lag in relevant basic research.

This review aims to explore the progression of pruritus pathogenesis and discover potential drug targets. By systematically reviewing the latest research progress, we hope to provide novel insights and directions for the management of clinical pruritus.

Receptors in itch transduction

The itch sensation, as a subjective perception of abnormal human senses, depends on the sensory nervous system for signal transmission, which is initiated mainly by excitability changes in itch-specific pruriceptors. To date, G protein-coupled receptor (GPCR) and transient receptor potential (TRP) channels have been identified as the two main types of itch receptors (Fig. 1).

Fig. 1. Different receptors and ion channels involved in the pruritus process.

Under conditions of skin disease or pruritogen irritation, these receptors and ion channels are activated and play important roles in the itching process. GPCRs G protein-coupled receptors, Mrgpr MAS-related G protein-coupled receptor, BAM8-22 bovine adrenal medulla 8-22, IL-4/6/13/31/33 Interleukin-4/6/13/31/33, IL-31RA IL-31 receptor A, IL-4Rα IL-4 receptor α, IL-13Rα1 IL-13 receptor α1, IL-1RAcp IL-1 receptor accessory protein, ST2 growth stimulation expressed gene 2, PAR1/2 protease-activated receptor 1/2, TRPV1-4 transient receptor potential vanilloid 1–4, TRPC3/4 transient receptor potential canonical 3/4, TRPM8 transient receptor potential melastatin 8, ET-1 endothelin 1, TLRs Toll-like receptors, 5-HT 5-hydroxytryptamine, 5-HT_2AR/5-HT₇R 5-HT_2A receptor/5-HT₇ receptor, CXCR3 C-X-C motif chemokine receptor 3, BNP brain natriuretic peptide, TSLP thymic stromal lymphopoietin, SSRIs selective serotonin reuptake inhibitors, LPA lysophosphatidic acid, NPPB natriuretic peptide B, SST somatostatin, NPR1 natriuretic peptide receptor 1, H1R/H4R histamine H1/4 receptor, DRG dorsal root ganglion, OSMR onconstatin M receptor, Th2 T-helper 2 cell. Created with BioRender.com.

Mrgprs

In 2001, by comparing the cDNA libraries of neurogenin 1 (Ngn1)-deficient mice and normal mice, Dong et al. identified a new GPCR family that is broadly expressed in mice, rats, gerbils, red-tailed monkeys, macaques, and humans. Studies have shown that some Mrgprs are critically involved in the development of itch and pain, revealing the molecular basis for somatosensation in the periphery [8]. These findings provide a new perspective for the study of sensory biology and constitute new targets for related drug development.

MrgprA3

Malaria patients in Africa often suffer from unbearable itchiness after using chloroquine (CQ), and the scratching bouts in Mrgpr-cluster Δ^−/− mice (with 12 complete Mrgpr genes knocked out) were significantly decreased in response to CQ injection compared with those in the control group, suggesting a role of neuronal Mrgprs in itch sensation [9]. Strikingly, studies have shown that CQ can directly activate MrgprA3 and that genetic ablation of MrpgrA3-expressing neurons, which account for approximately 5%–8% of DRGs, can alleviate multiple pruritogen-induced acute itch events as well as spontaneous chronic itch in mice [9], establishing MrpgrA3 as a unique marker for itch-specific nonpeptidergic 2 (NP2) neurons.

MrgprC11/MrgprX1

hMrgprX1 and mMrgprC11 are homologous receptors that can be activated by agonists such as BAM8-22 and γ2-MSH [10, 11]. In situ hybridization experiments revealed that MrgprX1 is expressed in 8% of human DRG neurons [12] and that MrgprC11 accounts for approximately 3% of the total number of DRG neurons [13]. The endogenous peptide fragment bovine adrenal medulla (BAM) 8-22 is a potent agonist of MrgprC11 and MrgprX1 [9]. Interestingly, the activation of MrgprC11 and MrgprX1 at different locations results in different somatosensory effects in mice. For example, the subcutaneous application of pruritogens can cause itching by stimulating MrgprC11- and MrgprX1-expressing nerves innervating the skin [9], whereas the intrathecal injection of MrgprC11 agonists can induce analgesia [14, 15]. Understanding the function of MrgprC11/MrgprX1 may be important in the development of therapies targeting pain and itch disorders.

MrgprD

Like MrgprC11 and MrgprA3, MrgprD is expressed on small-diameter DRG and TG neurons [8]. MrgprD⁺ nerve fibres are nonpeptidegic, unmyelinated, mechanically sensitive C fibres that extensively innervate the skin [16]. Studies have shown that β-alanine is the natural ligand of MrgprD in humans and mice, and some people develop severe skin itching after oral administration of β-alanine [17]. Calcium imaging and electrophysiological studies have shown that β-alanine directly activates MrgprD, whereas neurons isolated from MrgprD^-/- mice have no response to β-alanine [18]. Moreover, it has been reported that the excitability of MrgprD⁺ neurons is increased in mice with AD, indicating a role of MrgprD⁺ neurons not only in the acute allergic response but also in chronic itch [19].

MrgprB2/MrgprX2

MrgprB2 and its human orthologue MrgprX2 are exclusively expressed on connective tissue mast cells and can be activated by either exogenous small-molecule drugs associated with systemic pseudoallergic or endogenous neuropeptides [20]. Functionally, SPs released by peripheral nerves can activate MrgprX2 and MrgprB2 and mediate neurogenic inflammation and pain [21]. Notably, although IgE-mediated mast cell degranulation is critically involved in histaminergic itch, Mrgprb2 activation mainly evokes the release of tryptase from mast cells, resulting in excitation of the nonhistaminergic itch pathway [22]. In addition, MrgprX2 expression was elevated in patients with AD, psoriasis, allergic contact dermatitis and chronic urticaria, whereas MrgprB2^-deficient mice presented alleviated itch symptoms and skin inflammatory infiltration in mouse models of AD and allergic contact dermatitis [21, 23]. Taken together, these data suggest that MrgprX2 may be a valuable target for the treatment of allergic pruritus.

MrgprA1/MrgprX4

Various metabolites are upregulated in the serum of patients with cholestasis and are thought to be closely associated with intense nonhistaminergic pruritus. Using Ca²⁺ imaging, researchers have found that pathophysiologically relevant levels of numerous bile acids (BAs) can directly activate MrgprX4 [24]. Interestingly, genetic ablation of MrgprA1, the homologous mouse receptor of MrgprX4, significantly reduced itch symptoms in two mouse models of pathologic hyperbilirubinemia [25]. To further assess the direct activation effect of BAs on MrgprX4, a humanized mouse model was generated, and it was shown that humanized MrgprX4 knock-in mice scratched more in both the acute BA injection model and the chronic cholestatic pruritus model, shedding new light on the role of MrgprX4 as a promising target for relieving cholestatic pruritus [26].

Other MrgPRs

In addition to those Mrgprs closely associated with itch, the roles of other members of the Mrgpr family need to be further elucidated. For example, in situ hybridization data demonstrated that MrgprX3 is expressed in small-diameter human DRG neurons [27]. Mouse MrgprA9 is found in the brain and spleen, and the rat lineal homologues of MrgprA9 are found mainly in small-diameter DRG neurons [28]. MrgprE is widely expressed in several brain regions and the enteric nervous system and is thought to be involved in the development of neuropathic pain [27, 29]. MrgprF is commonly expressed in most tissues, including smooth muscle, and can interact with angiotensin metabolites and the cysteine protease cathepsin S [30, 31]. Further research is needed to determine whether these Mrgprs are involved in somatosensation, including itch or pain sensation, in response to exogenous and endogenous stimuli.

