Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, FranceDepartment of Dermatology and Venereology, University Hospital of Brest, Brest, France
Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, FranceDepartment of Dermatology and Venereology, University Hospital of Brest, Brest, France
Laboratoire Interactions Neurones-Keratinocytes (LINK), University of Brest, Brest, FranceDepartment of Dermatology and Venereology, University Hospital of Brest, Brest, France
Pruritus (or itch) is an unpleasant sensation leading to a desire to scratch. In the epidermis, there are selective C or Aδ epidermal nerve endings that are pruriceptors. At their other ends, peripheral neurons form synapses with spinal neurons and interneurons. Many areas in the central nervous system are involved in itch processing. Although itch does not occur solely because of parasitic, allergic, or immunologic diseases, it is usually the consequence of neuroimmune interactions. Histamine is involved in a minority of itchy conditions, and many other mediators play a role: cytokines (eg, IL-4, IL-13, IL-31, IL-33, and thymic stromal lymphopoietin), neurotransmitters (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, neuropeptide Y, NBNP, endothelin 1, and gastrin-releasing peptide), and neurotrophins (eg, nerve growth factor and brain-derived neurotrophic factor). Moreover, ion channels such as voltage-gated sodium channels, transient receptor potential vanilloid 1, transient receptor ankyrin, and transient receptor potential cation channel subfamily M (melastatin) member 8 play a crucial role. The main markers of nonhistaminergic pruriceptors are PAR-2 and MrgprX2. A notable phenomenon is the sensitization to pruritus, in which regardless of the initial cause of pruritus, there is an increased responsiveness of peripheral and central pruriceptive neurons to their normal or subthreshold afferent input in the context of chronic itch. 瘙痒（或瘙痒）是一种令人不快的感觉，会导致抓挠的欲望。在表皮中，有选择性的 C 或 Aδ 表皮神经末梢，它们是瘙痒感受器。在它们的另一端，外周神经元与脊髓神经元和中间神经元形成突触。中枢神经系统的许多区域都参与瘙痒处理。虽然瘙痒不仅仅是因为寄生虫病、过敏性疾病或免疫性疾病而发生的，但它通常是神经免疫相互作用的结果。组胺与少数瘙痒疾病有关，许多其他介质也起作用：细胞因子（如IL-4、IL-13、IL-31、IL-33和胸腺基质淋巴生成素）、神经递质（如P物质、降钙素基因相关肽、血管活性肠肽、神经肽Y、NBNP、内皮素1和胃泌素释放肽）和神经营养因子（如神经生长因子和脑源性神经营养因子）。此外，离子通道如电压门控钠通道、瞬时受体电位香草酸 1、瞬时受体锚蛋白和瞬时受体电位阳离子通道亚家族 M（美拉司他素）成员 8 起着至关重要的作用。非组胺能瘙痒感受器的主要标志物是 PAR-2 和 MrgprX2。一个值得注意的现象是对瘙痒的敏感，其中无论瘙痒的最初原因如何，在慢性瘙痒的背景下，外周和中枢瘙痒神经元对其正常或阈下传入输入的反应性增加。
Although itch is known to occur in all mammals, the age at which it first occurs remains poorly known; it is speculated to first occur during fetal life.
Itch is not related only to allergic or immune diseases. According to the classification by the International Forum for the Study of Itch, itch is classified into 4 clinical categories, without prior knowledge of the pathophysiologic mechanisms
: (1) dermatologic itch, arising from skin diseases (allergic, inflammatory, or infectious diseases and insect bites); (2) systemic itch, associated with extracutaneous diseases (from liver, kidney, blood, or other organs) or drugs; (3) neuropathic itch, which is secondary to neurologic diseases
Although the key therapeutic strategy is an etiologic treatment, a symptomatic strategy is also commonly used to ameliorate itch. To date, therapeutic options have frequently been reported as inadequate. Since the 1990s however, there have been many breakthroughs in the pathogenesis of itch, which facilitate the identification of therapeutic targets and emerging treatments.
In this review, we explore the molecular and cellular mechanisms underlying the itch sensation in the skin, peripheral nervous system (PNS), and central nervous system (CNS). We have focused on data from humans; however, in some instances we have included data from other animals (mainly mice) in the absence of human data. 在这篇综述中，我们探讨了皮肤、周围神经系统（PNS）和中枢神经系统（CNS）瘙痒感的分子和细胞机制。我们专注于来自人类的数据;然而，在某些情况下，在没有人类数据的情况下，我们纳入了来自其他动物（主要是小鼠）的数据。
Skin and nerve endings 皮肤和神经末梢
Skin nerve endings originate from sensory neurons and are classified into 3 groups: Aβ, A∂, and C. Moreover, close contacts, signifying neurokeratinocyte synaptic contacts, were recently identified, suggesting a sensory role of keratinocytes.
Aβ skin nerve endings are myelinated fibers located in the dermis and specialized in the perception of pressure, stretch, or hair movement; thus, these are mechanoreceptors. In the epidermis, the free nerve endings passing between keratinocytes' A∂ fibers and unmyelinated C fibers are thermoreceptors and nociceptors.
and express a wide variety of specific membrane receptors for several exogenous and endogenous pruritogens. Pruritogens are synthesized by keratinocytes and immune cells (mast cells, T lymphocytes, and granulocytes) or conducted to the skin by blood flow. They activate 1 of the 2 major signaling pathways of itch: the histaminergic or nonhistaminergic pathway.
