Chronic Itch Research Articles

Parvalbumin Neurons in Zona Incerta Regulate Itch in Mice.

Pain and itch are intricately entangled at both circuitry and behavioral levels. Emerging evidence indicates that parvalbumin (PV)-expressing neurons in zona incerta (ZI) are critical for promoting nocifensive behaviors. However, the role of these neurons in itch modulation remains elusive. Herein, by combining FOS immunostaining, fiber photometry, and chemogenetic manipulation, we reveal that ZI PV neurons act as an endogenous negative diencephalic modulator for itch processing. Morphological data showed that both histamine and chloroquine stimuli induced FOS expression in ZI PV neurons. The activation of these neurons was further supported by the increased calcium signal upon scratching behavior evoked by acute itch. Behavioral data further indicated that chemogenetic activation of these neurons reduced scratching behaviors related to histaminergic and non-histaminergic acute itch. Similar neural activity and modulatory role of ZI PV neurons were seen in mice with chronic itch induced by atopic dermatitis. Together, our study provides direct evidence for the role of ZI PV neurons in regulating itch, and identifies a potential target for the remedy of chronic itch.

Mild Skin Heating Evokes Warmth Hyperknesis Selectively for Histaminergic and Serotoninergic Itch in Humans.

Chronic itch can severely affect quality of life. Patients report that their chronic itch can be exacerbated by exposure to warm conditions (“warmth hyperknesis”). The aim of this mechanistic study was to investigate the effect of mild heating of the skin in humans on various experimental models of itch. A total of 18 healthy subjects were recruited to the study. Itch was provoked by histamine, serotonin, or cowhage in 3 different sessions. The provoked area was heated with an infrared lamp, and the skin temperature was either not altered, or was increased by 4°C or 7°C. Subsequent to induction of itch, the itch intensity was recorded for 10 min while the skin was heated continuously throughout the entire period of itch induction. Heating the skin resulted in a significant increase in itch intensity when provoked by histamine or serotonin. It is possible that thermoception and pruriception interact and selectively produce a higher itch intensity in histaminergic and serotoninergic itch.

Involvement of Sensory Neurone-TRPV4 in Acute and Chronic Itch Behaviours

Abstract is missing (Short communication)

Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor-dependent itch.

Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca 2+ -activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca 2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1 -deficient mice rescued the impaired itching observed in Ano1 -deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.

MMrgprA3/mMrgprC11/hMrgprX1: Potential therapeutic targets for allergic contact dermatitis-induced pruritus in mice and humans.

Although the Mas-related G-protein-coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD)-associated itch remains unclear. To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets. Mrgpr-clusterΔ-/- mice and human MrgprX1 (hMrgprX1) transgenic mice were used to evaluate the function of Mrgprs in oxazolone-induced ACD. Utilizing an ACD model, we found that Mrgpr-clusterΔ-/- mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr-clusterΔ-/- mice, the expression of MrgprC11 and MrgprA3 was significantly increased in the ACD model, which also innervated the skin and spinal cord at higher-than-normal densities. The proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8-22 and chloroquine were also remarkably increased in the ACD model, resulting in enhanced itch behaviour. To study the function of human Mrgprs in ACD-induced itch, we used hMrgprX1 transgenic mice, which rescued the severe itch defect of Mrgpr-clusterΔ-/- mice in the ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse. Our study provides the first evidence that Mrgprs are involved in ACD-induced chronic itch, which provides new avenues for itch management in ACD.

Type 2 inflammation drives transcriptional remodeling of itch-sensory neurons

Type 2 inflammation is associated with chronic itch in the context of many conditions including atopic dermatitis (AD), chronic spontaneous urticaria, and prurigo nodularis. We thus hypothesized that chronic type 2 inflammation leads to remodeling of itch neurons, rendering them more pruritogenic than in a healthy host.

Mild Skin Heating Evokes Warmth Hyperknesis Selectively for Histaminergic and Serotoninergic Itch in Humans.

Chronic itch can severely affect quality of life. Patients report that their chronic itch can be exacerbated by exposure to warm conditions ("warmth hyperknesis"). The aim of this mechanistic study was to investigate the effect of mild heating of the skin in humans on various experimental models of itch. A total of 18 healthy subjects were recruited to the study. Itch was provoked by histamine, serotonin, or cowhage in 3 different sessions. The provoked area was heated with an infrared lamp, and the skin temperature was either not altered, or was increased by 4°C or 7°C. Subsequent to induction of itch, the itch intensity was recorded for 10 min while the skin was heated continuously throughout the entire period of itch induction. Heating the skin resulted in a significant increase in itch intensity when provoked by histamine or serotonin. It is possible that thermoception and pruriception interact and selectively produce a higher itch intensity in histaminergic and serotoninergic itch.