TRP channels

TRP channels are a superfamily of cation permeable channels that are widely expressed by multiple cell types [32]. In response to various stimuli, TRP channels actively participate in the coding of pain and itch signals, making them potential therapeutic targets with considerable translational benefits.

TRPV1

Known as the capsaicin receptor, TRPV1 is widely expressed in skin and DRG sensory neurons and is involved in the sensation of pain, noxious heat and itch [32]. Various pathways of histamine-induced pruritus are ultimately generated through the activation of TRPV1; thus, TRPV1 is generally believed to be essential for histamine-dependent pruritus [33]. Moreover, TRPV1 was also found to be involved in immune dysfunction-related itch. For example, in vitro calcium imaging revealed that the percentage of IL-31-responsive neurons was significantly reduced in DRGs isolated from TRPV1-deficient mice, which was consistent with in vivo data showing that the number of scratches induced by IL-31 was significantly reduced in TRPV1 knockout mice [34]. In an AD model induced by epidermal sensitization of mice by ovalbumin (OVA), the expression of PAR2 mRNA in the skin tissue was 3.7 times greater than that in the saline treatment group [35]. In addition, itch-related behaviour can be inhibited by PAR2-neutralizing antibodies in a dose-dependent manner. Mechanistically, PAR2 is coexpressed with TRPV1 on DRG neurons and acts synergistically with TRPV1 through the protein kinase C pathway to evoke a series of neuroinflammatory processes [36]. Therefore, the TRPV1 channel has great potential as a drug target for itch relief, and several compounds targeting TRPV1 (e.g., PAC-14028 and ASN008) are currently being evaluated in clinical trials [37].

TRPV2

Expressed on medium- to large-diameter DRG and TG neurons and nonneuronal cells such as keratinocytes and mast cells, the TRPV2 channel is a temperature-sensitive TRP channel that can be activated by harmful high temperatures (above 52 °C) [38]. Moreover, it also responds to osmotic pressure and mechanical and chemical stimuli and plays an important role in maintaining physiological functions [39]. Activation of TRPV2 may lead to mast cell degranulation, which in turn releases histamine and other types of endogenous pruritus [40]. In addition, the TRPV2 gene was found to be upregulated in the skin of AD patients [41]. Although further research is needed, these data suggest that TRPV2 may also be involved in the pathogenesis of itch.

TRPV3

Like TRPV1, the TRPV3 channel is a calcium-permeable, nonselective cation channel that participates in pruritus [42]. Studies have shown that keratinocytes lacking TRPV3 display impaired PAR2 function, leading to reduced neuronal activation and scratching behaviour in response to PAR2 agonists [43, 44]. In addition, gain-of-function variants of TRPV3 genes have been found to contribute to a variety of skin disorders, such as AD and Olmsted syndrome (OS), while inhibition of TRPV3 function has also been shown to reduce atopic pruritus [45–47].

Research has established a connection between TRPV3 and AD, revealing that IL-31 prompts sensory neurons to synthesize and release BNP. Subsequently, BNP binds to the natriuretic peptide receptor (NPR1) on keratinocytes, leading to the upregulation of TRPV3 expression. This cascade ultimately increases the release of serine protein E1 and facilitates the transduction of itch signals (Fig. 1) [48, 49].

TRPV4

Studies have shown that keratinocyte expression of TRPV4 mediates acute histamine-, endothelin-1- and 5-hydroxytryptamine (5-HT)-induced pruritus [43, 50]. Although it remains controversial whether DRG neurons express functional TRPV4 channels, genetic ablation of TRPV4 from macrophages and keratinocytes reduces allergic and AEW-induced chronic pruritus in mice, respectively [51]. Consistent with the data from mouse studies, clinical studies also confirmed that skin biopsy samples from patients with chronic idiopathic pruritus presented significantly increased TRPV4 expression compared with those from healthy subjects [52], indicating that TRPV4 plays a critical role in pruritus and that selective inhibition of TRPV4 channel function may be beneficial in pruritus management.

TRPA1

Unlike TRPV1, TRPA1 primarily plays a role in nonhistamine-dependent pruritus. TRPA1 knockout mice displayed significantly reduced scratching behaviour in response to CQ and BAM 8-22, as did a mouse model of AD [53]. In addition, the increased expression of TRPA1 in the itchy skin of AD patients was highly correlated with itch intensity [41]. A mechanistic study revealed that epithelial cell-derived thymic stromal lymphopoietin (TSLP) could directly act on TRPA1-expressing DRG neurons to drive persistent itch in mice [54]. Moreover, lysophosphatidic acid (LPA) is an itch mediator found in cholestatic itch patients, whereas TRPA1 and TRPV1 are indispensable in LPA-induced scratching behaviour, suggesting that TRPA1 is closely associated with cholestatic pruritus [55]. Notably, although TRPA1 is broadly involved in many chronic itch disorders, the safety and efficacy of TRPA1 antagonists in treating chronic pruritus need to be further improved.

TRPC3/C4

TRPC3 is highly expressed in primary sensory neurons and is associated with the parasensitization induced by proinflammatory mediators. Scratching caused by intradermal injections of common nonhistaminergic pruritus-inducing agents, such as endothelin-1 and SLIGRL-NH2, was significantly reduced in TRPC3-deficient mice. Moreover, in a contact hypersensitivity (CHS) mouse model, the expression level and function of TRPC3 mRNA in the TG were increased. Pharmacological inhibition and global knockout of TRPC3 significantly mitigated spontaneous scratching behaviour without affecting concurrent skin inflammation [56].

Selective serotonin reuptake inhibitors (SSRIs) can cause different side effects in the skin, including itching. Subcutaneous injection of the SSRI drug sertraline caused a robust itch sensation, while scratching behaviour was significantly diminished by genetic ablation of TRPC4 in mice [57, 58]. Notably, SSRIs have been used in humans as effective therapies for chronic pruritus, which may be TRPC4-independent, but through potential modulation of serotonin and noradrenaline-related pruriceptive signalling in chronic itch [59].

TRPM8

Topical cooling is frequently used in itch management, and the TRPM8 channel is the primary member of the TRP channel family that specifically responds to cold stimuli, such as menthol and icilin [60]. Although current studies have shown that activation of TRPM8 can effectively inhibit acute and chronic itch [61], the underlying mechanisms remain unclear. Cool temperature directly reduces the excitability and conduction velocity of itch nerves, while activation of TRPM8 may also suppress itch signal transduction through the formation of synapses with dorsal horn inhibitory B5-I neurons [60]. More importantly, cold stimulation-mediated antipruritic effects require continuous TRPM8 activation, which needs to be considered in the design of drugs that target TRPM8.

TLRs

Activated by either pathogen-associated molecular patterns or danger-associated molecular patterns, immune cell-expressing Toll-like receptors (TLRs) are essential for both innate and adaptive immunity [62]. Moreover, TLRs expressed by other cell types (such as neurons, oligodendrocytes and Schwann cells) were found to be critically involved in the pathogenesis of noninfective diseases such as Alzheimer’s disease, stroke and diabetes. Interestingly, recent studies have demonstrated that the knockout of specific types of TLRs alleviates pain/itch-related behaviour in mice, indicating unrecognized roles of TLRs in sensory disorders.