Biochemical receptors involved in pruritus are of different types; they may be coupled to a G protein–coupled receptor (GPCR)—which is the main subtype—or coupled to the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway (ie, cytokine/chemokine receptors). Both transmit the pruritogenic signal downstream by the activating channels, such as transient receptor potential (TRP) vanilloid 1 (TRPV1), transient receptor ankyrin 1 (TRPA1), and voltage-gated sodium (NaV) channels. The opening of these channels induces an action potential in sensory neurons, and thus, the pruritogenic signal is transmitted first to the spinal cord and then to the brain (Fig 1). 参与瘙痒的生化受体有不同的类型;它们可能与主要亚型 G 蛋白偶联受体 （GPCR） 偶联，或与 Janus 激酶 （JAK）/信号转导和转录激活因子 （STAT） 信号通路（即细胞因子/趋化因子受体）偶联。两者都通过激活通道向下游传递瘙痒信号，例如瞬时受体电位 （TRP） 香草酸 1 （TRPV1）、瞬时受体锚蛋白 1 （TRPA1） 和电压门控钠 （NaV） 通道。这些通道的打开在感觉神经元中诱导动作电位，因此，瘙痒信号首先传递到脊髓，然后传递到大脑（图1）。
Fig 1Schematic representation of the pruritus pathway from the skin to the brain. Two types of pruriceptors are present at the cutaneous level: a histamine-dependent (histaminergic) pathway and a histamine-independent (nonhistaminergic) pathway. They are activated by exogenous or endogenous pruritogens produced by cells located in the skin. The pruritus signal is then transmitted first to the spinal cord and then to the brain to induce scratching. B, basophils; E, eosinophils; Hist., histamine; HR, histamine receptor; IDP, inhibitory descending pathway; IL-R, interleukin receptor; L, T lymphocytes; M, mastocytes; MrgprX, Mas-related G protein–coupled receptor; N, neutrophils; NK-1R, neurokinin-1 receptor; NMDA-R, N-methyl-D-aspartic acid; PAR, protease-activated receptor; PDE-4, phosphodiesterase 4. Figure adapted from “Sensing noxious stimuli: nociception copy template” by BioRender.com (2021) (available at: https://app.biorender.com/biorender-templates). 图1从皮肤到大脑的瘙痒通路示意图。皮肤水平存在两种类型的瘙痒感受器：组胺依赖性（组胺能）通路和组胺非依赖性（非组胺能）通路。它们由位于皮肤中的细胞产生的外源性或内源性瘙痒原激活。然后，瘙痒信号首先传递到脊髓，然后传递到大脑以诱发抓挠。B， 嗜碱性粒细胞;E， 嗜酸性粒细胞;Hist.，组胺;HR，组胺受体;IDP，抑制性下降通路;IL-R，白细胞介素受体;L， T淋巴细胞;M， 肥大细胞;MrgprX，Mas相关G蛋白偶联受体;N， 中性粒细胞;NK-1R，神经激肽-1受体;NMDA-R，N-甲基-D-天冬氨酸;PAR，蛋白酶活化受体;PDE-4，磷酸二酯酶4。图改编自 BioRender.com （2021） 的“感知有害刺激：伤害感受复制模板”（可在：https://app.biorender.com/biorender-templates 获得）。
It is possible to develop in vitro models to investigate the basic mechanics of itch. Previous studies have reported the development of an integrative model of a reinnervated human skin explant, which facilitated the study of all skin tissue components in the context of itch.
The culture or coculture of keratinocytes (possibly in reconstructed human epidermis) and sensory neurons cell is easier but less physiologic. The release of neuropeptides and electrophysiology may be studied in these models. 可以开发体外模型来研究瘙痒的基本机制。先前的研究已经报告了一种神经再支配的人类皮肤外植体的综合模型的开发，该模型有助于在瘙痒的背景下研究所有皮肤组织成分。
Numerous mediators and receptors are involved in itch pathophysiology. They mostly play a role in the interactions between skin and nerve endings; however, they may also operate in the CNS.
Histamine is the most studied mediator, but the histaminergic pathway is not the main mediator in chronic pruritus. Histamine is synthesized mainly by mast cells and basophils
Histamine is released from mast cell after IgE through its cell surface high-affinity receptor, FcεRI or non-IgE (eg, neuropeptides, infections, thrombin). Itch-sensory nerve fibers close to mast cells bind a variety of itch-inducing molecules or pruritogens, including histamine. In humans, 2 of the 4 known histamine receptors, histamine H1 receptor (H1R)
The activation of these receptors leads to neuropeptide release (mainly CGRP and SP) through TRPV1 activation, TRPA1 activation, membrane depolarization, and subsequent activation of an action potential by voltage-gated ion channels (including Nav channel 1.7 and Nav channel 1.8) inducing neurogenic inflammation.
Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update.
Activated mast cells and basophils release preformed mediators whose histamine is the most important. Symptoms of urticaria are well relieved by H1 antihistamines.
Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update.
In contrast, atopic dermatitis (AD) and psoriasis are associated with mast cell degranulation of histamine, but H1 antihistamines are largely ineffective against them.
Then, research efforts have been focused on H4R. However, new data are needed to confirm their ability to attenuate itch. 组胺是荨麻疹的关键介质，由于血管通透性较高，可诱发风团和耀斑反应。
Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update.
Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update.
A recent study suggested a key role of histamine in the regulation of the IL-18/IL-18R axis. Stimulation with histamine induced the upregulation of IL-18Rα and IL-18 in human eosinophils from patients with AD versus in eosinophils from healthy controls.
Many neuropeptides play an important role in pruritus signaling. Among these, SP, CGRP, neurokinin A (NKA), and vasoactive intestinal peptide (VIP) are the best known.
A member of the tachykinin family, SP works primarily through neurokinin receptors that are GPCRs: NK1, NK2, and NK3 (with a higher specificity of NK1 for SP). SP is released mainly by cutaneous sensory nerve endings but also by other cell types such as keratinocytes.
A new tool to test active ingredient using lactic acid in vitro, a help to understand cellular mechanism involved in stinging test: an example using a bacterial polysaccharide (Fucogel®).
NK1 is expressed in multiple cells involved in the initiation and transmission of pruritus, such as sensory nerve endings, keratinocytes, immune cells, endothelial cells, and fibroblasts.
Recently, MrgprX2 has been identified as an SP receptor mediating mast cell degranulation in an SP-dependent manner, with the release of histamine and tryptase.