Paeonol Ameliorates Chronic Itch and Spinal Astrocytic Activation via CXCR3 in an Experimental Dry Skin Model in Mice.

Paeonol is a bioactive phenol presents mainly in Paeonia suffruticosa Andr. (Paeoniaceae), Paeonia lactiflora Pall., and Dioscorea japonica Thunb. (Dioscoreaceae), harboring various pharmacological activities including anti-inflammatory, antioxidant, immune regulatory activity and reverse chemoresistance. Recent reports revealed paeonol exhibited good effects on chronic dermatitis, such as atopic dermatitis (AD) and psoriasis. However, whether paeonol is effective for dry skin disease and its mechanism of action still remain unclear. In this study, we analysed the effects of paeonol on a mouse model of dry skin treated with acetone-ether-water (AEW), which showed impressive activities in reducing scratching behavior and skin inflammation. To elucidate the underlying molecular targets for the anti-pruritic ability of paeonol, we screened the expression of possible chemokine pathways in the spinal cord. The expression of CXCR3 was significantly alleviated by paeonol, which increased greatly in the spinal neurons of AEW mice. In addition, treatment of paeonol significantly inhibited AEW-induced expression of astrocyte activity-dependent genes including Tlr4, Lcn2 and Hspb1 et al. The inhibitory effects of paeonol on scratching behavior and astrocytic activation in the spinal cord induced by AEW were abolished when CXCR3 was antagonized or genetically ablated. Taken together, our results indicated that paeonol can ameliorate AEW-induced inflammatory response and itching behavior, and reduce the expression of spinal astrocyte activity-dependent genes induced by AEW, which are driven by CXCR3.

The Role of Transient Receptor Potential A1 and G Protein-Coupled Receptor 39 in Zinc-Mediated Acute and Chronic Itch in Mice.

Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.

Association of atopic dermatitis with delinquent behaviors in US children and adolescents.

Childhood atopic dermatitis (AD) is associated with chronic itch, pain and sleep disturbance, which may predispose children to high-risk behaviors in their school and home environments. We examined the association between AD and delinquent/high-risk behaviors in children and adolescents. Data were analyzed from The Fragile Families and Child Wellbeing Study, a longitudinal birth cohort study consisting of 4898 children born in urban cities between 1998 and 2000. A 1-year history of AD was associated with ≥ 75th percentile of mean delinquent behavior scores at age 9 (adjusted odds ratio (aOR) [95% confidence interval] 1.39 [1.14-1.68]), but not age 15 (1.05 [0.86-1.29]). At age 9, a 1-year history of AD was associated with a higher number of delinquent behaviors (adjusted risk ratio [95% CI] 1.12 [1.03-1.23]). AD at ages 5 (aOR [95%CI] 1.31 [1.04-1.64]) and 9 (1.38 [1.14-1.67]) was associated with the highest quartile of mean delinquent behavior scores at ages 9 or 15. Children with AD persisting at multiple age groups had significantly increased odds of ≥ 75th percentile of mean delinquent behavior scores at age 15 (aOR [95%CI] 1.41 [1.09-1.81]). AD was found to be associated with the following delinquent problems: damaging property (aOR [95%CI] 1.38 [1.08-1.77]), cheating on a test (1.62 [1.17-2.26]), fist fight involvement (1.47 [1.21-1.79]) and school suspension (1.36 [1.08-1.71]). This study suggests that childhood AD may precede the onset of delinquent and high-risk behaviors later in childhood and adolescence.

Study of the Involvement of the P2Y12 Receptor in Chronic Itching in Type 2 Diabetes Mellitus.

Itching is a common clinical symptom in diabetic patients. This research is to carry out experiments on the pathological changes in the P2Y12 receptor in type 2 diabetes mellitus complicated with chronic itching. Changes in body weight, fasting blood glucose (FBG), thermal hyperalgesia, cold hyperalgesia, spontaneous itching, and sciatic nerve conduction velocity were detected. The content of reactive oxygen species (ROS) in the dorsal root ganglion was detected by chemical fluorescence. The expression of the P2Y12 receptor, NLRP3, ASC, interleukin-1β (IL-1β), and IL-18 was detected by Western blotting, real-time quantitative PCR, immunofluorescence double labelling, and enzyme-linked immunosorbent assay. Itching and pain behaviours of the mice in the type 2 diabetes mellitus + itch group were significantly increased, and the expression of P2Y12 and NLRP3 as well as the content of ROS increased, and these changes were significantly reversed by treatment with P2Y12 short hairpin RNA (shRNA) or P2Y12 antagonist ticagrelor. Upregulated P2Y12 receptor expression after the activation of satellite glial cells contributes to the increase in ROS content in vivo, followed by NLRP3 inflammasome activation, increased inflammatory cytokine release, and damage to peripheral nerves, which leads to chronic itching. Treatment with P2Y12 shRNA or ticagrelor can inhibit these pathological changes, thus improving itching behaviour. Development mechanism of diabetes mellitus complicated with chronic itching. Notes: The upregulation of P2Y12 receptor expression and the activation of SGCs lead to the increase of ROS content in vivo, followed by the activation of NLRP3 inflammasome, the increase of inflammatory cytokine release, the abnormal excitation of DRG neurons, and the damage of peripheral nerves, resulting in chronic itching. P2Y12 receptor-related inflammatory injury involves chronic itching in type 2 diabetes mellitus. Treatment with P2Y12 receptor shRNA or P2Y12 antagonist ticagrelor can inhibit these pathological changes and improve itching behaviour.