TLR3 is expressed in a subpopulation of DRG neurons and is characterized by the expression of TRPV1. In response to TLR3-selective agonists, DRG neurons display inwards current and action potential firings, which are correlated with the robust scratching behaviour observed in WT but not TLR3-deficient mice. Although TLR7 partially overlaps with TLR3 in DRG neurons, knockout of TLR7 is effective only in nonhistaminergic itch, while TLR3 is widely involved in both histaminergic and nonhistaminergic acute itch [63]. On the other hand, TLR2/TLR3 may be involved in dry skin-associated chronic itch, whereas imiquimod-induced TLR7/TLR8 activation initiates proinflammatory signalling pathways in a psoriasis-like chronic itch model [64–66].

Well known as the LPS receptor, TLR4 is broadly expressed in the DRG, trigeminal ganglia and spinal cord glia [67]. Although the activation of spinal TLR4 clearly contributes to chronic pain hypersensitivity, TLR4-deficient mice exhibit normal itch behaviour in response to the intradermal injection of Compound 48/80 and CQ. On the other hand, significantly reduced scratching behaviour was observed in histamine-induced itch behaviour, which is dependent mainly on indirect sensitization of downstream TRPV1 activity [53]. Moreover, TLR4-dependent spinal astrocyte activation and astrogliosis are critically involved in multiple types of chronic itch.

In marked contrast to other neurons expressing TLRs, which are expressed in small-diameter neurons, in situ hybridization and immunohistochemical analysis revealed that flagellin, which recognizes TLR5, is expressed mainly on medium- to large-diameter DRGs [68]. Recent studies have shown that TLR5-expressing Aβ low-threshold mechanoreceptors (Aβ-LTMRs) not only transmit mechanical pain [68] but also participate in the process of mechanical itch through exciting spinal urocortin 3-expressing interneuron subpopulations [69]. In addition, miRNA (let-7b) can mediate pain sensation by activating TLR7 and TRPA1 in nociceptive neurons [70]. Moreover, keratinocyte-specific let-7b downregulates the expression of IL-6 and decreases the ERK1/2 signalling pathway, highlighting the negative regulatory role of let-7b in epidermal differentiation during psoriasis [71]. Taken together, these data suggest that TLRs are critical molecular sensors in pruriceptive signalling pathways. Although their roles in itch sensation remain to be further determined, targeting specific cell-expressing TLRs has strong potential in the treatment of acute and chronic itch in the future.

Piezo channels

Mechanical itch is an itch caused by light tactile stimuli on the skin, such as pressure, stroking, or vibration. Piezo proteins play important regulatory roles in the transduction of mechanical itch. Recently, researchers have demonstrated that Piezo1 is selectively expressed in itch-specific Nppb/SST-expressing neurons and that genetic ablation of Piezo1 in this population significantly reduces the mechanical itch response in mice. Moreover, gain of function studies revealed enhanced mechanical itch in mice, revealing a role for Piezo1 in itch-related sensory disorders [72]. On the other hand, the Meckel cell-expressed Piezo2 channel is crucial for the regulation of mechanical itch by activating downstream inhibitory SAI-LTMRs and plays a role in chronic itch through exciting pruriceptive MrgprA3⁺ fibres under pathological conditions [73]. Thus, targeting mechanosensitive Piezo channels may be effective in breaking the itch–scratch cycle in chronic itch.

Mediators involved in itching

Histamine

Histamine is the best-known itch mediator and is mainly released by mast cells, basophils, and occasionally keratinocytes [74]. In histamine-dependent acute itch, histamine can directly act on sensory nerves expressing H1R and/or H4R receptors and then trigger Ca²⁺ influx and neuronal excitation [75]. Although blocking histamine signalling has minimal effects in treating most chronic itch [76], histamine plays a critical role in the development of the rubella reaction, and antihistamines are among the most widely used drugs that can effectively relieve the symptoms of urticaria [77].

Neuropeptide

Neuropeptides are crucial in the initiation and transmission of itch signals from the periphery to the spinal cord. Studies have shown increased expression of BNP and receptors in the pathogenic skin of patients with AD [78, 79]. In addition, a mechanism of crosstalk between BNP and neuregulin B (NMB) in the spinal cord, in which BNP promotes itching behaviour driven by NMB through the coupling of the NPRC and NMBR receptors, has been identified [80]. Moreover, gastrin releasing peptide can specifically activate gastrin-releasing peptide receptor (GRPR), which was identified as the first itch-specific receptor in the spinal cord, to induce robust scratching behaviour in mice. GRPR-expressing neurons are key parts that transmit itch information from the periphery to the brain [81] and play an important role in the spinal cord circuit of chronic itch [82, 83].

Several other neuropeptides, including calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP), are involved in the regulation of skin inflammation through a neuroimmune crosstalk mechanism [84], indicating that a comprehensive network including immunologic pathways integrated with itch-specific circuits is involved in the development of chronic itch.

Cytokines

Cytokines are a large class of signalling molecules that are critically involved in immune responses. Recently, single-cell RNA sequencing combined with immunohistochemical staining data has shown that several cytokine receptors colocalize with specific pruriceptors, indicating potential roles of cytokines in the regulation of itch sensation [85]. For example, it has been reported that type 2 cytokines activate mouse and human DRG neurons and are essential for the development of chronic itch through the activation of neuronal IL-4Rα-Janus kinase 1 (JAK1) signalling [86, 87]. Furthermore, IL-31 transgenic mice displayed AD-like skin lesions with spontaneous scratching behaviour, and plasma IL-31 levels were found to be higher in AD patients than in healthy individuals and were particularly correlated with itching severity [88, 89]. Strikingly, the IL-31 receptor IL-31Ra is exclusively expressed in Nppb/SST-expressing pruriceptors, indicating a role for IL-31 in itch sensation via a neuroimmune communication pathway [90]. Moreover, while IL-33 potentiates acute histaminergic itch through a mast cell- and IL-13-dependent mechanism [91], it was further shown that IL-33-IL-33R signalling is required for dry skin-related, but not AD-related, chronic itch in mice [92].

Interestingly, some cytokines cannot directly evoke a calcium response in DRG neurons to drive scratching behaviour in mice, and their role in chronic itch/skin inflammation cannot be neglected. For example, oncostatin M (OSM) is a pleiotropic cytokine that can be released by various immune cells under proinflammatory conditions [93]. Although OSM does not activate sensory neurons, OSM can sensitize Nppb-positive neurons to aggravate both pruritogen-induced acute itch and chronic inflammatory itch [94]. Similarly, IL-17 may also contribute to increased neuronal sensitivity in psoriatic itch. Chronic spontaneous urticaria patients with severe pruritus have higher plasma IL-17 concentrations than healthy individuals do [95], and blocking IL-23 or IL-17 signalling with monoclonal antibodies results in a substantial reduction in psoriatic skin and chronic itch in patients. In addition, CXCR3 has been found to increase the expression of itch signalling molecules and activate sensory neurons to promote itch by inducing its ligand CXCL10 through neutrophils, while antagonizing CXCR3 can alleviate itch. These findings suggest that drugs targeting neutrophils or CXCR3 may relieve itch [96].

Taken together, specific cytokines and their respective receptors play crucial roles in the pathogenesis of chronic itch, and laboratory studies and clinical trials support the idea that targeting these signalling pathways is a promising strategy for relieving chronic itch.