Products of mast cell degranulation induce SP released by sensory nerve endings, thus exacerbating itch. NK1 antagonists have been shown to be effective in the inhibition of itch.
However, their moderate effects may be related to the effects of SP through other receptors. 许多神经肽在瘙痒信号传导中起着重要作用。其中，SP、CGRP、神经激肽A（NKA）和血管活性肠肽（VIP）最为著名。
A new tool to test active ingredient using lactic acid in vitro, a help to understand cellular mechanism involved in stinging test: an example using a bacterial polysaccharide (Fucogel®).
Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigen-positive T cells in patients with atopic dermatitis.
Plasma levels of CGRP were significantly lower in patients with AD than in healthy individuals regardless of disease stage (exacerbation or remission). Although patients with AD in remission with severe pruritus showed higher plasma CGRP levels than did patients with exacerbated AD, these levels remained lower than those in healthy individuals.
Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigen-positive T cells in patients with atopic dermatitis.
Brain-derived natriuretic peptide (BNP), expressed by pruriceptors, is a recently identified neuropeptide involved in pruritus. BNP levels are reported to be increased in the skin of patients with AD; its synthesis and release are upregulated by Il-31.
Expression of BNP and its receptor, NPR1, is also observed in healthy skin, where it may enhance the release of serpinE1 via the TRPV3 channel. The TRPV3/serpin E1 pathway is closely associated with AD severity.
Endothelin-1 (ET-1) is released by the spinal cord and sensory neurons, keratinocytes, and endothelial cells. ET-1 signals through ET-A and ET-B receptors. An upregulation of ET-1 expression, closely associated with IL-25 expression, has been observed in the skin of patients with AD.
suggesting a role of the IL17A/ET-1 axis in the pathogenesis of prurigo nodularis. Together, these data indicate that ET-1 plays a role in pruritus in pruritic dermatoses, suggesting that ET-1 may be a potential target in psoriasis therapy.
Endogenous opioids constitute a unique family of neuropeptides. In pruritus, endogenous opioids such as β-endorphin (βE), dynorphin A, and met-enkephalin act through specific GPCRs (μ-opioid receptor [MOR] for βE and κ-opioid receptor [KOR] for dynorphin A) present in both the PNS and CNS. These ligand-receptor pairs have contradictory effects on pruritus, with MOR-βE promoting it and dynorphin A-KOR inhibiting it. The imbalance between MOR- and KOR-binding endogenous opioids (MOR/KOR ligand ratio) in the plasma and epidermis has been suggested to potentiate itch in psoriasis, AD, and liver diseases.
Thus, these contrasting effects on itch have facilitated the development of drugs that activate KOR (nalfurafine, difelikefalin, and asimadoline), inhibit MOR (naltrexone and rifampin), or do both (nalbuphine, propofol, and diphenhydramine). 内源性阿片类药物构成了一个独特的神经肽家族。在瘙痒症患者中，内源性阿片类药物（如β-内啡肽 （βE）、强啡肽 A 和甲脑啡肽）通过存在于 PNS 和 CNS 中的特异性 GPCR（βE 的 μ-阿片受体 [MOR] 和强啡肽 A 的 κ-阿片受体 [KOR]）起作用。这些配体-受体对瘙痒有相互矛盾的作用，MOR-βE促进瘙痒，强啡肽A-KOR抑制瘙痒。血浆和表皮中 MOR 和 KOR 结合内源性阿片类药物（MOR/KOR 配体比值）之间的不平衡被认为会加剧银屑病、AD 和肝病的瘙痒。
Among the KOR agonists, difelikefalin has recently been approved to treat moderate-to-severe chronic pruritus associated with patients undergoing hemodialysis.
The efficacy and safety of nalfurafine in the treatment of refractory pruritus in patients undergoing hemodialysis has been reported in a clinical trial in Japan.
The promising antipruritic activity of KOR agonists has been confirmed in refractory pruritus in chronic liver diseases and has been associated with an improvement in sleep quality in patients with chronic liver disease.
Among combination drugs with MOR antagonists and/or KOR agonist effects, nalbuphine has resulted in noteworthy outcomes in the treatment of uremic pruritus, with a significantly lower itch severity score than placebo but only at the higher dose tested (120 mg per day).
A recent phase II/III trial in prurigo nodularis has demonstrated that twice daily oral administration of nalbuphine resulted in measurable antipruritic effects after at least 10 weeks. Improvement in itch severity by nalbuphine and its safety were confirmed during the extended open-label treatment phase.
Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.
Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.
NGF was found to be overexpressed in skin lesions (epidermis and neurons) or serum from patients with cutaneous T-cell lymphoma, prurigo nodularis, psoriasis vulgaris, AD, or dermatomyositis or patients with sine materia pruritus.
Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin -- an exploration of the cause of neurohyperplasia.
Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis.
The level of NGF was correlated with severity of itch in Sézary syndrome, AD, and psoriasis. NGF induce sensitization of itch; itch was more intense with cowhage but not with histamine bovine adrenal medulla peptide 8-22 (BAM8-22), β-alanine (β-ALA), or ET-1 after application of NGF.
Participation of NGF in itch appears mainly related to the increase in innervation in the skin. 发现NGF在皮肤T细胞淋巴瘤、结节性痒疹、寻常型银屑病、AD或皮肌炎患者的皮肤病变（表皮和神经元）或血清中过表达，或瘙痒正弦线患者。
Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin -- an exploration of the cause of neurohyperplasia.
Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis.
Differential up-regulation of neurotrophin receptors and functional activity of neurotrophins on peripheral blood eosinophils of patients with allergic rhinitis, atopic dermatitis and nonatopic subjects.
Differential up-regulation of neurotrophin receptors and functional activity of neurotrophins on peripheral blood eosinophils of patients with allergic rhinitis, atopic dermatitis and nonatopic subjects.
Differential up-regulation of neurotrophin receptors and functional activity of neurotrophins on peripheral blood eosinophils of patients with allergic rhinitis, atopic dermatitis and nonatopic subjects.