Pathophysiological Role of TLR4 in Chronic Relapsing Itch Induced by Subcutaneous Capsaicin Injection in Neonatal Rats.

Despite the high prevalence of chronic dermatitis and the accompanied intractable itch, therapeutics that specifically target itching have low efficacy. Increasing evidence suggests that TLRs contribute to immune activation and neural sensitization; however, their roles in chronic itch remain elusive. Here, we show that the RBL-2H3 mast cell line expresses TLR4 and that treatment with a TLR4 antagonist opposes the LPS dependent increase in mRNA levels of Th2 and innate cytokines. The pathological role of TLR4 activation in itching was studied in neonate rats that developed chronic itch due to neuronal damage after receiving subcutaneous capsaicin injections. Treatment with a TLR4 antagonist protected these rats with chronic itch against scratching behavior and chronic dermatitis. TLR4 antagonist treatment also restored the density of cutaneous nerve fibers and inhibited the histopathological changes that are associated with mast cell activation after capsaicin injection. Additionally, the expression of IL-1β, IL-4, IL-5, IL-10, and IL-13 mRNA in the lesional skin decreased after TLR4 antagonist treatment. Based on these data, we propose that inhibiting TLR4 alleviated itch in a rat model of chronic relapsing itch, and the reduction in the itch was associated with TLR4 signaling in mast cells and nerve fibers.

Characterization of chronic itch in college students in China.

Chronic itch affects a wide range of individuals and has a noticeable influence on human health. However, epidemiological characteristics of chronic itch have not yet been adequately addressed. To investigate the prevalence and associated factors for chronic itch. This was a cross-sectional study of first-year students in five universities in different regions of China. Chronic itch was defined as moderate-to-severe itch for more than six weeks. Social and behavioural factors were measured through an online questionnaire survey. Environmental factors including humidity, temperature and levels of air pollutants at district/county level were obtained from public datasets. Generalized linear-mixed models were used to fit multi-level data. A total of 27,144 students were enrolled to the universities and 18,360 subjects who completed the survey were included in the final analysis. The mean age of participants was 18.3 ± 0.8 years, and 51.1% were women. The point prevalence of chronic itch was 16.9%. Chronic itch was associated with female sex (OR = 0.78, p < 0.001) and was inversely associated with higher parental educational levels. With respect to environmental factors, chronic itch was significantly associated with relative humidity (OR = 1.01, p = 0.02), temperature (OR = 1.03, p<0.001) and O3 (OR = 0.91, p < 0.001). Regarding behavioural factors, chronic itch was significantly associated with smoking, exposure to second-hand smoke, drinking alcohol, less physical activity, intake of pepper, preference for spicy food, bathing (temperature, frequency, and duration) and sunscreen. Chronic itch affects a substantial proportion of Chinese college students, and is attributable to demographic, dermatological, environmental and behavioural factors.

Involvement of Mas-related G protein-coupled receptor X1 (MrgprX1) in the chronic itch

Atopic dermatitis (AD) is a common dermatologic disease that is accompanied by severe chronic pruritus. Recently, it has been reported that mas-related G protein-coupled receptor (Mrgpr) involves in the control of histamine-independent itch and the modulation of Mrgpr might be a promising target for the treatment of chronic itch. In the present study, we used the transgenic mice expressed human MrgprX1 in the sensory nerve and Mrgpr cluster KO (Mrgpr-KO) mice and evaluated the scratching behaviors in the acute itch model evoked by BAM8-22. In addition, the modulation of Mrgpr and the effect of steroid drug in the MC903-induced chronic itch model in both transgenic mice were examined. Intradermal BAM8-22 did not induce the scratching behaviors in the Mrgpr-KO mice over vehicle-treatment, on the other hand, it evoked scratching behaviors in the hMrgprX1 transgenic mice compared to the vehicle-treated animals. In the chronic itch model evoked by the repetitive application of MC903 produced the scratching behaviors in both Mrgpr-KO and hMrgprX1 transgenic mice over vehicle-treatment, but the ones in the hMrgprX1 mice evidently outweighed them in the Mrgpr-KO mice. In addition, dexamethasone, a steroid drug, significantly attenuated the scratching behaviors evoked by MC903 in both Mrgpr-KO and hMrgprX1 transgenic mice to the same extent. From these observations, it is suggested that the itch in the AD patients might be able to be inhibited completely by the combination of steroid and hMrgprX1 antagonist.