TSLP

In the MC903-induced chronic itch model, thymic stromal lymphopoietin (TSLP) is significantly increased in both local ear tissue and serum, suggesting a role of TSLP in the initiation of AD-like skin inflammation [97]. Although it remains controversial whether TSLP directly excites DRG neurons, mechanistic studies have shown that TSLP can activate TRPA1-expressing pruriceptors indirectly by acting on cytokine-releasing immune cells in mice [54, 98]. Thus, AD-associated chronic itch may partially result from epithelial–immune–neuronal crosstalk in a TSLP-dependent manner.

5-Hydroxytryptamine (5-HT)

5-Hydroxytryptamine is one of the major neurotransmitters in the central nervous system and plays an important role in the pathogenesis of depression, anxiety and chronic pain [99]. Recently, 5-HT was shown to function as an essential factor in itch signalling by acting on a variety of different subtypes of its receptors. For example, glucosylsphingosine (GS), an endogenous sphingolipid, can activate 5-HT_2A and promote pruriceptive TRPV4 function via PLC‒PKC signalling [100]. Moreover, 5-HT₇ has been shown to play an important role in both acute serotonergic itch and AD-associated chronic itch through coupling with the TRPA1 channel [57]. Strikingly, although 5-HT acts downstream of TRPV4-dependent chronic itch, specific 5-HT receptors, such as 5-HT_2A, mediate SADBE-induced allergic chronic itch, whereas 5-HT₇ is essential for AEW-induced nonallergic chronic itch [100]. Taken together, these results suggest that precisely targeting different types of 5-HT receptors is essential for the personalized treatment of chronic itch in patients.

Cellular mechanisms in itch sensation

Itch in the skin

The skin is the largest organ and it serves as a physical barrier against external insults. Disruption of the epithelial barrier can lead to increased permeability and exposure of sensory nerve endings to environmental allergens and irritants, which is crucial for both the initiation and regulation of itch responses. For example, the S. aureus serine protease V8 can directly activate sensory neuron-expressing PAR1 to evoke both spontaneous itch and mechanical itch in mice [101], suggesting a potential drug target for itch treatment in bacterial infection (Fig. 1).

In addition to the typical structure consisting of the epidermis, dermis and hypodermis layers, the skin also harbours various immune cells that participate in immune responses and is densely innervated by numerous sensory afferents. This neuroimmune–cutaneous network also actively participates in the response to complicated environmental insults, including chemical, mechanical, and microbial stimuli. For example, keratinocyte-expressing TSLP primes naïve T cells towards a Th2 phenotype [102]. Th2 cytokines such as IL-4 and IL-13 not only orchestrate various aspects of the immune response but also bind to their receptors expressed by Trpv1-positive neurons to induce itch [85]. Additionally, the release of histamine from mast cells, which are recruited and activated by IL-4 and IL-13, can also induce itch through the activation of histamine receptors on sensory neurons. In addition to classic IgE-FcεRI signalling-dependent mast cell activation-mediated histaminergic itch, mast cell-expressing MrgprB2 can also promote the release of tryptase to excite distinct populations of sensory neurons and evoke histamine-independent itch [23]. Moreover, recent studies have revealed that multiple types of immune cells, including basophils, dendritic cells and eosinophils, are critically involved in allergic reactions and can contribute to itch sensations through their interactions with other immune cells and the release of itch-inducing mediators [103]. Taken together, the interplay between neuroimmune interactions and epithelial cells plays a significant role in the pathogenesis of chronic itch. Understanding these interactions is crucial for developing effective treatments for chronic itch associated with skin disorders such as allergic reactions, inflammatory skin diseases, and neuropathic pruritus.

Itch in the spinal cord

Itch sensation involves a complex interplay of excitatory and inhibitory circuits within the spinal cord. While the precise mechanisms are still being elucidated, several key components involved in the transmission and modulation of itch signals have been identified. For example, GRP-expressing neurons in the spinal cord receive itch signals from peripheral sensory neurons and release GRP to bind to GRPR on postsynaptic neurons, leading to the generation and propagation of itch signals [104, 105]. On the other hand, peripheral nociceptive inputs may activate Bhlhb5 interneurons to inhibit GRP⁺-GRPR⁺ signalling to reduce chemical itch, whereas somatostatin may bind Sst2a to inhibit inhibitory dynorphin neurons, which results in a robust itch sensation through the disinhibition of GRPR neurons [78, 106].

Similar spinal circuit mechanisms were also observed in the modulation of mechanical itch. Inputs from cutaneous low-threshold mechanoreceptors (LTMRs) activate downstream excitatory Ucn3 INs and/or NPY1R INs to induce mechanical itch, whereas the activation of inhibitory NPY INs inhibits mechanical itching [69, 107]. Notably, spinoparabrachial Calcrl^Lbx1 projection neurons are required for mechanical itch transmission, whereas chemical itch is partially transmitted through Tac1^Lbx1 neurons [108, 109], supporting a labelled line theory for the transmission circuitry in different types of itch.

Itch in the brain

Although it is processed primarily within the spinal cord and peripheral nervous system, a complex interplay of neural circuits within the brain is also involved in itch perception. Recently, the brain regions related to pruritus have been extensively studied, including the primary somatosensory cortex (SI), thalamus, parabrachial nucleus (PBN), central amygdala (CeA), midbrain periaqueductal grey matter (PAG) and ventral tegmental area (VTA).

The parabrachial nucleus (PBN) is a critical brain region involved in the processing of itch sensations [110]. Neurons in the PBN are strongly activated in response to histamine and CQ, while conditionally knocking out the glutamate transporter in these neurons significantly reduces itch-related behaviours, further supporting its role in itch perception [84]. Interestingly, the PBN is also implicated in other sensory modalities, including pain and temperature sensation, highlighting its importance as a central hub for integrating and processing sensory information [111, 112]. The amygdala receives input from various brain regions and is associated primarily with emotional processing. Although the role of the amygdala in itch sensation is not as well understood as its involvement in other sensory perceptions, such as fear, anxiety and pleasure, the inputs from different sensory pathways provide a potential pathway through which the amygdala could influence itch sensation. For example, histamine can increase activity in projection areas to the amygdala, whereas optogenetic activation of these neurons in the amygdala contributes to scratching and anxiety-like behaviour in mice [113]. Moreover, the ventral tegmental area (VTA) is known primarily for its role in reward processing and motivation, particularly in the context of addictive behaviours. It has been shown that VTA GABA neurons are involved in itch-associated aversion, whereas VTA DA neurons are associated with scratching-induced reward [114]. Moreover, the brain can influence itch processing in the spinal cord through descending pathways, as elucidated by data showing that lateral and ventrolateral periaqueductal grey Tac1⁺ neurons modulate spinal itch processing via a rostral ventromedial medulla-dependent pathway [114].

Overall, itch perception is thought to involve a distributed network of brain regions that process sensory, emotional, and cognitive aspects of itch sensation. Further research is needed to elucidate the specific contributions of brain circuits to itch processing to develop targeted therapies.

Marketed drug targets

Although significant progress has been made in understanding the signalling mechanisms of itch perception over the past few decades and several potential therapeutic targets and signalling pathways for treating chronic itch have been identified, the complexity of multisystem interactions and the diversity of pathogenic mechanisms involved in chronic itch have led to a lack of effective treatment strategies. For example, the effectiveness of antihistamine drugs in treating chronic itch is not significant, highlighting the considerable deficiency in clinical approaches to effectively manage chronic itch.

