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Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons, termed pruriceptors, which express molecular receptors that are activated by itch-evoking ligands. Also expressed in pruriceptors are several types of Transient Receptor Potential (TRP) channels. TRP channels are a diverse class of cation channels that are responsive to various somatosensory stimuli like touch, pain, itch, and temperature. In pruriceptors, TRP channels can be activated through intracellular signaling cascades initiated by pruritogen receptors and underly neuronal activation. In this review, we discuss the role of TRP channels TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPC3/4 in acute and chronic pruritus. Since these channels often mediate itch in association with pruritogen receptors, we also discuss Mas-related G-protein-coupled receptors (Mrgprs) and protease-activated receptors (PARs). Additionally, we cover the exciting therapeutic targets amongst the TRP family, as well as Mrgprs and PARs for the treatment of pruritus.

Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is one of the most prevalent intractable chronic itch diseases worldwide. In recent years, new molecular-targeted drugs have emerged, but side effects and economic challenges remain. Therefore, since it is important for AD patients to have a wider range of treatment options, it is important to explore new therapeutic agents. Gabapentinoids, gabapentin and pregabalin, have been shown to be effective for the clinical treatment of several chronic itch. Recently, mirogabalin (MGB) was developed as a novel gabapentinoid. MGB is a drug for neuropathic pain and has a margin of safety between its side effects and the analgesic effect for animal experiments. Herein, we showed that MGB exhibited an antipruritic effect in a mouse model of AD using NC/Nga mice. Methods and results: The oral administration of MGB (10 mg/kg) inhibited spontaneous scratching behavior in AD mice and its effect was dose dependently. Then, when MGB (10 mg/kg) was orally administrated to healthy mice, it did not affect motor function, including locomotor activity, wheel activity, and coordinated movement. Moreover, gabapentin (100 mg/kg) and pregabalin (30 mg/kg), inhibited spontaneous scratching behavior in AD mice and decreased motor function in healthy mice. Furthermore, intracisternal injection of MGB (10 μg/site) significantly suppressed spontaneous scratching behavior in AD mice. Discussion: In summary, our results suggest that MGB exerts an antipruritic effect via the spinal dorsal horn using NC/Nga mice. We hope that MGB is a candidate for a novel therapeutic agent for AD with relatively few side effects. [ABSTRACT FROM AUTHOR]

BackgroundPostherpetic itch (PHI) is an easily overlooked complication of herpes zoster that greatly affects patients' quality of life. Studies have shown that early intervention can reduce the occurrence of itch. The aim of this study was to develop and validate a predictive model through a machine learning approach to identify patients at risk of developing PHI among patients with herpes zoster, making PHI prevention a viable clinical option.MethodWe conducted a retrospective review of 488 hospitalized patients with herpes zoster at The First Affiliated Hospital of Zhejiang Chinese Medical University and classified according to whether they had PHI. Fifty indicators of these participants were collected as potential input features for the model. Features associated with PHI were identified for inclusion in the model using the least absolute shrinkage selection operator (LASSO). Divide all the data into five pieces, and then use each piece as a verification set and the others as a training set for training and verification, this process is repeated 100 times. Five models, logistic regression, random forest (RF), k-nearest neighbor, gradient boosting decision tree and neural network, were built in the training set using machine learning methods, and the performance of these models was evaluated in the test set.ResultsSeven non-zero characteristic variables from the Lasso regression results were selected for inclusion in the model, including age, moderate pain, time to recovery from rash, diabetes, severe pain, rash on the head and face, and basophil ratio. The RF model performs better than other models. On the test set, the AUC of the RF model is 0.84 [(95% confidence interval (CI): 0.80–0.88], an accuracy of 0.78 (95% CI: 0.69–0.86), a precision of 0.61 (95% CI: 0.45–0.77), a recall of 0.73 (95% CI: 0.58–0.89), and a specificity of 0.79 (95% CI: 0.70–0.89).ConclusionsIn this study, five machine learning methods were used to build postherpetic itch risk prediction models by analyzing historical case data, and the optimal model was selected through comparative analysis, with the random forest model being the top performing model.

Abstract is missing (Short communication)

The unclear pathogenesis of chronic itch originating from several systemic disorders poses challenges to clinical intervention. Recent studies recapitulate the spinal neurocircuits associated with neuroinflammation and synaptic plasticity responsible for pruriceptive sensations. The resolution of nociception and inflammation by Annexin 1 (ANXA1) has been identified. Given that pain and itch share many neural mechanisms, we employed two mice models of chronic itch to study the underlying targets and therapeutic potential of ANXA1, comprising allergic contact dermatitis-induced itch and cholestatic itch. Herein, we report that spinal expression of ANXA1 is down-regulated in mice with dermatitis-induced itch and cholestatic itch. Repetitive injections of ANXA1-derived peptide Ac2-26 (intrathecal, 10 μg) reduce itch-like scratching behaviors following dermatitis and cholestasis. Single exposure to Ac2-26 (intrathecal, 10 μg) alleviates the established itch phenotypes. Moreover, systemic delivery of Ac2-26 (intravenous, 100 μg) is effective against chronic dermatitis-induced itch and cholestatic itch. Strikingly, Ac2-26 therapy inhibits transferrin receptor 1 over-expression, iron accumulation, cytokine IL-17 release and the production of its receptor IL-17R, as well as astrocyte activation in the dorsal horn of spinal cord in mouse with dermatitis and cholestasis. Pharmacological intervention with iron chelator deferoxamine impairs chronic itch behaviors and spinal iron accumulation after dermatitis and cholestasis. Also, spinal IL-17/IL-17R neutralization attenuates chronic itch. Taken together, this current research indicates that ANXA1 protects against the beginning and maintenance of long-term dermatitis-induced itch and cholestatic itch, which may occur via the spinal suppression of IL-17-mediated neuroinflammation, astrocyte activation and iron overload. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein–coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of μ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD. [ABSTRACT FROM AUTHOR]