Differential up-regulation of neurotrophin receptors and functional activity of neurotrophins on peripheral blood eosinophils of patients with allergic rhinitis, atopic dermatitis and nonatopic subjects.
The receptor system and downstream signaling pathway for IL-13/IL-4 differ between hematopoietic and nonhematopoietic peripheral cells. Keratinocytes express 2 receptors, called IL-4Rα/IL-13Rα1 and IL-13Rα2; the former transduces a functional IL-13 signal, whereas the latter acts as a nonfunctional decoy receptor.
The serum levels of IL-4 and IL-13 were higher in the patients with AD than in the controls but were not correlated with itch severity. In patients with psoriasis, the levels of IL-4 were higher than those in the controls, whereas the levels of IL-13 were lower than those in the controls.
suggesting that these cytokines are associated with disruption of the epidermal barrier. Furthermore, the IL-4/IL-13 axis upregulates production of thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 in keratinocytes. All of these mechanisms contribute to the vicious circle of neurogenic inflammation. However, transcriptomic studies suggest that in AD, IL-13 gene expression levels showed higher correlations with the intensity of skin inflammation than did IL-4 gene expression levels.
IL-13 promotes inflammation in AD via the IL-4Rα/IL-13Rα1 axis but simultaneously triggers a negative feedback signal via the decoy receptor (IL-13Rα2), which downregulates extracellular IL-13.
Many biologic therapeutic methods targeting these cytokines are currently being developed and assessed in various clinical trials. The proposed treatments either inhibit the specific interaction of the cytokines and their receptors (eg, dupilumab, tralokinumab, lebrikizumab) or inhibit the intracellular pathways activated by the IL-4/IL-13 receptors with JAK inhibitors (eg, tofacitinib, baricitinib, delgocitinib, upadacitinib, ruxolitinib).
Its heterodimeric receptor—IL-31 receptor A (IL31RA)/oncostatin M receptor (OSMRβ)—is expressed by keratinocytes, innate immune cells, eosinophils, T cells, and cutaneous nerve endings that coexpress TRPV1.
Regulation of Skin Barrier Function via Competition between AHR axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis.
IL-31 acts as a pruritogen, and when it is applied intradermally, it does not induce an immediate itch response; rather, it induces a delayed itch response.
Nuclear IL-33 plays an important role in IL-31‒mediated downregulation of FLG, keratin 1, and keratin 10 by regulating signal transducer and activator of transcription 3 activation in human keratinocytes.
Regulation of Skin Barrier Function via Competition between AHR axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis.
Nuclear IL-33 plays an important role in IL-31‒mediated downregulation of FLG, keratin 1, and keratin 10 by regulating signal transducer and activator of transcription 3 activation in human keratinocytes.
The role of IL-31 in other itchy dermatoses has also been investigated. Higher plasma levels of IL-31 have been reported in chronic spontaneous urticaria,
In considertion of the multiple roles of IL-31 in pruritic and autoimmune chronic inflammatory pathologies, efforts have been focused on the development of drugs targeting the IL-31/IL-31R axis. Recently, nemolizumab, a humanized mAb against IL-31RA, has been assessed in several clinical trials.
Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study.
A study of the use of nemolizumab in prurigo nodularis showed that inhibition of the receptor of IL-31 decreased pruritus and the symptoms of prurigo nodularis after 12 weeks of treatment.
Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study.
IL-33, a cytokine of the IL-1 family, is considered a dual-function protein acting both as a cytokine and a nuclear factor. On the one hand, IL-33 binds the ST2 receptor expressed on TH2 cell surface, which regulates the production of cytokines such as IL-17A and IL-31, and induces mast cell degranulation.
IL-33 is constitutively expressed in healthy skin and released by epithelial cells to initiate and amplify the TH2 cell response in the skin of patients with AD.
On the other hand, IL-33 acts as transcriptional regulator of nuclear factor κB (NF-κB) p65 in the nucleus of endothelial cells to participate in inflammatory reactions.
This form stored in the nucleus is considered an epithelial alarmin. However, the role of intracellular IL-33 has not been characterized completely, and its role in the pathophysiology of AD remains unclear. IL-33 downregulates the expression of filaggrin,
keratin 1, and keratin 1092 triggering skin barrier dysfunction, thus contributing to neurogenic inflammation. IL-33 levels are increased in the skin and plasma of patients with AD
Nuclear IL-33 plays an important role in IL-31‒mediated downregulation of FLG, keratin 1, and keratin 10 by regulating signal transducer and activator of transcription 3 activation in human keratinocytes.
Nuclear IL-33 plays an important role in IL-31‒mediated downregulation of FLG, keratin 1, and keratin 10 by regulating signal transducer and activator of transcription 3 activation in human keratinocytes.
TSLP is not expressed in healthy skin but is highly expressed in the lesional skin of patients with AD (in keratinocytes, epithelial cells, dendritic cells, mast cells, and fibroblasts).
TSLP signals through a heterodimeric receptor (TSLP receptor [TSLPR] and IL-7 receptor α-chain [IL-7Rα]) associated with the intracellular JAK/STAT pathway. The activation of JAK1 (via IL-7Rα), JAK2, STAT5A, and STAT5B promotes the transcription of target genes of proinflammatory cytokines such as IL-4, IL-5, and IL-13. Stimulation of the H4R upregulated TSLP in human keratinocytes,
It was found to be overexpressed in acute and chronic lesional skin of patients with AD, particularly in the apical layer of the epidermis, but not expressed in the nonlesional skin of the same patients
TSLP released by differentiated keratinocytes induces pruritus by activating cutaneous sensory neurons and inflammation by activating dendritic cells and their migration.