H1/H4 receptor antagonists

Widely utilized for the management of histamine-mediated pruritus, antihistamines have been found to play a significant role in therapeutic regimens. The mechanism by which antihistamines are applied in the treatment of itch primarily involves the blockade of histamine receptors, which inhibits the propagation of itch signals along sensory nerves to the central nervous system. Commercially available antihistamines are specifically crafted to function as H1 receptor antagonists, obstructing the attachment of histamine and the ensuing signal transmission, which in turn reduces or eliminates the sensation of itch. In particular, second-generation H1 antihistamines (Table 1) are recommended as the medication of choice for the first-line treatment of chronic urticaria because of their commendable safety profiles and proven clinical efficacy [115].

Table 1.

Overview of marketed medications targeting receptors related to itch and their modes of action.

Target	Medication	Mode	Disease	References
H1R	Cetirizine,Desloratadine, Doxepin…	Antagonist	Urticaria	[115, 117]
H4R	JNJ-39758979 ZPL-3893787	Antagonist	Atopic dermatitis	[120, 121]
MOR	Naloxone	Antagonist	Chronic pruritus	[124]
KOR	Nalfurafine Difelikefalin	Agonist	Uremic pruritus	[122, 125]
Calcium channel	Gabapentin, Pregabalin	Blocker	Neuropathic pruritus Uremic pruritus	[127–129]
Calcium phosphatase	Tacrolimus,Cyclosporine	Inhibitor	Atopic dermatitis	[130]
PDE4	Crisaborole, OPA-15406	Inhibitor	Atopic dermatitis Psoriasis	[137, 138]
JAK	Delgocitinib,Ruxolitinib,Baricitinib Tofacitinib,Upadacitinib, Filgotinib,Ivarmacitinib, Brepocitinib, Deucravacitinib, Jaktinib,ATI-1777,CEE321, NDI-034858,QL-12001869	Inhibitor	Atopic dermatitis Chronic eczema Lupus erythematosus Psoriasis Vitiligo	[141–149]

Despite the prevalent clinical use of antihistamines for AD, robust evidence supporting the reduction in itch in AD patients receiving nonsedating antihistamines or an improvement in symptom control with sedating antihistamines is lacking [76]. While a small subset of patients with widespread pruritus are responsive to H1 receptor antagonists, there is a dearth of clinical studies with a high level of evidence for the treatment of systemic pruritic disorders [116]. Some tricyclic antidepressants have also displayed considerable efficacy as H1 receptor antagonists. Doxepin (Table 1), for example, has been employed in the treatment of itch in patients suffering from AD and chronic idiopathic urticaria. Compared with typical first- and second-generation H1 antihistamines, Doxepin has a greater affinity for the histamine H1 receptor [117].

However, although most cells involved in the inflammatory response express H1 and H2 receptors, drugs targeting these two receptors are generally ineffective in the clinic for a variety of chronic pruritic conditions. Researchers have begun to focus on the potential therapeutic effects of H4 receptor antagonists. Gene sequencing of HRH4 in patients with AD and healthy subjects revealed that three exonic polymorphisms of HRH4 are associated with AD [118], suggesting new hope for histamine receptors as therapeutic targets for pruritus. Recent reports have also indicated that stimulation of the histamine H4 receptor can increase the production of IL-9 in Th9-polarized cells, increasing their proinflammatory potency [119], suggesting the potential of H4 receptor antagonists for use in inflammatory and allergic diseases. Strikingly, a clinical trial of the H4R antagonist JNJ-39758979 (Table 1) in adult patients with moderate AD was prematurely terminated because of severe granulocytopenia in two patients in Japan, but the data initially indicated that H4R antagonists may be beneficial for AD, especially for relieving pruritic symptoms [120]. Another clinical trial revealed that the histamine H4 receptor antagonist ZPL-3893787 (Table 1), which can improve inflammatory skin lesions but does not significantly differ from the placebo in decreasing pruritus scores, is safe and well tolerated in AD patients [121].

Opioid receptor modulators

In the context of clinical therapeutics, the strategic modulation of opioid receptors has been leveraged to combat the discomfort of chronic itch. For example, the MOR antagonist naloxone (Table 1) is clinically deployed to mitigate the symptoms of chronic pruritus, whereas the KOR agonist nalfurafine (Table 1) has been adopted in the treatment of uraemic pruritus. Furthermore, the peripherally selective KOR agonist difelikefalin (Table 1) significantly reduced the intensity of pruritus associated with chronic kidney disease (CKD) in a phase 2 randomized clinical trial and improved the quality of life of haemodialysis patients with pruritus [122]. Strikingly, it was approved by the U.S. Food and Drug Administration (FDA) in 2021 with the brand name KORSUVA for the treatment of moderate to severe CKD-associated pruritus [123]. Despite these applications, the intricate mechanisms through which these modulators exert their effects remain to be fully discerned, but serious side effects, including physical and/or mental status changes, have been reported by patients.

Emerging studies have shed light on the intriguing role of mu-type opioid drugs, such as morphine and DAMGO, which appear to precipitate itch by targeting MORs on GABAergic inhibitory interneurons within the spinal cord [124]. This interaction results in the suppression of neuronal activity, consequently increasing inhibitory control over itch signalling pathways and culminating in the manifestation of pruritus. Naloxone’s therapeutic mechanism in the context of itch treatment is hypothesized to be linked to its antagonistic effects on central MORs, counteracting the pruritic signals triggered by MOR activation and thereby alleviating itch.

Moreover, research has revealed convergence between KOR and GRPR within the spinal cord [125]. The activation of KOR has been demonstrated to attenuate GRPR-mediated itch, a process that notably bypasses the need for the conventional Gαi signalling pathway. This phenomenon involves the KOR-stimulated migration of PKCδ from the cytoplasm to the cell membrane, which in turn phosphorylates and inhibits GRPR activity, a sequence that requires the participation of the PLC signalling pathway. Consequently, the antipruritic properties of KOR agonists may be attributed to the intricate KOR‒PLC‒PKCδ‒GRPR signalling network in the spinal cord.

The potential involvement of opioidergic signalling dysregulation in the pathophysiological mechanisms of AD has also been hypothesized [126]. These findings suggest that pharmaceutical agents targeting the opioidergic system might serve as effective tools for ameliorating AD-related itch. This promising avenue warrants further investigation to substantiate its therapeutic potential.

Calcium channel blockers

Calcium channel blockers, such as gabapentin and pregabalin (Table 1), are used to treat uraemic pruritus and neuropathic pruritus. The main target of gabapentin and pregabalin is the α2δ (alpha-2-delta) subunit, an auxiliary subunit of voltage-gated calcium channels (VGCCs). These calcium channels are widely distributed in the central and peripheral nervous systems and play crucial roles in regulating the release of neurotransmitters. When gabapentin or pregabalin bind to the α2δ subunit, they are able to reduce the influx of calcium ions into nerve cells, leading to a decrease in the release of neurotransmitters involved in pain and itch [127–129].

Calcineurin inhibitors

By blocking the activity of calcineurin, calcineurin inhibitors such as tacrolimus and cyclosporine (Table 1) can regulate T-cell signal transduction and reduce the production of inflammatory mediators [130]. In addition to its immunosuppressive activity, tacrolimus may also inhibit itch sensation through multiple potential mechanisms, including the inhibition of inflammatory cell infiltration and sensory nerve fibre elongation as well as direct inhibitory effects on sensory neurons to downregulate the expression of substance P and calcitonin gene-related peptides [131]. Moreover, clinical trial data demonstrated a significant reduction in total disease scores following tacrolimus administration in AD patients [132]. Similarly, clinical trials evaluating tacrolimus in the treatment of contact dermatitis have shown that 80% of patients experienced significant improvement [133]. Another calcineurin inhibitor, cyclosporine, exhibited a notable ability to improve the quality of life and pruritus scores in clinical trials related to psoriasis [134], and it also showed effectiveness in alleviating pruritus in a separate clinical trial related to chronic urticaria [135]. These clinical trials have confirmed their safety and efficacy, establishing them as potential drugs for itch treatment.

