Chronic Itch Research Articles

Imperatorin activates TRPV1/GRPR pathway to induce scratching behaviors in mice.

Vitexin alleviates atopic dermatitis-associated itch via TRPV4 inhibition in sensory neurons and MRGPRX2/MrgprB2 blockade in mast cells.

Nav1.7 has emerged as a promising target for developing novel analgesics that avoid central side effects, yet clinical trials involving systemically administered Nav1.7 inhibitors have thus far yielded disappointing outcomes. In this study, we explored whether delivering PF-05089771-a highly selective Nav1.7 inhibitor previously tested in clinical settings-directly into the intrathecal space could elicit potent analgesic effects. We assessed pain responses using a range of behavioral assays, including the Hargreaves, hot plate, von Frey hair, and Randall-Selitto tests, while evaluating motor coordination and gastrointestinal transit through the rotarod test and a charcoal meal gavage method, respectively. Intrathecal administration of PF-05089771 produced rapid (within 15 minutes) and long-lasting (>4 hours) analgesia across multiple pain models, including nociceptive, inflammatory, neuropathic, and morphine-tolerant pain, as well as both acute and chronic itch. However, no significant effect was observed in a visceral pain model. The analgesic effects were abolished by naloxone pretreatment, implicating endogenous opioid signaling in the mechanism of action. Importantly, repeated intrathecal injections did not lead to analgesic tolerance, and no adverse effects on motor function or gastrointestinal motility were detected. These results indicate that changing the delivery route of Nav1.7 inhibitors may overcome limitations seen with systemic administration and highlight the potential of intrathecal PF-05089771 as a powerful and well-tolerated analgesic.

Background. Itch is a key dermatological symptom with variety of clinical characteristics, provoking and etiological factors, as well as consequences, including its impact on psychological parameters. Previously, we have proposed an integrative psychodermatological typology of itch based on the assessment of its duration and impact on quality of life. Aim: Based on a comparative clinical and psychometric assessment, to rank by severity the types of itch previously identified according to the chronicity criteria and impact on quality of life, taking into account their associations with psychosomatic characteristics (anxiety, depression, dysmorphophobia, perceived stress, and stigmatization), and to determine the predictors of a patient getting into the groups with severe types of itch. Methods: This was a multicenter, cross-sectional observational study conducted in three outpatient dermatology clinics from November 2021 to December 2024. During the initial study step, 203 patients with itch were selected for subsequent analysis from those with atopic dermatitis (n = 106), psoriasis (n = 101), acne (n = 104), melanocytic nevi (n = 105), melanoma (n = 88), and skin toxic reactions to anti-tumor treatments (n = 93). Based on a two-step cluster analysis of seven quantitative characteristics of itch (intensity, numerical rating scale), frequency, impact on everyday life, communication with others, sleep, life satisfaction and mood (5PLQ), as well as one categorical variable qualifying itch as acute / chronic (less / more than 6 weeks), we have identified four itch clusters (types): 1) chronic itch with a little impact on quality of life; 2) acute itch with a little impact on quality of life; 3) acute itch with a strong impact on quality of life; 4) chronic itch with a strong impact on quality of life. In this study (step 2), the types of itch identified were compared depending to the severity of associated psychosomatic disorders according to psychometric evaluation for anxiety (GAD-2), depression (PHQ-2, both parts of PHQ-4 anxiety and depression screening scale), for perceived stress (PSS-10), stigmatization (PSQ), and dysmorphophobia (DCQ). We also looked for predictors of severe itch types. Results: The study included 203 patients with itch and various dermatoses and skin neoplasms, as well as skin toxic reactions to antitumor therapy (71.9% women, median age 45 years, 95% confidence interval [CI]: 30–60 years). The patients with the identified four types of itch did not differ in terms of education (p = 0.07), marital status (p = 0.653), employment (p = 0.124), and body mass index (p = 0.192). There were significant differences between the patients with different types of itch on all the scales used and the parameters evaluated, with an increase in parameters from cluster 1 to cluster 4, respectively, as follows: the median total score of anxiety and depression (PHQ-4: 3,00; 3,00; 5,00; 8,00; p 0,001), anxiety score (GAD-2: 2; 2; 3; 4; p 0.001), depression (PHQ-2: 1; 1; 3; 3; p 0.001), dysmorphophobia score (DCQ: 5; 5; 5; 11; p 0.001), stigmatization level (PSQ: 11; 16; 17; 26.5; p 0.001), the proportion of patients with depression (17.7; 17.8; 51.4; 65.9%; p 0.001), anxiety (15.2; 28.9; 51.4; 65.9%; p 0.001) and dysmorphophobia (6.3; 4.4; 17.1; 34.1; p 0.001) above diagnostic thresholds, the level of perceived stress on the PSS-10 scale (p 0.001). Dysmorphophobia parameters and the perceived stigmatization level were the predictors of more severe types of itch: an increase in these indices was associated with an increase in the odds ratio (OR) of getting into itch clusters 3 and 4 (OR 1.77, 95% CI: 1.33–2.36 and OR 1.66, 95% CI: 1.25–2.19, respectively). Conclusion: The validity of the previously proposed by us typology is confirmed by identification of statistically significant differences found in this study with the psychometric assessment of associated psychosomatic characteristics. The increments in the parameters from the 1st to the 4th cluster allow us to rank the previously selected types of itch according to severity: 1) chronic itch, which has little effect on quality of life, as mild; 2) acute itch with little effect on quality of life as mild-to-moderate; 3) acute itch severely affecting quality of life, as moderate-to severe; 4) chronic itch with strong effects on quality of life, as severe one. Differentiation of the types of itch by severity is of practical importance, since it allows us to reasonably identify groups of patients most severely affected by and potentially being in need of comprehensive interdisciplinary management.