Moreover, in AD, TSLP increases nuclear expression of IL-33 in human keratinocytes by activating the MAPK pathway, originally called the extracellular signal–regulated kinase/c-Jun N-terminal kinase (ERK/JNK) pathway,
thus impairing barrier integrity. Tezepelumab, a human immunoglobulin G2 mAb, is currently being investigated in several clinical trials; its effectiveness as monotherapy in the treatment of AD remains to be confirmed. TSLP has been studied extensively not only in AD but also in psoriasis, chronic spontaneous urticaria,
TRPV1, previously known as the capsaicin receptor, is expressed on sensory C and A∂ fibers and is activated by several stimuli such as noxious heat (>42°C), low pH (<5.9), or capsaicin. TRPV1 is ubiquitously expressed in the skin, including in dermal mast cells, dendritic cells, sebocytes, dermal blood vessels, hair follicles, sweat glands, and keratinocytes, and it contributes to epidermal barrier homeostasis.
Histamine receptor activation leads to activation of TRP channels, particularly TRPV1, and thus, to sensory neuron activation. Other TRPV channels are expressed in the skin: TRPV2 is expressed in keratinocytes and macrophages, and TRPV3 is expressed in blood vessels and keratinocytes.
Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) is a channel sensitive to cold (8°C-28°C) and cooling compounds (menthol and icilin) expressed mainly on sensory C and A∂ fibers. Topical cooling agents such as menthoxypropanediol or menthol (producing a cooling sensation) are frequently applied to produce an antipruritic effect.
TRPA1 is an ionotropic channel considered to be a pain and/or pruritus receptor activated at a lower temperature than TRPM8 (<17°C) by natural compounds such as menthol, menthoxypropanediol, or polygodial. In the skin, TRPA1 is expressed in keratinocytes, melanocytes, and fibroblasts.
Because TRPA1 is expressed on cells associated with pruritus in human skin, there is little ambiguity about its involvement in the pruritus pathway in humans; however, its precise role remains to be clearly demonstrated. TRPA1 是一种离子型通道，被认为是一种疼痛和/或瘙痒受体，在低于 TRPM8 （<17°C） 的温度下被薄荷醇、薄荷氧基丙二醇或多角质化合物激活。 在皮肤中，TRPA1 在角质形成细胞、黑色素细胞和成纤维细胞中表达。
There are no data available on the contribution of NaV channels to itch in humans. The contributions of the NaV channels 1.7, 1.8. and 1.9 to itch were compared for their contribution to itch by analyzing NaV channel–specific knockout mice.
Both were involved in acute signaling; more precisely, NaV channels 1.7 and 1.9 participate in itch signaling (in whole), whereas NaV channel 1.8 sustains prolonged itching.
These interesting data may provide targets in pruritus therapy. Of the total NaV channels expressed in human dorsal root ganglion (DRG) sensory neurons, the percentages of Nav channel 1.7 (∼50%) and Nav channel 1.8 (12%) are higher and lower, respectively, than that in murine DRG (18% in the case of Nav channel 1.7 and ∼45% in the case of Nav channel 1.8).
Expression and role of voltage-gated sodium channels in human dorsal root ganglion neurons with special focus on Nav1.7, species differences, and regulation by paclitaxel.
Therefore, the data obtained from murine models are not directly translatable to humans owing to the different expression patterns of NaV channels in human DRG. Further research on human models is needed to reinforce interest in use of these NaV channels for relieving itch. 由于其在感觉神经元中的强表达，NaV 通道对于瘙痒感觉信号的产生和传播至关重要。
Expression and role of voltage-gated sodium channels in human dorsal root ganglion neurons with special focus on Nav1.7, species differences, and regulation by paclitaxel.
因此，由于人类DRG中NaV通道的表达模式不同，从小鼠模型中获得的数据不能直接转化为人类。需要对人体模型进行进一步研究，以加强对使用这些 NaV 通道缓解瘙痒的兴趣。
Periostin 骨膜素
Periostin is a protein of the extracellular matrix that is localized predominantly in the nucleus of human keratinocytes and also expressed by human fibroblasts.
Periostin seems to contribute significantly to itch in prurigo nodularis, in which intensity of periostin immunostaining in the dermis is correlated with itch.
The itch intensity of bullous pemphigoid is correlated with dermal expression of periostin and other parmaters (numbers of eosinophils, basophils, IL-13+ cells, and possibly IL-31+).
Local production of periostin is significantly enhanced in AD lesions. Moreover, severity of AD is correlated with lesional level in the skin and serum periostin levels.
In AD patients, periostin acts directly through the stimulation of sensory nerve fibers or indirectly with immune and nonimmune cells that express its integrin receptor.
Further research is needed to clarify the precise roles of periostin in itch. Periostin and its receptors may be promising therapeutic targets for relieving chronic itch.
Peripheral sensory neurons convey somatosensory information to the dorsal horn of the spinal cord through synapse formation between their central afferent terminals and a large panel of spinal interneurons and projection neurons, which relay information to the supraspinal levels of the CNS. Chronic itch conditions may involve altered spinal transmission of itch (ie, increased excitatory circuits, decreased inhibitory/regulatory pathways, or both).
High-frequency electroacupuncture has been shown to increase the content of the endogenous antipruritic opioid dynorphin in the spinal cord in a dry skin mouse model of chronic itch without inflammation.
Recent insights into how the somatosensory system encodes itch and distinguishes it from pain also highlight the key role of spinal (rather than peripheral) pathways.
The vast majority of available data on spinal neurons and mediators involved in itch transmission or suppression described in this review have been obtained in rodents rather than in humans or nonhuman primates. 外周感觉神经元通过其中央传入末梢与一大组脊髓中间神经元和投射神经元之间的突触形成，将体感信息传递到脊髓的背角，这些神经元将信息传递到中枢神经系统的脊髓上水平。慢性瘙痒疾病可能涉及瘙痒的脊柱传递改变（即兴奋性回路增加、抑制/调节通路减少，或两者兼而有之）。
Pruriceptive primary afferents (subsets of C- and A∂- type nociceptors) mostly terminate in the superficial dorsal horn (SDH) (in laminae I, IIo, and IIi), where they connect with excitatory interneurons (EINs) for itch transmission.
toward which excitatory and inhibitory inputs converge, specifically control the transmission of itch information. Selective neurotoxic ablation of GRPR+ neurons in the spinal cord significantly reduced the scratching behavior acutely induced by intradermally injected histamine-dependent and histamine-independent pruritogens (histamine, compound 48/80, ET-1, serotonin, chloroquine, and SLIGRL) as well as chronic itch in a mouse model of allergic contact dermatitis (ACD), without affecting acute, inflammatory, or neuropathic pain.