PDE4 inhibitors

Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines through the degradation of cAMP. In patients with AD, the increased activity of PDE4 in inflammatory cells leads to an increase in the production of proinflammatory cytokines and chemokines. PDE4 inhibitors can reduce the production of inflammatory mediators by increasing cAMP levels, inhibiting the activity of inflammatory cells, and possibly reducing the sensitivity of nerve fibres, thereby alleviating itching [136]. The United States Food and Drug Administration has approved 2% crisaborole (Table 1) ointment for the treatment of AD in children over 2 years old and in adults. Clinical trials have demonstrated that crisaborole ointment also exhibits good tolerability and effectiveness in the treatment of psoriasis [137]. Additionally, a new selective PDE4 inhibitor, OPA-15406 (difamilast) (Table 1), has shown safety and effectiveness in a phase II clinical trial for paediatric AD patients [138]. Other PDE4 inhibitors are still under development.

JAK inhibitors

JAK inhibitors act by blocking the cytokine-mediated JAK/STAT signalling pathway, reducing the production of inflammatory mediators such as IL-4, IL-31, IL-33, and TSLP [139, 140]. The first-generation nonselective JAK inhibitor delgocitinib (Table 1) has demonstrated excellent safety and efficacy in clinical trials and has been approved for itch relief in moderate to severe AD patients [141, 142]. The JAK1/JAK2 inhibitor ruxolitinib (Table 1) has not only shown excellent efficacy in AD [143] but also has the potential to treat skin diseases such as vitiligo and lupus erythematosus [144, 145]. Baricitinib (Table 1), a systemic JAK1/JAK2 inhibitor, has been affirmed in multiple clinical trials for its effectiveness and safety in patients with moderate to severe AD who have inadequate responses to corticosteroids [146–148]. Tofacitinib (Table 1) is widely used to treat psoriasis and psoriatic arthritis. After a network meta-analysis of JAK inhibitors used to treat plaque psoriasis, tofacitinib showed superior efficacy and safety to peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib [149]. Compared with dupilumab, upadacitinib (Table 1) provides better and more rapid itch relief with a tolerable safety profile in patients with moderate-to-severe AD [150]. Filgotinib and ivarmacitinib (Table 1) have been tested in phase II clinical trials for the treatment of AD and lupus erythematosus, but further clinical tests are needed [151, 152]. Brepocitinib (Table 1), a JAK1/TYK2 inhibitor, initially showed good efficacy and safety in phase II clinical trials for mild-to-moderate AD but did not show significant efficacy in phase II clinical trials for the treatment of psoriasis [153, 154]. Another TYK2 inhibitor, defravacitinib (BMS-986165) (Table 1), which improves biomarker indicators of the IL-23/TH17 and IFN pathways in psoriasis [155], has shown significant efficacy and safety in several phase III clinical trials for the treatment of psoriasis [156–158], as well as in phase II clinical trials for lupus erythematosus [159], where it has shown preliminary efficacy and safety. In addition, JAK inhibitors such as jaktinib (pan-JAKi) [160], ATI-1777 (JAK1/JAK3) [161], CEE321 (pan-JAKi) [162], NDI-034858 (TYK2) [163] and QL-12001869 (TYK2) [164] are still under development (Table 1).

Emerging targets and potential drugs

Bile acid metabolism pathway

BAs are integral components of digestive fluids produced by the human liver and are essential for the digestion and absorption of fats as well as the assimilation of fat-soluble vitamins within the organism. Despite their importance, bile acids can exhibit potential cytotoxicity and proinflammatory properties. It is postulated that the retention of toxic hydrophobic BAs plays a pivotal role in the manifestation of cholestatic pruritus. Consequently, the modulation of BA metabolism might serve as a therapeutic approach to mitigate the symptoms associated with cholestatic pruritus.

FXR, the nuclear receptor for BAs, acts as a key regulator in maintaining bile acid equilibrium and thus has become a core therapeutic target in the treatment of cholestatic liver diseases [165]. FXR agonists favour the excretion of BAs while simultaneously inhibiting their uptake and synthesis, effectively diminishing the levels of BAs within hepatic cells [166]. Nevertheless, the FXR agonist obeticholic acid has not been proven effective in suppressing pruritus. Instead, its administration during the treatment of liver diseases has been associated with a mild exacerbation of pruritus scores, rendering itching a common adverse effect of obeticholic acid [167].

With respect to BA metabolism, MrgprX4 (mass-related G protein-coupled receptor X4) has also been identified as a receptor for BAs that potentially contributes to cholestatic pruritus. MrgprX4⁺ humanized mice exhibit increased scratching behaviour in both acute BA injection scenarios and chronic models of cholestatic pruritus. The activation of MrgprX4 by specific agonists is known to elicit itching in human subjects, highlighting the potential of MrgprX4 as an innovative therapeutic target in the treatment of cholestatic pruritus [24, 26]. Indeed, a potent MrgprX4 agonist has been identified in the form of a purine derivative featuring a phosphoric acid substituent. The optimized analogues of this compound, which showed high efficacy and metabolic stability, may be utilized as tool compounds in mechanistic studies of the MrgprX4-mediated itch sensation [168]. Concurrent research has revealed that the interaction between MrgprX4 and RAMP2 results in reduced biological signalling, which is correlated with decreased cell surface expression of MrgprX4. RAMP1 and RAMP3, however, do not influence MrgprX4 expression or signalling, indicating a specific modulatory effect of RAMP2 on MrgprX4 [169].

NK1R antagonists

SP serves as a neuropeptide that mediates the transmission of itch signals, with NK1R being one of its target receptors. In many pruritic skin diseases, there is an overexpression of NK1R in the epidermis, along with an increased presence of nerve fibres expressing SP and inflammatory cells within the skin [41]. NK1R antagonists are able to traverse the blood‒brain barrier and selectively occupy the NK1R receptors within the central nervous system. The SP-NK1R pathway represents a potential target for the treatment of chronic pruritus associated with various diseases [170]. Aprepitant (Table 2), an NK1R antagonist, has been extensively studied for the treatment of chronic pruritus induced by various diseases, such as mycosis fungoides (MF) and Sézary syndrome, and has demonstrated significant antipruritic activity [171]. Another NK1R antagonist, tradipitant (Table 2), has also alleviated itching symptoms in patients with mild AD in clinical trials [172]. Despite its good safety and tolerability, maropitant did not show any antipruritic activity induced by epidermal growth factor receptor inhibitors (EGFRIs) compared to the placebo group [173]. Notably, SP not only binds to NK1R but also binds to Mrgprs, which also plays a role in the process of itch [174]. Therefore, a potential reason for the lack of efficacy of NK1R antagonists in clinical studies may be the alternative activation of Mrgpr signalling [171].

Table 2.

Overview of emerging medications targeting receptors related to itch and their modes of action.