Psoriatic arthritis (PsA) is a chronic inflammatory disorder with autoimmune features, often associated with psoriasis. Its prevalence in Indian psoriasis patients is around 8.47%. In Ayurveda, early skin and muscle symptoms relate to Uttana Vatarakta, while joint involvement indicates Gambhira Vatarakta, involving Vata, Rakta, and deeper dhatus. A 9-year-old female with chronic itching, burning, and recent joint pain was treated with Shamana and Shodhana Chikitsa. Marked improvement in both skin and joint symptoms was observed, highlighting the effectiveness of Ayurvedic management in PsA.

Type 2 cytokines pleiotropically modulate sensory nerve architecture and neuroimmune interactions to mediate itch.

Sensory neurons residing in dorsal root ganglia (DRG) transmit sensory information such as pain, itch, touch, pressure and bodily position to the central nervous system. The activity of sensory neurons is regulated by non-neuronal cell types in the DRG, including satellite glial cells (SGCs) and fibroblasts. Dysregulated gene expression in DRG cells contributes to sensory nervous system disorders such as chronic pain and itch. Understanding the genetic underpinnings of these conditions requires dissecting transcriptional regulation in human DRG (hDRG). In this study, we profiled transcriptomic and chromatin accessibility landscapes from postmortem hDRG samples at single-cell level. We demonstrate that sequencing depth significantly impacts downstream analysis, with deeper sequencing yielding more detected cells and features, improved data integration, refined clustering and annotation, and more accurate scientific interpretations. We identified nine major cell types, defined their molecular signatures, and mapped cis-regulatory landscapes. Integration of gene expression with chromatin accessibility enabled peak-gene association and transcriptional network analyses, revealing transcription factors, their target genes, and their regulatory elements. This approach uncovered cell types, genes, and cis-regulatory regions potentially driving pain conditions. Our unbiased genome-wide analysis confirmed known pain-related genes and highlighted novel candidates. These findings provide new insight into molecular mechanisms and candidate cell types involved in pain. Importantly, our results demonstrate that non-neuronal cell types, including endothelial cells, fibroblasts, macrophages, and SGCs, play critical roles in pain pathogenesis and should be investigated as therapeutic targets.

CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis.

Identification of disease-specific regulatory networks in prurigo nodularis versus atopic dermatitis through ATAC/RNA single-nucleus profiling.

Vulvar pruritus refers to itching affecting the skin and mucosal surfaces of the external genital and perineal regions. It is most frequently associated with infections, inflammatory skin disorders, or neoplastic conditions. Due to the distinctive anatomical and physiological features of the anogenital area, clinical manifestations in this region are often subtle or atypical, which can complicate both diagnosis and management. Because vulvar itch can be highly distressing, timely identification and appropriate intervention are crucial for improving patient quality of life. A comprehensive clinical approach is essential when evaluating patients with vulvar pruritus. This includes a detailed medical history, focused physical examination, and relevant diagnostic testing. Management should involve elimination of contributing or exacerbating factors and treatment directed at the underlying cause. This review article discusses the common causes of vulvar pruritus, emphasizing the diagnostic approach and outlining current treatment strategies. The importance of an individualized patient-centered management plan is emphasized.