Report on 25 Notalgia paresthetica cases: Clinical features and treatments.

Notalgia paresthetica (NP) is a neuropathic condition that manifests as a chronic itch on the back. The aim of this retrospective study was to examine the characteristics of patients diagnosed with NP. A total of 25 female patients, aged 26-64 years (mean+-10.67 years; median 47.17 years), were studied to determine the spinal or peripheral origin of NP. On radiological examination, discopathy was observed in 24% of the patients, arthrosis in 32%, and degeneration in 56%. There was no significant relationship found between dermatological symptoms and magnetic resonance imaging posi-tivity (p=0.188). The patients' treatment programs were based on either physical therapy (44%), local injection (28%), exercise therapy (16%), or physical therapy and kinesiotherapy (12%). Subjective measures for pain were validated with an average visual analog scale (VAS), and the 'Douleur Neuropathique 4' (DN4) questionnaire was used to screen for neuropathic pain. The VAS score of the patients before treatment was 7, and after treatment was 2. The mean DN4 score was 7 before treatment and 2 after treatment. NP is a rare syndrome of unknown etiology. We aim in this study to analyse NP clinical properties and treatment.

The role of TRPV4 channels in cutaneous epithelia.

Transient receptor potential vanilloid 4 (TRPV4) channels are multi-modally activated cation permeable channels that are expressed most organ tissues including the skin. TRPV4 is highly expressed in the skin and functions in skin resident cells such as epidermal keratinocytes, melanocytes, immune mast cells and macrophages, and cutaneous neurons. TRPV4 plays many crucial roles in skin homeostasis to affect an extensive range of processes such as temperature sensation, osmo-sensation, hair growth, cell apoptosis, skin barrier integrity, differentiation, nociception and itch. Since TRPV4 functions in a plenitude of pathological states, TRPV4 can become a versatile therapeutic target for diseases such as chronic pain, itch and skin cancer.

Development and preliminary validation of the patient-reported Chronic Itch Burden Scale assessing health-related quality of life in chronic pruritus.

Chronic pruritus (CP) significantly affects patients' health-related quality of life (HRQoL). Very few self-reported HRQoL questionnaires exploring CP have been developed according to international guidelines, thus limiting their use in preauthorization trials. To develop a self-reported HRQoL questionnaire in patients with CP owing to psoriasis, atopic dermatitis, seborrhoeic dermatitis of the scalp or idiopathic dermatitis, and to explore the preliminary psychometric properties of the questionnaire. The study was performed in France. A conceptual framework was developed based on a structured literature review and expert insight, and was improved using three focus groups involving 19 participants. A 50-item questionnaire was created and tested with 21 participants using cognitive debriefings; 11 items were removed. A cross-sectional study including 251 participants was performed to explore the preliminary psychometric properties of the 39-item questionnaire. Dimensionality was explored using principal component analysis. Cronbach's alpha and correlation coefficients (interitem, item-total score and item-dimension score) were measured. The number of items was reduced through expert consensus. In the 39-item version, three main dimensions were identified (Cronbach's alpha = 0·94) and all correlation coefficients were > 0·34. Upon review, 13 items were deleted owing to poor quality and six items were deleted by the team, generating a 20-item version. The questionnaire's factorial structure was best reflected with a two-dimension solution, i.e. (i) social and emotional repercussions and (ii) relation to others, fear of judgement. The Chronic Itch Burden Scale patient-reported questionnaire explores broad aspects of HRQoL that are relevant for patients with various skin diseases. Its good cross-sectional validity makes it useful for trials and practitioners.

Inhibitory effect of mirogabalin for chronic itch in atopic dermatitis model mice

Inhibitory effect of mirogabalin for chronic itch in atopic dermatitis model mice

The ‘Chronic Itch Burden Scale’: giving patients with chronic pruritus a voice

Abstract Linked Article: Theunis et al. Br J Dermatol 2022; 186:86–95.

Variations of symptoms of atopic dermatitis and psoriasis in relation to menstrual cycle

To the Editor: Atopic dermatitis (AD) is a multifactorial, chronic relapsing, itchy, T helper 2 (Th2)-cytokine–driven skin disease.1,2 Type 2 cytokines, including interleukin 4 (IL-4), IL-13, and IL-31, also act as master regulators of chronic itch.2 Circulating sex hormones regulate skin homeostasis; in particular, progesterone impairs skin barrier function.3 Estradiol and progesterone directly or indirectly modulate the secretion of Th2 cytokines, with higher Th2 polarization during the luteal phase and pregnancy.