Target	Medication	Mode	Disease	References
MRGPRX4	–	Antagonist	Cholestatic pruritus	–
NK1R	Aprepitant Tradipitant	Antagonist	Atopic dermatitis Mycosisfungoides Sézary syndrome	[171–173]
PAR2	PZ-235	Antagonist	Atopic dermatitis	[178]
TRPV1	Asivatrep	Antagonist	Histamine-induced itch	[181, 182]
TRPV3	Coumarin osthole Citrusinine-II Alpha-Mangostin Isochlorogenic acid Dyclonine Trpvicin	Antagonist	Atopic dermatitis Olmsted syndrome Psoriasis	[46, 183–188]
TRPV4	Crotamiton Vitexin	Antagonist	Atopic dermatitis Contact dermatitis Psoriasis	[189, 190]
TRPM8	Cryosim-1 Borneol	Agonist	Chronic pruritus Urticaria	[191–195]
CCR4	Mogamulizumab RPT193	Antagonist/Antibody	Atopic dermatitis Psoriasis Sézary syndrome	[199, 200]
OX40/OX40L	Amlitelimab Rocatinlimab GBR830 KHK4083	Antibody	Atopic dermatitis Psoriasis	[205–209]
TSLP	Tezepelumab	Antibody	Atopic dermatitis	[212]
IL-31/IL-31R	Nemolizumab	Antibody	Atopic dermatitis	[214]
IL-13/IL-13R	Lebrikizumab Tralokinumab	Antibody	Atopic dermatitis	[215, 216]
IL-4/IL-4R	Dupilumab	Antibody	Atopic dermatitis	[217]
IL-17/IL-17R	Secukinumab	Antibody	Psoriasis	[219]
IL-23/IL-23R	Guselkumab	Antibody	Psoriasis	[220]
TYK2	Deucravacitinib	Inhibitor	Psoriasis	[222]
RORγt	JNJ-61803534	Agonist	Psoriasis	[223]

PAR2-TRPV pathway

Proteinase-activated receptor-2 (PAR2) is a G protein-coupled receptor associated with itch and pain. The activation of PAR2 can regulate the activity of TRPV3 and TRPV4 through various mechanisms [175]. Activation of the PAR2-TRPV4 pathway can lead to the release of tissue protease S (Cat-S) and SP [176]. Studies have indicated that the lack of TRPV3 in keratinocytes weakens the function of PAR2, resulting in reduced neuronal activation and scratching behaviour induced by PAR2 agonists. Additionally, the upregulation of TRPV3 and PAR2 in the skin biopsies of AD patients and mice has been linked to scratching behaviour and inflammatory responses in a mouse model of AD, illustrating the role of PAR2 in mediating itch through TRPV3 signalling in keratinocytes [44]. Moreover, the overexpression of PAR2 in sensory neurons not only increases the sensitivity of animals to allergens but also contributes to the development of itch in atopic skin diseases [177]. Studies have shown that PZ-235, a PAR2-based liver-homing pepducin, inhibits the expression of inflammatory markers in keratinocytes by up to 98% and reduces the levels of IL-4 and IL-13 in mast cells by 83%. In animal models, PZ-235 slowed the development of skin lesions, reduced skin thickness and leukocyte infiltration, and improved overall skin condition. Furthermore, PZ-235 significantly alleviated itch induced by wasp venom peptide, similar to the protective effect observed in PAR2-deficient mice, indicating its effective inhibition of PAR2-related inflammatory responses [178].

Transient receptor potential (TRP) channels

The TRPV1 and TRPA1 channels are also involved in the propagation of histaminergic itch. Animal experiments indicate that TRPV1 inhibition can reduce H1R- and H4R-induced pruritus, whereas TRPA1 inhibition reduces H4R-induced pruritus only [179]. Additionally, research has shown that the core sequence of miRNA-711 can bind extracellularly and activate TRPA1, leading to TRPA1-dependent itch behaviour. Moreover, chronic pruritus in CTCL patients is associated with an imbalance in miRNA-711, suggesting the potential of miRNA-711 as a therapeutic target and disease marker in conditions such as CTCL [180]. As a TRPV1 antagonist, Asivatrep (Table 2) showed significant efficacy in improving the clinical signs and symptoms of AD, with good tolerability in a phase III clinical trial [181]. However, another TRPV1 antagonist, SB705498, did not show efficacy over placebo against histamine-induced itch in phase II clinical trials [182].

In addition to TRPV1 and TRPA1, members such as TRPV3, TRPV4, and TRPM8 are widely expressed in keratinocytes and sensory neurons and are also involved in itch sensation [43]. Several compounds derived from plants, including coumarin osthole, citrusinine-II, alpha-mangostin, and isochlorogenic acid (Table 2), have been reported to exhibit anti-itch activity through the inhibition of TRPV3 [46, 183–186]. The topical anaesthetic Dyclonine (Table 2), which is traditionally used for local itch and pain relief, was recently revealed to be a TRPV3 blocker [187]. A noteworthy study revealed that the TRPV3-selective inhibitor Trpvicin (Table 2) has significant anti-itching effects, and further clinical trials are needed [188]. For the TRPV4 channel, glucosylsphingosine was revealed to cause itching by activating the 5-HT receptor and TRPV4 in sensory neurons [100]. Crotamiton and the natural product vitexin (Table 2) alleviate itching symptoms in mouse models by inhibiting TRPV4 activity [189, 190].

TRPM8 is a temperature-sensitive receptor expressed in peripheral nerve endings. Research has shown that cooling or cold mimetics such as menthol can inhibit both histaminergic and nonhistaminergic itch pathways, as well as chronic itch, which depends on the activation of the TRPM8 channel [61]. The TRPM8 agonist Cryosim-1 gel (Table 2) has shown rapid efficacy in treating itch in clinical trials. Compared with the H1 receptor antagonist, Cryosim-1 provides relief within minutes and could be used for rapid control of urticaria-related symptoms [191]. In addition, in clinical trials for scalp itch, Cryosim-1 also displayed significant efficacy [192, 193]. In addition to Cryosim-1, borneol (Table 2) has been shown to alleviate both acute and chronic itch by inhibiting TRPA1 and activating TRPM8 [194, 195].

Recombinant chemokine C-C-motif receptor 4 (CCR4) antagonists

CCR4 is the primary chemokine receptor expressed by Th17 cells. After binding to a ligand, activated CCR4 signalling triggers a broad range of cellular activities through intracellular signalling pathways such as the MAPK and PLC pathways. Studies have suggested that CCR4 plays a significant role in the pathogenesis of many pruritic skin diseases, such as AD, psoriasis, and Sézary syndrome [196].

Research has indicated that in imiquimod-induced psoriasis, lymph nodes from wild-type mice exhibit an aggregation of memory Th17 cells expressing CCR4 and dendritic cells expressing CCL22 (a ligand of CCR4). This cell cluster is significantly reduced in CCR4-deficient mice, suggesting that CCR4 might contribute to the pathogenesis of psoriasis through the expansion of Th17 cells, as supported by in vivo and in vitro experiments [197]. Other studies have shown that CCR4 inhibitors can improve AD symptoms by inhibiting the recruitment and expansion of Th2 and Th1 cells [198].

Mogamulizumab-kpkc (Table 2), a CCR4 monoclonal antibody, has been approved by the FDA for the treatment of Sézary syndrome [199]. Moreover, a phase 1 study of the CCR4 antagonist RPT193 (Table 2) for AD treatment revealed significant improvement compared with the placebo [200]. This is the first clinical study in which a CCR4 antagonist was given orally.