Small-fiber neuropathy (SFN) develops due to the impairment of fibers responsible for mediating temperature, pain, and autonomic functions. SFN complicates a number of common diseases such as diabetes mellitus, human immunodeficiency virus, and COVID-19, and is likely to be increasingly encountered. The associated pain contributes significantly to the morbidity of these diseases. Progression is slow, and most people affected by SFN do not develop large-fiber involvement over time. However, mixed polyneuropathies often start as SFN, and SFN often coexists with large fiber–predominant neuropathy. Symptoms of SFN, including painful paresthesia and dizziness, and sedative side effects of pain medications can negatively affect the quality of life. Standardized diagnostic criteria for SFN are not fully established, and skin biopsy remains the diagnostic test considered most reliable. Autonomic testing is useful when autonomic symptoms are present along with screening for associated conditions. Treatment should be individualized to control underlying causes and alleviate pain. Early diagnosis and individualized treatment are important for controlling SFN symptoms and optimizing daily functions. Here, we review the common but increasingly ignored condition, SFN, and discuss its diagnosis and management.

Abstract Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD.

Aims and Objectives: To map out the primary research studies relating to how virtual reality (VR) has been used to distract children and young people with long‐term conditions from pain or pruritus. Background: Pharmacologic treatment of chronic pain and pruritus may have side effects; hence, non‐invasive non‐pharmacological treatments are being sought. Design: The scoping review followed the methodology recommended by the Joanna Briggs Institute, PAGER framework and PRISMA‐ScR checklist. The protocol was registered with the Open Science Registration on 14 February 2022 https//doi.org/10.17605/OSF.IO/K2R93. Methods: Five databases (Medline, CINAHL, PsycINFO, Web of Science and Scopus) were searched. Data were extracted from primary research studies published between 2000 and 2022 involving children and adolescent populations (<21 years) with a long‐term condition that had an element of enduring pruritus and/or pain. Results: Of 464 abstracts screened, 35 full‐text papers were assessed with 5 studies meeting the eligibility criteria. Three main themes emerged from the included studies: (1) Improvements in pain and daily functioning; (2) positive perceptions of VR and (3) accessibility and feasibility of VR. No papers were found on the effect of VR on alleviating pruritus. Conclusion: VR is feasible, acceptable, and safe for children and adolescents with chronic pain in a range of long‐term conditions and offers promise as an adjunctive treatment for improving chronic pain and quality of life. No studies were identified that targeted pruritis or measured pruritis outcomes; thus, the effects of VR for pruritis are unknown. There is a need for rigorously designed, randomised controlled trials to test the clinical and cost‐effectiveness of VR interventions for chronic pain and pruritis in children and adolescents. The use of the PAGER (Patterns, Advances, Gaps, Evidence for Practice and Research Recommendations) framework for scoping reviews helped to structure analysis and findings and identify research gaps. Relevance to Clinical Practice: VR interventions offer promise in improving chronic pain related to long‐term conditions. [ABSTRACT FROM AUTHOR]

Chronic itch is a debilitating condition with limited treatment options, severely affecting quality of life. The identification of pruriceptors has sparked a growing interest in the therapeutic potential of TRP channels in the context of itch. In this regard, we provided a comprehensive overview of the site-specific expression of TRP channels and their associated functions in response to a range of pruritogens. Although several potent antipruritic compounds that target specific TRP channels have been developed and have demonstrated efficacy in various chronic itch conditions through experimental means, a more thorough understanding of the potential for adverse effects or interactions with other TRP channels or GPCRs is necessary to develop novel and selective therapeutics that target TRP channels for treating chronic itch. This review focuses on the mechanism of itch associated with TRP channels at specific sites, from the skin to the sensory neuron, with the aim of suggesting specific therapeutic targets for treating this condition. [ABSTRACT FROM AUTHOR]

Itch is one of the commonest complaints of patients of patients in skin clinics. Chronic itch is defined itch lasting more than 6 weeks, which suffers the patients and significantly reduces their quality of life. In this review, we explain pathogenesis and available treatments as a whole. In addition, we summarize pathogenesis and therapeutic options of some common conditions with chronic pruritus, except eczema, such as chronic kidney disease, cholestasis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD. [ABSTRACT FROM AUTHOR]

Purpose Pruritus is an unpleasant sensation that creates the urge to scratch. In many chronic conditions, relentless pruritus and scratching perpetuates a vicious itch-scratch cycle. Uncontrolled itch can detrimentally affect quality of life and may lead to sleep disturbance, impaired concentration, financial burden, and psychological suffering. Recent strides have been made to develop guidelines and investigate new therapies to treat some of the most common severely pruritic conditions, however, a large group of diseases remains underrecognized and undertreated. The purpose of this article is to provide a comprehensive review of the challenges hindering the treatment of pruritus.Methods An online search was performed using PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1994 to 2024. Included studies were summarized and assessed for quality and relevance in treating pruritus.Results Several barriers to treating pruritus emerged, including variable presentation, objective measurement of itch, and identifying therapeutic targets. Itch associated with autoimmune conditions, connective tissue diseases, genodermatoses, cutaneous T-cell lymphoma, and pruritus of unknown origin were among the etiologies with the greatest unmet needs.Conclusion Treating pruritus poses many challenges and there are many itchy conditions that have no yet been addressed. There is an urgent need for large-scale controlled studies to investigate potential targets for these conditions and novel therapies.