Cutaneous T-cell lymphomas (CTCL) are rare skin-predominant lymphomas, with Mycosis fungoides being the most common subtype. In Europe, the incidence is about 0.3 per 100 000 patient years. The majority of patients are suffering from limited disease with a 5-year survival of 90 %. Clinically, skin lesions can mimic eczema or psoriasis, leading to delayed diagnosis. CTCL diagnosis requires a combination of clinical examination, skin biopsy with histopathological analysis and blood tests to assess systemic involvement. CTCL treatment is stage-dependent. Depending on the stage of the disease, local or systemic therapies can be used. Individually optimised combinations are common. Novel targeted therapies such as brentuximab vedotin and mogamulizumab have expanded the treatment landscape, offering more effective and personalized options. Allogeneic stem cell transplantation is the only curative approach. In CTCL, quality of life is often impaired due to chronic itching, fatigue, and stigmatizing skin lesions. Psychodermatologic care plays a key role in comprehensive patient support.

Alloknesis refers to itch caused by normally non itch-inducing stimuli, particularly light mechanical stimuli, such as contacts with clothes or other human bodies. This symptom occurs in patients suffering from chronic itch. While it has been mainly described in patients with atopic dermatitis, it is probably present in numerous other conditions and it could induce a severe burden. Until now, it is mainly diagnosed using Von Frey filaments and validated questionnaires are lacking. Alloknesis differs from mechanical pruritus in that it is linked to sensitization to pruritus and therefore occurs in pathological conditions, whereas mechanical pruritus (triggered by the presence of insects on the skin, for example) is a physiological phenomenon. While the role of central sensitization to pruritus in alloknesis is still poorly understood, the role of peripheral sensitization is becoming clearer. Interactions between low-threshold mechanoreceptors (LTMRs) and spinal interneurons are especially involved. Both the mechanical labelled pathway and the polymodal pathway have been shown to contribute to mechanical alloknesis. The mechanical labelled pathway comprises dedicated primary sensory neurons, spinal interneurons, and projection neurons that are functionally distinct from those involved in chemical itch. The polymodal pathway relies on a subset of primary sensory neurons traditionally associated with chemical itch, which can also transduce light mechanical stimuli through the activation of the mechanosensitive ion channel PIEZO1. Both converge onto the gastrin-releasing peptide (GRP) - GRP receptor (GRPR) chemical itch pathway in the spinal cord. Alloknesis is largely unknown to healthcare professionals and even more so to patients, and is not actively investigated. The objective of reducing alloknesis should be considered a therapeutic goal. To date, it has not been investigated in clinical trials. A novel research domain is emerging concerning this symptom, which exerts a substantial impact on the daily lives of numerous patients.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a significant psychological impact. The cardinal symptom of all phenotypes and severities is chronic pruritus with repetitive itching and scratching due to a vicious itch-scratch cycle that can be worsened or triggered by stress. Neuroimaging of brain areas responsible for itch processing in healthy subjects versus patients with AD has provided insights into the brain circuits involved in itch central perception. In patients with AD, the dorsolateral prefrontal cortex appears to be overactive while regulating the itch-scratch circuit, and this persistent hyperactivation over time may disrupt this brain region. Common mechanisms between addiction and scratching could explain why some patients with AD continue to scratch despite showing clinical improvements from conventional treatments. In addition, molecular knowledge indicates bidirectional neuroimmune circuits between the peripheral nervous and immune system and dysregulated skin cells may aggravate and perpetuate AD severity. We provide an overview of the basic mechanisms that underlie the itch-scratch cycle in AD, especially neural sensitization of nonhistaminergic itch-specific pathways, and discuss how integrative therapies may interfere with central and peripheral mechanisms of chronic itch to reduce neuroinflammation and break the itch-scratch cycle. The connection between mind and body in the itch-scratch cycle, involving central mechanisms, suggests that integrative and multidisciplinary treatment approaches could be helpful as an adjunct to pharmacological treatment in the clinical management of AD. Integrative therapies may potentially help to reduce pruritus and scratching, psychological stress and sleep disturbances, and improve immune and skin barrier dysregulation, AD outcomes, and patient well-being.