OX40-OX40L antibodies

The interaction between the T-cell costimulatory molecule OX40 and its homologous ligand OX40L can accelerate the differentiation of Th1 and Th2 effector cells, making it a potential therapeutic target for various tumours and autoimmune diseases [201]. Furthermore, dysregulation of the T-cell-dependent inflammatory pathway is a key factor in the pathogenesis of AD. Analysis of blood samples from AD patients and healthy subjects has revealed a decrease in soluble OX40 levels in the serum of AD patients, accompanied by an increase in OX40 expression in activated skin-homing CD4⁺ T cells. Further research has revealed the association of the OX40 axis with both systemic and localized manifestations of AD [202]. These findings establish OX40-OX40L as a novel therapeutic target for skin diseases [203, 204]. Interestingly, clinical trials have demonstrated the efficacy of the humanized anti-OX40 monoclonal antibody GBR 830 (Table 2) in improving the skin gene characteristics and clinical scores of AD patients [205]. Additionally, the fully human anti-OX40 monoclonal antibody KHK4083 (Table 2) improved the clinical manifestations of patients with mild to severe AD, with a favourable safety profile [206]. Furthermore, the OX40L monoclonal antibodies amlitelimab and rocatinlimab (Table 2) have exhibited excellent efficacy and safety in phase II clinical trials for the treatment of AD [207, 208]. In a phase I clinical study, the OX40 monoclonal antibody KHK4083 also showed good safety and tolerability in patients with mild to moderate plaque psoriasis [209].

TSLP antibodies

TSLP is an important cytokine in skin diseases such as AD and psoriasis. Keratinocyte-releasing TSLP promotes Th2 responses and itch pathways by interacting with subpopulations of sensory neurons. Thus, TSLP-related signalling is a promising therapeutic target for improving or preventing the progression of AD [210]. Tezepelumab (Table 2) is the first human IgG2λ monoclonal antibody that inhibits the effects of TSLP by binding to the TSLP receptor, thereby blocking downstream inflammatory pathways [211]. In a phase 2a clinical trial in which tezepelumab was used to treat moderate-to-severe AD, the proportion of patients with clinical improvement was greater in the tezepelumab plus TCS group than in the placebo group, but the difference between the groups did not reach statistical significance [212]. Currently, clinical trials on TSLP antibodies are focused mainly on their role in asthma, and there is no strong clinical evidence yet showing the efficacy of TSLP antibodies in pruritic skin diseases. New drugs targeting TSLP or TSLPR are still worth investigating in the future.

Interleukin antibodies

IL-31 is a key mediator of AD that mediates Th2 cell-dependent itch by binding to the IL-31 receptor. Studies have shown that IL-31 promotes the release and synthesis of BNP in the skin and coordinates the release of itch-related cytokines and chemokines from skin cells [90]. In addition to IL-31, the IL-4 and IL-13 inflammatory pathways have also been identified as hallmarks of AD pathogenesis, cooperatively leading to immune and barrier abnormalities in AD patients as well as key symptoms such as itching [213]. According to the results of two phase III long-term studies, 60 mg nemolizumab (Table 2), a monoclonal antibody targeting the IL-31 receptor α subunit, can sustainably improve itching in patients with moderate to severe AD for up to 68 weeks [214]. Lebrikizumab (Table 2), a monoclonal antibody targeting interleukin-13, has been shown to be effective in adolescents and adults with moderate to severe AD in two phase III trials [215]. Another antibody targeting IL-13, tralokinumab (Table 2), has shown sustained improvement in AD symptoms [216]. The efficacy of the monoclonal antibody targeting the interleukin-4 receptor α dupilumab (Table 2) was compared with that of the JAK1 inhibitor abrocitinib, except for the anti-itching response at week 2, where the 200 mg dose of abrocitinib was superior to that of dupilumab, and there was no significant difference in efficacy between the two [217].

IL-23 and IL-17 are two proinflammatory cytokines associated with the pathogenesis of inflammatory diseases such as psoriasis, AD, and lupus erythematosus [218]. The inhibition of IL-17A with secukinumab (Table 2) can induce early clinical, histopathological and molecular remission of psoriasis [219]. Guselkumab (Table 2) specifically inhibits IL-23 by binding to the p19 subunit of the cytokine and has also demonstrated significantly superior efficacy to placebo in phase III clinical trials for active psoriatic arthritis [220]. Therapies targeting IL-23, IL-17 and IL-17R have been approved for clinical use in psoriasis. The IL-23 and IL-17 intracellular signal transduction inhibitors TYK2 and RORγt are also in clinical development [221]. The use of the selective TYK2 inhibitor decucravacitinib (Table 2) for the treatment of psoriasis has passed phase II clinical trials [222]. The RORγt transcriptional agonist JNJ-61803534 (Table 2) has shown acceptable safety in healthy volunteers in a phase I clinical trial, with clear evidence of its pharmacodynamic effects in humans [223].

Conclusion

In conclusion, this review has examined the diversity and complexity of the classification and mechanisms underlying the complex sensation of itch. We have also delved into recent advancements in the field of itch mechanism research and how these findings hold potential for the development of new itch treatment medications.

The significant progress in understanding the mechanisms of itch is largely attributed to the rapid development of molecular biology and the interdisciplinary field of neuroimmunology. Multiple itch-related signalling pathways and neural pathways have been identified, many of which have been confirmed to be clinically relevant. The elucidation of key molecules and their receptors in the process of itch signal transduction has not only advanced our understanding of the biological basis of itch but also provided a variety of molecular targets for the development of anti-itch drugs. However, the treatment of clinical itch symptoms still faces significant challenges. Future research needs to continue to delve deeper, not only to discover more itch-related pathways but also to explore how to improve treatment efficacy through multitarget or combination therapy.

Moreover, burgeoning technologies such as cell therapy, gene therapy, and optogenetics have paved unprecedented possibilities for the treatment of chronic itch. For example, cell therapy can alleviate itch by modulating key cells within the immune system. Adjusting the specific functions of these cells might aid in improving the understanding of the biological mechanisms of itching. Gene therapy, on the other hand, offers a revolutionary method that allows for direct modification of itch-related genes. Targeted correction of genes related to overexpressed itch receptors or dysfunction in itch signalling could effectively reduce itch sensation. Optogenetics, a technology that uses light to precisely control the activity of neurons or other cell types through the expression of light-sensitive ion channels, pumps or enzymes, specifically in target cells, offers a noninvasive strategy for controlling itch signal transduction. Therefore, enhancing the descending pain signal to suppress itch sensation is also a promising direction [224]. In addition, in recent years, microRNAs have been found to play important roles in itch regulation. Studies have revealed that miRNA-711 can bind extracellularly and activate TRPA1, inducing TRPA1-dependent itch [180]. These findings suggest the potential importance of microRNAs as biomarkers or treatments for itch in the future.

Although these techniques are all in the early stages of research, they provide a fresh perspective on itch therapy and highlight the importance of multitarget and systemic strategies for the treatment of sensory disorders. The development of these innovative technologies not only transforms our understanding of sensory disorders but also brings new hope to patients suffering from chronic itch. Through continuous scientific research and technological innovation, future strategies for treating chronic itch will become more diverse and precise.

Author contributions

MS: Writing- Original Draft. ZRC: Writing- Original Draft. HJD: Writing- Original Draft. JF: Resources, Supervision, Writing- Review & Editing.

Competing interests

The authors declare no competing interests.