Itch is an unpleasant physical sensation that can cause scratching behavior. Chronic itch is a burdensome clinical problem of many skin diseases and some systemic diseases. Stubborn and severe itch seriously affects the physical and mental health as well as the quality of life of patients. It is important to use assortments of preclinical itch models to identify itch mechanisms， and to foster the development of better anti-pruritus drugs. In recent years， a variety of animal models of itch have been established， and advances have been made in basic itch research. The present study summarizes the commonly used mouse models in the research of itch and the frequently utilized behavioral evaluation for assessing the scratching， that provides a reference for the future itching and antipruritic research. [ABSTRACT FROM AUTHOR]

Introduction: Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Methods: We measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing. Results: Type 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and nontype 2 inflammatory stimuli. Discussion: This study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons. [ABSTRACT FROM AUTHOR]

Abstract Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.

Abstract Background Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch. Methods Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-β were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-β elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI. Results We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-β are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-β exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus. Conclusions STING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief.

The unclear pathogenesis of chronic itch originating from several systemic disorders poses challenges to clinical intervention. Recent studies recapitulate the spinal neurocircuits associated with neuroinflammation and synaptic plasticity responsible for pruriceptive sensations. The resolution of nociception and inflammation by Annexin 1 (ANXA1) has been identified. Given that pain and itch share many neural mechanisms, we employed two mice models of chronic itch to study the underlying targets and therapeutic potential of ANXA1, comprising allergic contact dermatitis-induced itch and cholestatic itch. Herein, we report that spinal expression of ANXA1 is down-regulated in mice with dermatitis-induced itch and cholestatic itch. Repetitive injections of ANXA1-derived peptide Ac2-26 (intrathecal, 10 μg) reduce itch-like scratching behaviors following dermatitis and cholestasis. Single exposure to Ac2-26 (intrathecal, 10 μg) alleviates the established itch phenotypes. Moreover, systemic delivery of Ac2-26 (intravenous, 100 μg) is effective against chronic dermatitis-induced itch and cholestatic itch. Strikingly, Ac2-26 therapy inhibits transferrin receptor 1 over-expression, iron accumulation, cytokine IL-17 release and the production of its receptor IL-17R, as well as astrocyte activation in the dorsal horn of spinal cord in mouse with dermatitis and cholestasis. Pharmacological intervention with iron chelator deferoxamine impairs chronic itch behaviors and spinal iron accumulation after dermatitis and cholestasis. Also, spinal IL-17/IL-17R neutralization attenuates chronic itch. Taken together, this current research indicates that ANXA1 protects against the beginning and maintenance of long-term dermatitis-induced itch and cholestatic itch, which may occur via the spinal suppression of IL-17-mediated neuroinflammation, astrocyte activation and iron overload.

IntroductionChronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system.MethodsWe measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing.ResultsType 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli.DiscussionThis study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

Background: Symmetrical alopecia is a common symptom of endocrine and autoimmune diseases, which are rarely manifested with pruritus. Increased levels of stress in primates have been presented with increased levels of pruritus and alopecia appearance. Methods: A pruritic and alopecic disease was investigated in a group of tufted capuchin monkeys (N = 12), but due to ethical reasons, four random animals were further investigated by numerous diagnostic methods. The impact of food and enclosure enrichment was assessed and observed over a 2‐year period. Results: Histopathology of four random tufted capuchin monkeys revealed lymphocytic perifolliculitis, with an appearance of a "swarm of bees" which was suggestive of alopecia areata. Etiological classification of pruritus excluded dermatological, systemic, and neurological causes, making it behavioral. Enclosure and food enrichment had a beneficial impact on pruritus (12/12) and alopecia (10/12). Conclusion: The findings were suggestive of alopecia areata, while the pruritus was considered behavioral in origin. Alopecia and pruritus improved upon enclosure and food enrichment. [ABSTRACT FROM AUTHOR]

Chronic itch (CI) is an unpleasant skin sensation accompanied by an intense scratching desire that lasts 6 weeks or longer. Despite the high prevalence and negative impact on affected individuals and a huge healthcare burden, CI mechanisms are only partially understood, and consequently, treatment of CI remains sub-optimal. The complexity of CI treatment also stems from the comorbid existence of persistent itch with other somatic and psychological disorders. Etiologies of CI are multiple and diverse, although CI is often a result of dermatologically related conditions such as atopic dermatitis and psoriasis. Unfolding the pathophysiology of CI can provide possibilities for better therapy. Itch signaling is complex and neurons and non-neuronal cells play a role. This review focuses on recent findings on the role of glial cells in itch. Central glia (astrocytes and microglia) and peripheral glia (satellite glial cells and Schwann cells) are found to contribute to the development or persistence of itch. Hence, glial modulation has been proposed as a potential option in CI treatment. In experimental models of itch, the blockade of signal transducer and the activator of transcription (STAT) 3-mediated reactive astrogliosis have been shown to suppress chronic itch. Administration of a microglial inhibitor, minocycline, has also been demonstrated to suppress itch-related microglial activation and itch. In sensory ganglia, gap-junction blockers have successfully blocked itch, and hence, gap-junction-mediated coupling, with a potential role of satellite glial cells have been proposed. This review presents examples of glial involvement in itch and opportunities and challenges of glial modulation for targeting itch.

Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy. [ABSTRACT FROM AUTHOR]

Background: Spinal astrocytes contribute to chronic itch via sensitization of itch‐specific neurons expressing gastrin‐releasing peptide receptor (GRPR). However, whether microglia–neuron interactions contribute to itch remains unclear. In this study, we aimed to explore how microglia interact with GRPR+ neurons and promote chronic itch. Methods: RNA sequencing, quantitative real‐time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD‐like receptor family, pyrin‐containing domain 3) inflammasome activation and IL‐1β‐IL1R1 signaling in chronic itch. Grpr‐eGFP and Grpr KO mice were used to investigate microglia–GRPR+ neuron interactions. Results: We observed NLRP3 inflammasome activation and IL‐1β production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase‐1/IL‐1β axis attenuated chronic itch and neuronal activation. Type 1 IL‐1 receptor (IL‐1R1) was expressed in GRPR+ neurons, which are essential for the development of chronic itch. Our studies also find that IL‐1β+ microglia are localized in close proximity to GRPR+ neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL‐1β indicate that the IL‐1β‐IL‐1R1 signaling pathway enhanced the activation of GRPR+ neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase‐1/IL‐1β axis contributes to several different chronic itches triggered by small molecules and protein allergens from the environment and drugs. Conclusion: Our findings reveal a previously unknown mechanism in which microglia enhances the activation of GRPR+ neurons through the NLRP3/caspase‐1/IL‐1β/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch. [ABSTRACT FROM AUTHOR]

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex–midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch. Methods: Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-β were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-β elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI. Results: We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-β are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-β exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus. Conclusions: STING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief. [ABSTRACT FROM AUTHOR]

Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney disease-associated pruritus (CKD-aP) most often affects people with end-stage renal disease. The etiology of this condition is still not fully understood, but researchers are currently focusing on a thorough analysis of the association between disturbed opioid balance and increased neuronal signaling leading to pruritus. The aim of this study is to assess the concentration of endogenous opioids in dialysis patients with and without pruritus and in the control group, and to determine the correlation between the concentration of these substances and the occurrence and severity of itching. The study involved 126 dialysis patients and 50 healthy controls. Patients were divided into groups with pruritus (n = 62) and without pruritus (n = 64). The severity of pruritus was assessed using the NRS scale. The concentration of endogenous opioids was determined using the ELISA. The concentration of met-enkephalin was higher in the group of patients with pruritus compared to the control group. Moreover, significantly lower levels of β-endorphin and dynorphin A were observed in the group of dialysis patients compared to the control group. In addition, a statistically significant difference was seen between the β-endorphin concentration in the group of dialysis patients with pruritus compared to the group without pruritus. The ratio of β-endorphin/dynorphin A concentrations was significantly lower in the group of patients with pruritus compared to patients without pruritus and the control group. No correlations were found between serum level of studied opioids and the severity of pruritus. The concentrations of the studied opioids did not correlate with the severity of pruritus. Observed opioid imbalance may affect the occurrence of CKD-aP in dialysis patients, but a thorough understanding of the mechanism of action of these substances in the sensation of pruritus is necessary to assess the possibility of finding a new therapeutic target. [ABSTRACT FROM AUTHOR]

Chronic itch is a debilitating condition with limited treatment options, severely affecting quality of life. The identification of pruriceptors has sparked a growing interest in the therapeutic potential of TRP channels in the context of itch. In this regard, we provided a comprehensive overview of the site-specific expression of TRP channels and their associated functions in response to a range of pruritogens. Although several potent antipruritic compounds that target specific TRP channels have been developed and have demonstrated efficacy in various chronic itch conditions through experimental means, a more thorough understanding of the potential for adverse effects or interactions with other TRP channels or GPCRs is necessary to develop novel and selective therapeutics that target TRP channels for treating chronic itch. This review focuses on the mechanism of itch associated with TRP channels at specific sites, from the skin to the sensory neuron, with the aim of suggesting specific therapeutic targets for treating this condition.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

Chronic itch (CI) is an unpleasant skin sensation accompanied by an intense scratching desire that lasts 6 weeks or longer. Despite the high prevalence and negative impact on affected individuals and a huge healthcare burden, CI mechanisms are only partially understood, and consequently, treatment of CI remains sub-optimal. The complexity of CI treatment also stems from the comorbid existence of persistent itch with other somatic and psychological disorders. Etiologies of CI are multiple and diverse, although CI is often a result of dermatologically related conditions such as atopic dermatitis and psoriasis. Unfolding the pathophysiology of CI can provide possibilities for better therapy. Itch signaling is complex and neurons and non-neuronal cells play a role. This review focuses on recent findings on the role of glial cells in itch. Central glia (astrocytes and microglia) and peripheral glia (satellite glial cells and Schwann cells) are found to contribute to the development or persistence of itch. Hence, glial modulation has been proposed as a potential option in CI treatment. In experimental models of itch, the blockade of signal transducer and the activator of transcription (STAT) 3-mediated reactive astrogliosis have been shown to suppress chronic itch. Administration of a microglial inhibitor, minocycline, has also been demonstrated to suppress itch-related microglial activation and itch. In sensory ganglia, gap-junction blockers have successfully blocked itch, and hence, gap-junction-mediated coupling, with a potential role of satellite glial cells have been proposed. This review presents examples of glial involvement in itch and opportunities and challenges of glial modulation for targeting itch. [ABSTRACT FROM AUTHOR]