Through the use of a wide range of methods (eg, a pharmacologic approach, selective neurotoxic ablation, conditional knockout, optogenetic and chemogenetic approaches), the involvement of GRP, GRP+ neurons, or GRPR+ EINs has been demonstrated in itch triggered in mouse models of psoriasis,
Histologic studies have also demonstrated an increased density of cutaneous GRP+ nerve fibers in macaques with chronic idiopathic pruritus (together with an increased expression of GRPR in the spinal cord, both of which are correlated with itch severity)
Although spinal GRPR+ EINs are key components of both histaminergic and nonhistaminergic itch, GRP is the main neurotransmitter only in nonhistaminergic itch, in which GRP released by primary sensory (but not spinal) neurons is required, as has been demonstrated by conditional knockout studies and optogenetic and chemogenetic studies.
Instead, in histaminergic pruritus, neuromedin B (NMB) released by primary sensory neurons activates EINs that express its cognate receptor, NMB receptor (NMBR), which transmit itch information to GRPR+ EINs using glutamate as a neurotransmitter.
In contrast to its role in the dorsal horn of the spinal cord, the role of glutamate as a neurotransmitter of itch at the first synapse between primary C fibers and SDH neurons is rather inhibitory because mice lacking vesicular glutamate transporter 2 (VGLUT2) in cutaneous nociceptors exhibit spontaneous scratching and scratching responses to itch stimuli.
However, a recent study suggests that MrgprA3+ primary neurons may use glutamate and NMB to induce nonhistaminergic itch via the activation of NMBR+ EINs.
Therefore, the spinal transmission of itch may involve multiple neuropeptides and fast-acting neurotransmitters released in a context-, space-, and time-dependent manner rather than a single itch-specific neurotransmitter and dedicated circuit.
In addition, spinal nonneuronal cells, especially glial cells, may contribute to chronic itch. In models of acute and chronic itch (ACD and psoriasis, respectively), spinal microglial cells were activated and intrathecal administration of an inhibitor of microglial activation reduced scratching behavior.
In mouse models of AD and ACD with chronic itch, reactive astrocytes and their factor lipocalin-2 were shown to contribute to chronic itch by sensitizing the GRP/GRPR pathway.
The spinal transmission of chemical itch is locally gated by inhibitory interneurons and also modulated by pathways descending from the supraspinal areas (Fig 2). 化学瘙痒的脊柱传递由抑制性中间神经元局部门控，也由从脊柱上区域下降的通路调节（图2）。
Fig 2Spinal processing of itch signals. Spinal GRPR+ interneurons are activated by GRP, which is released by cutaneous pruriceptors, including MrgprA3+ afferents, as well as by NPRA+ interneurons. MrgprA3+ primary neurons also release glutamate and NMB to induce nonhistaminergic itch via the activation of NMBR+ NPRC+ interneurons. BNP is released in addition to NMB. Then, NMBR+ NPRC+ interneurons activate GRPR+ interneurons through glutamate. GRPR+ interneurons relay the pruritic signal to spinal projection neurons, most of which express the neurokinin 1 receptor (NK-1R). GRPR+ interneurons are also connected to glutamatergic projection neurons that project to the parabrachial nucleus. GRPR+ interneurons are locally inhibited by Bhlhb5+ galanin+ Sst2a + interneurons, which release γ-aminobutyric acid (GABA), glycine, and dynorphin (a KOR agonist) in response to the activation of TRPM8+ TRPV1+ primary sensory neurons by cooling or capsaicin. Descending pathways also modulate the activity of GRPR+ interneurons, activated by serotonin from the rostral ventromedial medulla and inhibited by noradrenalin from the locus coeruleus. 图2瘙痒信号的脊柱处理。脊髓 GRPR + 中间神经元由 GRP 激活，GRP 由皮肤瘙痒感受器（包括 MrgprA3 + 传入）以及 NPRA + 中间神经元释放。MrgprA3 + 初级神经元还释放谷氨酸和 NMB，通过激活 NMBR + NPRC + 中间神经元诱导非组胺能性瘙痒。除NMB外，还发布了BNP。然后，NMBR + NPRC + 中间神经元通过谷氨酸激活GRPR + 中间神经元。GRPR + 中间神经元将瘙痒信号传递给脊髓投射神经元，其中大多数表达神经激肽 1 受体 （NK-1R）。GRPR + 中间神经元还连接到投射到臂旁核的谷氨酸能投射神经元。GRPR + 中间神经元被 Bhlhb5 + 甘丙肽 + Sst2a + 中间神经元局部抑制，其释放γ-氨基丁酸 （GABA）、甘氨酸和强啡肽（一种 KOR 激动剂），以响应 TRPM8 + TRPV1 + 初级感觉神经元通过冷却或辣椒素激活。下行通路还调节 GRPR + 中间神经元的活性，这些中间神经元由来自喙腹内侧髓质的血清素激活，并被来自蓝斑的去甲肾上腺素抑制。
A specific class of inhibitory interneurons expressing the transcription factor basic helix–loop–helix family member b5 (Bhlhb5) has been identified as a key modulator of itch signal at the spinal level.
These various subpopulations of Bhlhb5+ interneurons gate chemical itch through the release of fast-acting neurotransmitters such as γ-aminobutyric acid (GABA), glycine, and dynorphin (a KOR agonist that acts on GRPR+ interneurons through inhibitory synapses to block itch transmission).