The human MAS-related G-protein-coupled receptors (MRGPRs) represent a promising therapeutic target for managing chronic itch and pain. Among them, MRGPRX4 is activated by bile acids in dorsal root ganglia (DRG) neurons and contributes to the cholestatic itch. Here, we report the design, synthesis, and in vitro evaluation of a focused library of functionalized terpene-based thiazole hydrazines targeting MRGPRX receptors. Functional assays identified two compounds, 1C and 3G, as negative allosteric modulators (NAMs) of MRGPRX4 with IC50 values of 337 nM and 15.5 μM, respectively, and showed weak activity at MRGPRX2. Computational analysis suggested a putative NAM binding site adjacent to the orthosteric pocket involving key interactions with residues H923.22, K963.26, and R1594.62. The resulting site overlaps with the receptor activity-modifying protein 2 (RAMP2) interaction region, where RAMP2 antagonizes MRGPRX4 as a NAM. These findings provide a foundation for developing selective MRGPRX4 NAMs as novel therapeutic agents for chronic itch and pain.

PurposeEpidermolysis bullosa (EB) is a rare genodermatosis characterized by fragility and blistering of the skin and mucous membranes following minor trauma. Attending school presents unique educational and psychosocial challenges for students with EB. This study aimed to investigate perceptions of school climate and educational experiences among students with EB in Saudi Arabia.MethodsA cross-sectional observational study was conducted involving students with EB, aged 3–22 years, recruited from the Saudi EB registry. Data were collected using a self-reported 23-item multidimensional questionnaire assessing physical, psychological, social, financial, and learning domains. Data were collected from January 2024 to April 2024. Descriptive and inferential statistical analyses were performed using SPSS software.ResultsThirty-one students with EB were enrolled in this study. The EB subtypes were as follows: EB simplex (n=10), junctional EB (n=7), dystrophic EB (n=11), Kindler EB (n=1), and two patients with unknown types. Participants had an overall negative perception of school climate (mean, 58.5±14.3). A significant proportion of students experienced delayed entry into elementary school due to EB (41.9%). Students with junctional EB, those in high school, late-entry grade 1 students, and those from low-income families reported more negative perceptions of the school climate. Key challenges included difficulty in physical education classes, stigmatization, bullying, social isolation, and chronic wound-related pain and itching. Frequent absences were reported by 51.6% of the students. Homeschooled students demonstrated better learning scores than those attending traditional schools. Students with severe EB subtypes (junctional and dystrophic EB) demonstrated a higher preference for homeschooling.ConclusionThis study highlights the unmet needs of students with EB and provides insights into recommendations to enhance their adjustment in schools. Students with EB face substantial educational and psychosocial challenges. Tailored accommodations are needed to promote inclusion and improve school experiences for this population.

Chronic itch can arise from a variety of etiologies, ranging from dermatological conditions like eczema and psoriasis to systemic diseases such as liver disease and kidney failure. However, it remains unclear whether there are common molecular features associated with chronic itch, and whether these features are selective for chronic itch compared to chronic pain. To identify potential genes or molecular characteristics that are specifically associated with chronic itch, we examined transcriptomic data from sensory neurons collected from 3 mouse models of chronic itch and a monkey model of contact dermatitis. We compared these data to transcriptomic data from 3 mouse models of pain and clinical data from patients with neuropathic pain. Our analyses revealed that the upregulation of Nppb expression in sensory neurons is consistently associated with models of itch, but not with models of pain. Further, our cellular characterization showed that the increased expression of Nppb arises from increased cell-autonomous expression rather than the recruitment of Nppb expression in other classes of sensory neurons. Given that Nppb is a well-established itch neurotransmitter, our findings suggest that the increased expression of Nppb in sensory neurons may contribute to chronic itch. In addition, based on our results, we propose that Nppb could serve as a conserved biomarker for chronic itch.

The parabrachial nucleus (PBN) plays a crucial role in transmitting itch and affective pain signals to the brain regions such as the central amygdala (CeA). While CGRP+ PBN neurons have been implicated in itch processing, the specific projections involved remain unclear. This study aimed to determine the proportion of itch-responsive PBN-CeA projections that express CGRP and to assess their functional role in itch and anxiety behaviors in mice. Using the Targeted Recombination in Active Populations system, we labeled itch-responsive PBN neurons with serotonin. Retrograde tracing revealed that approximately half of serotonin-responsive PBN neurons projecting to the CeA are CGRP+. Optogenetic stimulation of these PBN-CeA neurons elicited scratching behavior but did not enhance pruritogen-induced scratching or affect anxiety-like behaviors. In a mouse model of chronic itch, the inhibition of PBN-CeA neurons significantly reduced spontaneous scratching without impacting anxiety-like behaviors. These findings suggest that serotonin-responsive PBN-CeA neurons include both CGRP+ and non-CGRP+ populations and selectively mediate itch signaling.