Astrocytes, the most abundant type of glial cell, are electrically non-excitable cells that use intracellular calcium (Ca2+) for functional regulation. Changes in intracellular Ca2+ concentration play important roles in the central nervous system (CNS), as they are involved in the release of gliotransmitters and the control of extracellular ion concentrations, thereby affecting the regulation of neuronal excitability, CNS homeostasis, and behavior. Intracellular calcium mobilization in astrocytes is known to be mediated via inositol 1,4,5-trisphosphate receptors (IP 3 Rs), particularly IP 3 R2, and its association with CNS pathogenesis has been widely reported. In addition, the existence of IP 3 R2-independent calcium signaling has recently been postulated; however, the detailed mechanisms and its role in astrocyte functions and CNS pathogenesis are still poorly understood. In this paper, we describe the putative mechanisms underlying IP 3 R1-dependent calcium signaling in astrocytes and its effects on the reactive state, compare this signaling with IP 3 R2-dependent calcium signaling, and discuss its contribution to chronic itch-like behavior. • IP 3 R1-dependent Ca2+ signaling persistently activates STAT3 in astrocytes. • Astrocytic IP 3 R1-dependent Ca2+ responses are small and long-lasting. • Reactive astrocytes induced by IP 3 R1-dependent STAT3 activation underlie chronic itch. • IP 3 R1 and IP 3 R2 of astrocytes differ in the features of Ca2+ responses and function. [ABSTRACT FROM AUTHOR]

Dry skin induced chronic pruritus is an increasingly common and debilitating problem, especially in the elderly. Although keratinocytes play important roles in innate and adaptive immunity and keratinocyte proliferation is a key feature of dry skin induced chronic pruritus, the exact contribution of keratinocytes to the pathogenesis of dry skin induced chronic pruritus is poorly understood. In this study, we generated the acetone-ether-water induced dry skin model in mice and found that epidermal hyperplasia induced by this model is partly dependent on the β-catenin signaling pathway. XAV939, an antagonist of β-catenin signaling pathway, inhibited epidermal hyperplasia in dry skin model mice. Importantly, dry skin induced chronic pruritus also dramatically reduced in XAV939 treated mice. Moreover, acetone-ether-water treatment-induced epidermal hyperplasia and chronic itch were decreased in Trpv4 −/− mice. In vitro, XAV939 inhibited hypo-osmotic stress induced proliferation of HaCaT cells, and hypo-osmotic stress induced proliferation of in HaCaT cells and primary cultured keratinocytes were also significantly reduced by blocking TRPV4 function. Finally, thymic stromal lymphopoietin release was examined both in vivo and in vitro, which was significantly inhibited by XAV939 treatment and Trpv4 deficiency, and anti-TSLP antibody treatment significantly decreased AEW-induced scratching behavior. Overall, our study revealed a unique ability of TRPV4 expressing keratinocytes in the skin, which critically mediated dry skin induced epidermal hyperplasia and chronic pruritus, thus provided novel insights into the development of therapies for chronic pruritus in the elderly. [Display omitted] • Dry skin induced epidermal hyperplasia and pruritus dependent on β-catenin signaling pathway. • Dry skin induced epidermal hyperplasia and pruritus partly dependent on TRPV4. • Hypo-osmotic stress induced keratinocytes proliferation and TSLP release dependent on β-catenin signaling pathway. • Hypo-osmotic stress induced cytosol-nucleus transportation of β-catenin dependent on TRPV4. [ABSTRACT FROM AUTHOR]

Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons, termed pruriceptors, which express molecular receptors that are activated by itch-evoking ligands. Also expressed in pruriceptors are several types of Transient Receptor Potential (TRP) channels. TRP channels are a diverse class of cation channels that are responsive to various somatosensory stimuli like touch, pain, itch, and temperature. In pruriceptors, TRP channels can be activated through intracellular signaling cascades initiated by pruritogen receptors and underly neuronal activation. In this review, we discuss the role of TRP channels TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPC3/4 in acute and chronic pruritus. Since these channels often mediate itch in association with pruritogen receptors, we also discuss Mas-related G-protein-coupled receptors (Mrgprs) and protease-activated receptors (PARs). Additionally, we cover the exciting therapeutic targets amongst the TRP family, as well as Mrgprs and PARs for the treatment of pruritus.

Introduction: Pruritus in atopic dermatitis is one of the main symptoms of the disease and the one that causes a significant impact on quality of life. It is important to control itching because it’s not only an unplesant sense. Scratching topically deepen the dermatitis, damages the epidermal barrier causing additional infections possible and makes it harder to acheive a remission of the disease. It is also highly associated with stress and has an impact on mental health of the patient. In this article we present a summary of how pruritus affects the quality of life, mechanisms of pruritus and possible treatment. Materials and methods: Our work is based on the articles published in PubMed, medical books and websites. We were looking for the key words such as ‘stress and itch’, ‘pruritus treatment’, ‘chronic itch in atopic dermatitis’, ‘itch and quality of life’. Results: Patients with atopic dermatitis should come under miltidisciplinar treatment to acheive the best possible control of symptoms. This will result in higher quality of life and better mental health of the patient. Conclusions: There is a high need to develop new targeted medications as contemporary medicine knows a lot more about the mechanism of pruritus. Many new types of treatment are being studied and soon we may have more options to choose in systemic and topical therapy. We should also concetrate more on a mental side of the disease.