Bhlhb5+ interneurons receive excitatory inputs from primary sensory neurons that sense chemical counterstimuli such as cooling induced by menthol acting on TRPM8
These molecular and neural mechanisms underlie the relief of itch ensured by the cutaneous application of menthol and algogens. Furthermore, cutaneous nociceptors release glutamate, which has been identified as the neurotransmitter responsible for the inhibition of itch by noxious stimuli.
Moreover, somatostatin, which originates from spinal interneurons and cutaneous pruriceptors, inhibits Bhlhb5+ interneurons by acting on Sst2a, thus resulting in the disinhibition of GRPR+ interneurons.
The activity of GRPR+ interneurons is also modulated by several descending pathways. Serotonin (5-HT) released from neurons whose cell bodies are located in the dorsal raphe nucleus of the rostral ventromedial medulla activates GRPR+ interneurons by binding to 5-HT1A receptors jointly to GRP.
Conversely, noradrenalin released into the spinal cord by neurons located in the locus coeruleus inhibits GRPR+ interneurons. Noradrenalin binds to α-adrenergic receptors on GRPR+ interneurons, thus blocking the spinal acute and chronic itch transmission.
GRPR+ interneurons relay the pruritic signal to projection neurons whose cell bodies are also located in lamina I. A large population of these projection neurons is found to express the neurokinin 1 receptor NK-1R.
Spinothalamic and spinoparabrachial projection neurons are involved in the transmission of itch signals through distinct histamine-dependent and histamine-independent pathways.
Histamine-dependent and histamine-independent itch activate slightly different brain regions; however, several core brain areas are activated by both kinds of itch, as revealed by human functional imaging studies.
Although certain differences in the brain regions have been revealed by different studies using positron emission tomography scans and functional magnetic resonance imaging, activation of the thalamus, primary and secondary somatosensory cortices (S1 and S2, respectively), prefrontal cortex, anterior cingulate cortex, insular cortex, premotor and motor cortex, and parietal cortex has been observed.
Current understanding of the central circuit mechanisms of itch in the brain may be summarized as ascending transmission with 3 components (sensory, emotional, and motivational) and descending modulation of itch.
Although the primary sensory cortex (S1) is the main area involved in the sensory component, the posterior triangular nucleus and thalamic nuclei (reticular, posterior, ventral posteromedial, and ventral tegmental) are activated earlier. 目前对大脑瘙痒中枢回路机制的理解可以概括为具有 3 个组成部分（感觉、情绪和动机）的上行传递和瘙痒的下行调节。
Itch sensation is associated with a strong negative emotional component and a vicious circle associated with scratching behavior and increased stress, anxiety, and mood disorders.
The motivational component of itch plays a key role in driving scratching behavior, with specific roles played by the lateral shell of the nucleus accumbens and ventral tegmental area.
Other brain areas are simultaneously activated to inhibit sensory processing, especially noradrenergic and serotoninergic neurons from the locus coeruleus and other brainstem nuclei and glutaminergic periaqueductal gray area neurons and Bhlhb5+ interneurons in the cingulate cortex.
Similarly to pain matrices, itch matrices may also be described with one matrix contributing to the perception and location of itch, another responsible for the affective aspect, and a third involving decoding the cognitive aspect of itch.
The first itch matrix includes but is not restricted to the primary sensorimotor cortex, the parietal/central operculum, and the posterior insular cortex. The second itch matrix consists of the anterior singular cortex, anterior part of the middle cingulate cortex, anterior part of the insular cortex, amygdala, striatum, and hippocampus. The third itch matrix includes parts of the prefrontal cortex, posterior part of the middle cingulate cortex, and posterior cingulate cortex. 与疼痛矩阵类似，瘙痒矩阵也可以用一个矩阵来描述，一个矩阵有助于瘙痒的感知和位置，另一个矩阵负责情感方面，第三个矩阵涉及解码瘙痒的认知方面。
Itch sensitization refers to a state of increased responsiveness of pruriceptive neurons to their normal or subthreshold afferent input in the context of chronic itch (Fig 3).
Clinical consequences are alloknesis (abnormal sensory state where stimuli that do not ordinarily evoke itch cause itch), hyperknesis (overresponse to a normal pruritic stimulus),
Peripheral sensitization may be attributed to the increased excitability of sensory neurons owing to hyperinnervation or the loss of innervation, as well as to the increased expression, sensitivity, and responsiveness of receptors (including PAR-2, Mrgprs, TLR3, cytokine receptors, and TRP channels such as TRPV1 and TRPA1)
that contribute to the hypersensitivity of sensory neurons to mediators such as NGF, BDNF, neurotrophins 3 and 4, SP, CGRP, endorphins, TH2 cytokines (IL-4, IL-13, and IL-31), prostaglandin E2, and ET-1.
may be explained by the decreased release of the κ-opioid neuromodulator dynorphin A by Bhlhb5+ interneurons that control the GPR/GRPR chemical itch pathway
In the brain, functional changes in some areas, such as increased activation of the anterior cingulated cortex, posterior cingulated cortex, prefrontal cortex, and precuneus areas associated with structural changes such as decreased gray matter, have been described.