Skin disorders are very common and their burden on population is significant. Skin diseases are rarely fatal but due to chronicity of disease it causes considerable distress to patient. Eczema or dermatitis is a group of inflammatory skin diseases provoked by a wide variety of stimuli, i.e. direct injury from toxic chemicals, mechanical trauma and immunological reactions. Chronic Eczema is represented by severe itching, hyperkeratosis and lichenification. Lichen simplex chronicus one of the characteristic examples of chronic eczema. It is a skin condition characterized by chronic itching and scratching that leads to thickened [hypertrophied], hyperpigmented plaques with increased skin marking. Acharya Charaka Described Kitibha Kustha in context of Kshudra Kustha. The skin lesions in Kitibha Kustha are blackish [hyperpigmented], rough in touch like scar [hypertrophied], Dry & hard on touch. there is predominance of Vata-Kapha Dosha in Kitibha Kustha. The clinical presentation of Kitibha Kustha is resembling with lichen simplex chronicus. We have successfully treated this case of Lichen simplex chronicus with Shaman Snehapana, Jalauka-Awacharan, Khadira Lepa with Jatyadi Taila and Kashayapana.

Abstract Atopic dermatitis (AD) is a T helper 2-mediated inflammatory condition, resulting in erythematous and pruritic skin. Patients with AD often have chronic itching, leading to subsequent scratching, which further damages the skin and exacerbates cutaneous inflammation. Patients with AD often experience severe itching–scratching behaviour at night, leading to poor sleep quality. Chronic sleep disturbances during early childhood may alter brain development and neural connectivity, contributing to the increased risk of neuropsychological problems in patients with AD. In Mind & Skin, we aim to understand how inflammation and itch experienced by patients with AD can affect sleep, functional connectivity and cognitive function. Adolescent patients with AD were recruited from paediatric allergy and dermatology clinics, whereas healthy controls were recruited from patients’ healthy siblings or through internal newsletters. Resting-state functional magnetic resonance imaging (fMRI) scans were acquired from the participants. The participants also completed a series of cognitive tasks using the Maudsley Attention and Response Suppression task battery to assess their attention, motor and cognitive inhibition, and time perception. Eighteen adolescent patients with AD with a range of disease severities (median age 15 years, range 12–18) and nine healthy controls (median age 15 years, range 12–16) were recruited for the study. The patients with AD had a median Eczema Area and Severity Index score of 4.45 (range 0.8–30.9). Sixteen resting-state networks were identified from fMRI analysis. The patients with AD, relative to healthy controls, had significant increases in functional connectivity within the somatosensory motor network, likely associated with chronic itching–scratching behaviours. The patients with AD exhibited reduced functional connectivity between the visual cortex and the temporoparietal network compared with healthy controls. The cohort with AD also showed decreased performance in the Simon (cognitive interference inhibition) and time discrimination tasks compared with healthy controls. The temporoparietal junction (TPJ) has been suggested to be a multisensory integration hub and is crucial for visual–spatial attention to external stimuli. Enhanced somatosensory connectivity in AD may disrupt TPJ–visual connectivity, potentially affecting selective visual–spatial attention and contributing to reduced ability in the Simon task. Our preliminary findings provide insights into the neurocognitive effects of the chronic itch–scratch behaviours associated with AD and how they may be associated with changes in brain network connectivity. These insights highlight the need for a multidisciplinary approach to address the dermatological and neurodevelopmental impacts of AD, with future studies aimed at identifying targeted interventions that mitigate these specific cognitive difficulties and improve quality of life.

Itch is an unpleasant sensation and a primary symptom of skin diseases. Chronic itch is often pathological and can be a basis for inflammatory, infectious, neoplastic, and autoimmune skin diseases. Mast cells (MCs) are multifunctional innate immune cells situated at the host-environment interface with a pivotal role in the pathogenesis of pruritus. IgE-mediated and non-IgE-mediated MC activators can participate in different pruritus mechanisms in skin diseases. However, the exact functions of MCs in diverse pruritus conditions have not been addressed in detail. In particular, the role of non-histamine mediators released by MCs has been overlooked in chronic itch. This review aims to explore the role of MCs in chronic pruritus and outline the mechanisms of MC activation in various dermatological itch conditions.