Chronic kidney disease-associated pruritus (CKD-aP) is a bothersome condition that occurs in patients with advanced chronic kidney disease (CKD) and severely reduces their quality of life. Recently, much research has focused on the search for markers that are involved in the pathogenesis of CKD-aP and may become a therapeutic target. One of the suggested hypotheses is the increased activation of sensory neurons by molecules such as neurotrophins (NTs). An increased serum concentration of NTs has been demonstrated in pruritic patients, which may suggest their involvement in the pathogenesis of itch. The purpose of this study is to assess the serum concentration of neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF) in hemodialysis patients. The study enrolled 126 patients undergoing dialysis. Participants were divided into 2 groups: with and without CKD-aP. NRS scale was used to evaluate itch severity. Serum levels of NT-4 and BDNF have been assessed using ELISA. The results showed a significantly higher level of NT-4 in the group with pruritus. No significant difference was reported in the serum level of BDNF between the two groups of patients. There was also no correlation between serum NT-4 nor BDNF levels and the severity of pruritus. In summary, NT-4 may play an important role in the pathophysiology of pruritus in dialysis patients. More research is needed to understand the exact mechanism by which NTs influence the pathogenesis of CKD-aP. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) inhibitor and cannabinoid agonists ameliorate dry skin-induced chronic itch. We have recently reported that cannabinoids, hsp90 and nitric oxide (NO) are involved in dry skin-induced itch. Here, we investigated the contribution of the Th2 cell signaling pathway to the antipruritic effect of the hsp90 inhibitor 17-Alilamino-17-demethoxygeldanamycin (17-AAG), nitric oxide synthase (NOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and cannabinoid agonist WIN 55,212–2 on a dry skin-induced scratch. Dry skin-induced chronic itching was created by topical application of AEW (acetone/diethyl ether/water). WIN 55,212–2 (1 mg/kg, i.p.), L-NAME (1 mg/kg, i.p.) and increasing doses of 17-AAG (1, 3 and 5 mg/kg,i.p.) were administered to Balb/c mice (for each group, n = 6). After these applications, skin tissues were taken from the nape region of all of the mice. Gene and protein expressions of IL-13 and IL-31 were evaluated in skin tissues by RT-PCR and immunohistochemistry, respectively. IL-13 and IL-31 mRNA expressions and immune positive cell counts were increased in the AEW applied groups. WIN 55,212–2 reduced both of the increased cytokines levels, while L-NAME decreased only the IL-13. 17-AAG dose-dependently reduced the increased cytokine levels. IL-13 and IL-31 levels significantly decreased following the co-administration of these agents. These results show that increased levels of IL-13 and IL-31 are associated with pruritus. Hsp90 inhibition and cannabinoid system activation may induce antipruritic effects through down-regulation of these cytokines. [ABSTRACT FROM AUTHOR]

Background: Postherpetic itch (PHI) is an easily overlooked complication of herpes zoster that greatly affects patients' quality of life. Studies have shown that early intervention can reduce the occurrence of itch. The aim of this study was to develop and validate a predictive model through a machine learning approach to identify patients at risk of developing PHI among patients with herpes zoster, making PHI prevention a viable clinical option., Method: We conducted a retrospective review of 488 hospitalized patients with herpes zoster at The First Affiliated Hospital of Zhejiang Chinese Medical University and classified according to whether they had PHI. Fifty indicators of these participants were collected as potential input features for the model. Features associated with PHI were identified for inclusion in the model using the least absolute shrinkage selection operator (LASSO). Divide all the data into five pieces, and then use each piece as a verification set and the others as a training set for training and verification, this process is repeated 100 times. Five models, logistic regression, random forest (RF), k-nearest neighbor, gradient boosting decision tree and neural network, were built in the training set using machine learning methods, and the performance of these models was evaluated in the test set., Results: Seven non-zero characteristic variables from the Lasso regression results were selected for inclusion in the model, including age, moderate pain, time to recovery from rash, diabetes, severe pain, rash on the head and face, and basophil ratio. The RF model performs better than other models. On the test set, the AUC of the RF model is 0.84 [(95% confidence interval (CI): 0.80-0.88], an accuracy of 0.78 (95% CI: 0.69-0.86), a precision of 0.61 (95% CI: 0.45-0.77), a recall of 0.73 (95% CI: 0.58-0.89), and a specificity of 0.79 (95% CI: 0.70-0.89)., Conclusions: In this study, five machine learning methods were used to build postherpetic itch risk prediction models by analyzing historical case data, and the optimal model was selected through comparative analysis, with the random forest model being the top performing model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Dou, Ju, Lin and Cao.)

Patients with chronic itch describe their pruritus in a wide variety of ways. However, these subjective descriptions are often not taken into consideration by physicians. This study aimed to validate patients’ descriptions of pruritus, and to investigate the relationship between various descriptions of pruritus and the patient burden of chronic pruritus by examining the mediating effects of sleep disturbance and sexual dysfunction on patient’s quality of life, as predicted by various descriptions of pruritus. Exploratory and confirmatory factor analyses were performed to identify the factor structure measured by 11 descriptions of pruritus. The study then analysed differences in the degree of sleep disturbance, sexual dysfunction, and quality of life deterioration factors using a structural equation modelling method. Using data from 419 patients with chronic pruritus, 11 descriptions of pruritus were classified into 2 groups: (i) sensory pruritus (i.e. stinging, stabbing, burning, painful, formication, throbbing, and cold) that are linked with descriptions of pruritus patterns; and (ii) affective pruritus (i.e. annoying, unbearable, worrisome, and warm) from patient reports of psychological or emotional distress. The study found that affective pruritus decreases patient’s quality of life either directly or indirectly through sleep disturbance. In conclusion, clues about a patients’ sleep disturbance or poor quality of life can be obtained through their descriptions of pruritus.