Itch severely affects quality of life; however, in recent years, there has been remarkable growth in knowledge of the biochemical and neurophysiologic mechanisms of itch, facilitating the identification of novel therapeutic targets. Pruriceptors in the skin and specific or selective itch pathways in the nervous system have been identified. Although there is a predominantly nonhistaminergic pathway alongside the classical histaminergic pathway, the interactions of a large number of mediators and receptors have been highlighted and represent as many avenues for therapeutic research. As in pain, there is a sensitization to pruritus, which is a major factor of chronicization and autonomization of pruritus. 瘙痒严重影响生活质量;然而，近年来，对瘙痒的生化和神经生理机制的认识有了显着增长，促进了新治疗靶点的识别。皮肤中的瘙痒感受器和神经系统中的特定或选择性瘙痒通路已被鉴定。尽管除了经典的组胺能途径外，还有一种主要是非组胺能途径，但大量介质和受体的相互作用已被强调，并代表了治疗研究的许多途径。与疼痛一样，对瘙痒有敏感性，这是瘙痒慢性化和自主性的主要因素。
Disclosure statement 披露声明
Disclosure of potential conflict of interest: L. Misery reports receiving a grant from and serving as a speaker and an investigator for AbbVie; receiving a grant from and serving as a consultant, speaker, and investigator for Almirall, Galderma, Johnson & Johnson, Lilly, and Sanofi; serving as an investigator for Amgen, AstraZeneca, Dermira, Incyte, and Kiniksa; serving as a consultant for Bayer, Clexio, Estée Lauder, L’Oréal, and Vifor; receiving a grant from Beiersdorf, Clarins, and Expanscience; receving a grant from and serving as a speaker for Bioderma; serving as a speaker and investigator for Biogen, Leo, Novartis, and Pfizer; receiving a grant from and serving as a consultant and speaker for Gilbert; serving as a speaker for GSK, Intercept, UCB, Uriage, and Viatris; and serving as a consultant and investigator for Menlo and Trevi. O. Pierre reports receiving a grant from Johnson & Johnson. C. Le Gall-Ianotto reports grants from Beiersdorf and Clarins. N. Lebonvallet reports receiving grants from Expanscience and Johnson & Johnson, receiving a grant from and serving as a speaker for Gilbert, and serving as a consultant L’Oréal. M. Talagas reports serving as a consultant to L’Oréal. The rest of the authors declare that they have no relevant conflicts of interest. 潜在利益冲突的披露：L. Misery 报告从艾伯维获得资助并担任艾伯维的发言人和调查员;获得Almirall、Galderma、Johnson & Johnson、Lilly和Sanofi的资助，并担任顾问、演讲者和调查员;担任安进、阿斯利康、Dermira、Incyte 和 Kiniksa 的调查员;担任拜耳、Clexio、雅诗兰黛、欧莱雅和Vifor的顾问;获得拜尔斯道夫、娇韵诗和Expanscience的资助;接受Bioderma的资助并担任Bioderma的演讲者;担任 Biogen、Leo、Novartis 和 Pfizer 的演讲者和研究员;获得吉尔伯特的资助并担任其顾问和演讲者;担任 GSK、Intercept、UCB、Uriage 和 Viatris 的演讲者;并担任门洛和特雷维的顾问和调查员。O. Pierre报告说，他获得了强生公司的资助。C. Le Gall-Ianotto报告了拜尔斯道夫和娇韵诗的资助。N. Lebonvallet报告说，他获得了Expanscience和强生公司的资助，获得了Gilbert的资助并担任了演讲者，并担任了欧莱雅的顾问。M. Talagas 曾担任欧莱雅的顾问。其余作者声明他们没有相关的利益冲突。
Executive summary of the methods report for ‘The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update.
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Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.
Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin -- an exploration of the cause of neurohyperplasia.
Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis.
Differential up-regulation of neurotrophin receptors and functional activity of neurotrophins on peripheral blood eosinophils of patients with allergic rhinitis, atopic dermatitis and nonatopic subjects.
Regulation of Skin Barrier Function via Competition between AHR axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis.
Nuclear IL-33 plays an important role in IL-31‒mediated downregulation of FLG, keratin 1, and keratin 10 by regulating signal transducer and activator of transcription 3 activation in human keratinocytes.
Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study.
Expression and role of voltage-gated sodium channels in human dorsal root ganglion neurons with special focus on Nav1.7, species differences, and regulation by paclitaxel.
Fig 1Schematic representation of the pruritus pathway from the skin to the brain. Two types of pruriceptors are present at the cutaneous level: a histamine-dependent (histaminergic) pathway and a histamine-independent (nonhistaminergic) pathway. They are activated by exogenous or endogenous pruritogens produced by cells located in the skin. The pruritus signal is then transmitted first to the spinal cord and then to the brain to induce scratching. B, basophils; E, eosinophils; Hist., histamine; HR, histamine receptor; IDP, inhibitory descending pathway; IL-R, interleukin receptor; L, T lymphocytes; M, mastocytes; MrgprX, Mas-related G protein–coupled receptor; N, neutrophils; NK-1R, neurokinin-1 receptor; NMDA-R, N-methyl-D-aspartic acid; PAR, protease-activated receptor; PDE-4, phosphodiesterase 4. Figure adapted from “Sensing noxious stimuli: nociception copy template” by BioRender.com (2021) (available at: https://app.biorender.com/biorender-templates).
Fig 2Spinal processing of itch signals. Spinal GRPR+ interneurons are activated by GRP, which is released by cutaneous pruriceptors, including MrgprA3+ afferents, as well as by NPRA+ interneurons. MrgprA3+ primary neurons also release glutamate and NMB to induce nonhistaminergic itch via the activation of NMBR+ NPRC+ interneurons. BNP is released in addition to NMB. Then, NMBR+ NPRC+ interneurons activate GRPR+ interneurons through glutamate. GRPR+ interneurons relay the pruritic signal to spinal projection neurons, most of which express the neurokinin 1 receptor (NK-1R). GRPR+ interneurons are also connected to glutamatergic projection neurons that project to the parabrachial nucleus. GRPR+ interneurons are locally inhibited by Bhlhb5+ galanin+ Sst2a + interneurons, which release γ-aminobutyric acid (GABA), glycine, and dynorphin (a KOR agonist) in response to the activation of TRPM8+ TRPV1+ primary sensory neurons by cooling or capsaicin. Descending pathways also modulate the activity of GRPR+ interneurons, activated by serotonin from the rostral ventromedial medulla and inhibited by noradrenalin from the locus coeruleus.
Fig 3Itch sensitization. Peripheral sensitization involves the skin and peripheral neurons, whereas central sensitization involves the brain and spinal cord (central nervous system). PGE2, prostaglandin E2; NPY, neuropeptide Y; PAG, periaqueductal gray matter. Adapted from Yosipovitch et al.
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