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at "Quchi" (LI11) and "Hegu" (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch. [ABSTRACT FROM AUTHOR]

Chronic itch (CI) is a common symptom caused by both dermatological and systemic disorders. CI is also a frequent, burdensome symptom among renal transplant recipients (RTR); however, its pathophysiology is not fully understood. The aim of this study was to assess the differences in concentration of IL-31 among itchy RTR. The study was performed on a group of selected 129 RTRs (54 itchy and 75 non-itchy patients). Itch severity was assessed with the use of the numeral rating scale (NRS) and the 4-item itch questionnaire (4IIQ). Every subject had his blood drawn to measure the concentration of IL-31. The results were subsequently compared and correlated. The mean concentration differed significantly between RTR suffering from itch (602.44 ± 534.5 pg/mL), non-itchy RTR (161.49 ± 106.61 pg/mL), and HC (110.33 ± 51.81 pg/mL) (p < 0.001). Post-hoc analysis revealed a statistically significantly increased IL-31 serum concentration in itchy RTR in comparison to the non-itchy RTR group (p < 0.001) and HC (p < 0.001). No significant difference was observed in IL-31 serum levels between non-itchy RTRs and HC. No correlation between IL-31 and itch intensity was found. The results of our study clearly demonstrate the association between IL-31 levels and CI in patients after renal transplantation. [ABSTRACT FROM AUTHOR]

Chronic pruritus carries a significant burden of disease and is associated with a negative impact on quality of life. African Americans are disproportionately burdened by chronic pruritic disorders, including but not limited to atopic dermatitis, prurigo nodularis, inflammatory scalp dermatoses, pathologic scarring, and HIV-related dermatoses. Racial differences in skin structure and function may contribute to the pathogenesis of itch in African Americans. Itch perception and response to treatment in African Americans remain understudied and not well understood. As such, there is a large unmet need with regard to the knowledge and management of pruritus in African Americans. This review highlights notable differences in the epidemiology, pathophysiology, genetic predisposition, clinical presentation, and response to treatment for select pruritic skin conditions. By addressing itch as an unmet need in African Americans, we hope to improve patient outcomes and lessen disparities in dermatologic care. [ABSTRACT FROM AUTHOR]

BackgroundDespite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord gamma aminobutyric acidergic (GABAergic) inhibitory controls.ObjectivesWe sought to test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice).MethodsWe injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15 to 20 minutes prior to injection of various pruritogens (histamine, chloroquine, or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice.ResultsSystemic muscimol or baclofen are antipruritic against both histamine-dependent and -independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long-term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions.ConclusionsAlthough additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.

Chronic itch is a complex psychophysiological sensation, which can severely affect the quality of life in patients with atopic dermatitis and psoriasis. Itch depends on the irritation of receptors in the skin and the processing of sensory information in the central nervous system. Severe itch leads to activation and later on to disruption of the stress response, resulting in disorders of skin repair, functional and microstructural changes in the areas of the central nervous system that are responsible for the perception of itch. Psychosocial stress can be an essential factor, activating neurohumoral mechanisms which lead to increased itch and scratch, exacerbating skin damage. Patients with chronic itch often have sleep disorders, increased irritability, and depletion of the nervous system. They are characterized by disrupting social relationships, high incidence of anxiety, depressive disorders, and suicidal tendencies. Psychological methods of intervention can effectively influence various mechanisms in the pathogenesis of itch and scratch and improve social functioning in patients with chronic dermatological itch. In this mini-review, we discuss family constellation seminars as an effective method of psychological intervention that can reduce the intensity of itch, and improve sleep and performance in patients with atopic dermatitis and psoriasis. This method is insufficiently described in previous reviews of psychological interventions in atopic dermatitis and psoriasis patients. The positive impact of family constellations seminars in patients with chronic dermatological itch may be related to reducing stress by improving understanding of the family situation, appropriate management of family secrets, and enhancing interactions with the social environment.

Chronic itch is associated with sensitization of the somatosensory nervous system. Recent studies have identified the neural circuits transmitting acute itch; however, the mechanisms by which itch transforms into a pathological state remain largely unknown. We have previously shown that Aβ low-threshold mechanoreceptors, together with spinal urocortin 3-positive (Ucn3+) excitatory interneurons and neuropeptide Y-positive (NPY+) inhibitory interneurons, form a microcircuit that transmits and gates acute mechanical itch. Here, using whole-cell patch-clamp recordings, we observed increased excitability in spinal Ucn3+ neurons under chronic itch conditions. In contrast to Ucn3+ neurons, the excitability of spinal NPY+ neurons was largely reduced under chronic itch conditions. To explore the molecular mechanisms underlying sensitization of this microcircuit, we examined the mRNA expression levels of voltage-gated ion channels in recorded spinal Ucn3+ and NPY+ neurons by single-cell quantitative real-time PCR (qRT-PCR). We found that the expression levels of Nav1.6 and Cav2.3 channels were increased in spinal Ucn3+ neurons in chronic itch mice, while the expression level of SK3 channels was decreased. By contrast, the expression levels of Nav1.6 and BK channels were decreased in spinal NPY+ neurons in chronic itch mice. To determine the contribution of different ion channels in chronic itch sensitization, we then used a Markov Chain Monte Carlo method to parameterize a large number of biophysically distinct multicompartment models of Ucn3+ and NPY+ neurons. These models included explicit representations of the ion channels that we found to be up- or down-regulated under chronic itch conditions. Our models demonstrated that changes in Nav1.6 conductance are predominantly responsible for the changes in excitability of both Ucn3+ and NPY+ neurons during chronic itch pathogenesis. Furthermore, when simulating microcircuits of our Ucn3+ and NPY+ models, we found that reduced Nav1.6 conductance in NPY+ models played a major role in opening the itch gate under chronic itch conditions. However, changing SK, BK, or R-type calcium channel conductance had negligible effects on the sensitization of this circuit. Therefore, our results suggest that Nav1.6 channels may play an essential role in mechanical itch sensitization. The findings presented here may open a new avenue for developing pharmaceutical strategies to treat chronic itch. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Chronic itch is associated with sensitization of the somatosensory nervous system. Recent studies have identified the neural circuits transmitting acute itch; however, the mechanisms by which itch transforms into a pathological state remain largely unknown. We have previously shown that Aβ low-threshold mechanoreceptors, together with spinal urocortin 3-positive (Ucn3+) excitatory interneurons and neuropeptide Y-positive (NPY+) inhibitory interneurons, form a microcircuit that transmits and gates acute mechanical itch. Here, using whole-cell patch-clamp recordings, we observed increased excitability in spinal Ucn3+ neurons under chronic itch conditions. In contrast to Ucn3+ neurons, the excitability of spinal NPY+ neurons was largely reduced under chronic itch conditions. To explore the molecular mechanisms underlying sensitization of this microcircuit, we examined the mRNA expression levels of voltage-gated ion channels in recorded spinal Ucn3+ and NPY+ neurons by single-cell quantitative real-time PCR (qRT-PCR). We found that the expression levels of Nav1.6 and Cav2.3 channels were increased in spinal Ucn3+ neurons in chronic itch mice, while the expression level of SK3 channels was decreased. By contrast, the expression levels of Nav1.6 and BK channels were decreased in spinal NPY+ neurons in chronic itch mice. To determine the contribution of different ion channels in chronic itch sensitization, we then used a Markov Chain Monte Carlo method to parameterize a large number of biophysically distinct multicompartment models of Ucn3+ and NPY+ neurons. These models included explicit representations of the ion channels that we found to be up- or down-regulated under chronic itch conditions. Our models demonstrated that changes in Nav1.6 conductance are predominantly responsible for the changes in excitability of both Ucn3+ and NPY+ neurons during chronic itch pathogenesis. Furthermore, when simulating microcircuits of our Ucn3+ and NPY+ models, we found that reduced Nav1.6 conductance in NPY+ models played a major role in opening the itch gate under chronic itch conditions. However, changing SK, BK, or R-type calcium channel conductance had negligible effects on the sensitization of this circuit. Therefore, our results suggest that Nav1.6 channels may play an essential role in mechanical itch sensitization. The findings presented here may open a new avenue for developing pharmaceutical strategies to treat chronic itch.

Astrocytes are the most abundant glial cells in the central nervous system (CNS), including the spinal cord. Neuronal damage induces astrocytes to become reactive and contribute to various CNS pathologies. Recent studies have demonstrated that astrocytes in the spinal dorsal horn (SDH) become reactive in a transcription factor signal transducer and activator of transcription 3-dependent manner without neuronal damage under chronic itch conditions, causing release of the factor lipocalin-2, leading to induction of sensitization of gastrin releasing peptide-induced chemical itch signaling in the SDH. In this review, we describe recent advances in our understanding of SDH neuronal pathways for itch transmission, the mechanisms of SDH astrocytic activation and its contribution to abnormal itch processing and discuss the role of reactive astrocytes in the SDH in abnormal sensory processing under chronic itch conditions.

Abstract Background Dry skin itch is one of the most common skin diseases and elderly people are believed to be particularly prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. However, little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch. Methods Dry skin-induced chronic itch model was established by acetone-ether-water (AEW) treatment. Spontaneous scratching behavior was recorded by video monitoring. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes, transient receptor potential vanilloid type 1 (TRPV1), and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay (ELISA) kits. Nlrp1a knockdown was performed by an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. H.E. staining was used to evaluate skin lesion. Results AEW treatment triggers spontaneous scratching and significantly increases the expression of NLRP1, ASC, and caspase-1 and the levels of IL-1β, IL-18, IL-6, and TNF-α in the spinal cord and the skin of mice. Spinal cord Nlrp1a knockdown prevents AEW-induced NLRP1 inflammasome assembly, TRPV1 channel activation, and spontaneous scratching behavior. Capsazepine, a specific antagonist of TRPV1, can also inhibit AEW-induced inflammatory response and scratching behavior. Furthermore, elderly mice and female mice exhibited more significant AEW-induced scratching behavior than young mice and male mice, respectively. Interestingly, AEW-induced increases in the expression of NLRP1 inflammasome complex and the levels of inflammatory cytokines were more remarkable in elderly mice and female mice than in young mice and male mice, respectively. Conclusions Spinal cord NLRP1 inflammasome-mediated inflammatory response contributes to dry skin-induced chronic itch by TRPV1 channel, and it is also involved in age and sex differences of chronic itch. Inhibition of NLRP1 inflammasome may offer a new therapy for dry skin itch.

Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg -1 ·d -1 ) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)