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The Janus kinase 1/3 inhibitor tofacitinib has demonstrated an antipruritic effect in two phase III studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently investigated whether tofacitinib affects spontaneous itch as well as expression of itch-related cytokines and epidermal nerve fiber density (ENFD) in the imiquimod-induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was significantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and increased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD without a significant effect on nonpeptidergic ENFD. Tofacitinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epidermal innervation.

Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the activation of low-threshold mechanoreceptors. However, the mechanisms behind this inhibition remain unknown. We presently investigated whether stroking the skin reduces the responses of superficial dorsal horn neurons to pruritogens in male C57BL/6J mice. Single-unit recordings revealed that neuronal responses to chloroquine were enhanced during skin stroking, and this was followed by suppression of firing below baseline levels after the termination of stroking. Most of these neurons additionally responded to capsaicin. Stroking did not suppress neuronal responses to capsaicin, indicating state-dependent inhibition. Vesicular glutamate transporter 3 (VGLUT3)-lineage sensory nerves compose a subset of low-threshold mechanoreceptors. Stroking-related inhibition of neuronal responses to chloroquine was diminished by optogenetic inhibition of VGLUT3-lineage sensory nerves in male and femaleVglut3-cre/NpHR-EYFPmice. Conversely, in male and femaleVglut3-cre/ChR2-EYFPmice, optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited firing responses of spinal neurons to pruritogens after the termination of stimulation. This inhibition was nearly abolished by spinal delivery of the κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride, but not the neuropeptide Y receptor Y1 antagonist BMS193885. Optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited pruritogen-evoked scratching without affecting mechanical and thermal pain behaviors. Therefore, VGLUT3-lineage sensory nerves appear to mediate inhibition of itch by tactile stimuli.SIGNIFICANCE STATEMENTRubbing or stroking the skin is known to relieve itch. We investigated the mechanisms behind touch-evoked inhibition of itch in mice. Stroking the skin reduced the activity of itch-responsive spinal neurons. Optogenetic inhibition of VGLUT3-lineage sensory nerves diminished stroking-evoked inhibition, and optogenetic stimulation of VGLUT3-lineage nerves inhibited pruritogen-evoked firing. Together, our results provide a mechanistic understanding of touch-evoked inhibition of itch.

Background Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and scratching behaviour in these patients. Objectives We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD. Methods The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off-site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes). Results In patients with AD, stress induced by TSST caused a significant reduction of cowhage-evoked itch but significantly increased off-site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema. Conclusions We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress-related exacerbation of itch in patients with AD.

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Skin thermal changes modulate itch sensitivity. However, the mechanisms of this modulation are still unclear. Using mouse models of acute and chronic itch, we investigated whether local innocuous thermal stimulation of the skin alters itch sensitivity and if blockade of thermosensitive transient receptor potential (TRP) channels can reduce these changes. Localized thermal changes were achieved by placing a thermal probe in contact with the back skin for 30 s. Warming the skin significantly increased serotonin-evoked scratching and spontaneous scratching in the ovalbumin model of atopic dermatitis but decreased histamine-evoked scratching. These changes were blocked by a TRPV4 antagonist. Cooling the skin significantly increased serotonin-evoked scratching but reduced histamine-evoked scratching. The increase in serotonin-evoked scratching, but not the reduction of histamine-evoked scratching, was blocked by TRPM8 antagonism. Chloroquine-evoked scratching was unaffected by either warming or cooling. Our data indicate that different itch signaling pathways are differentially modulated by skin thermal changes.

Chronic itch is the most troublesome symptom of psoriasis, a chronic autoimmune skin disease of scaling and inflammation. Epidermal hyperinnervation by itch-signaling fibers is considered to be one cause of chronic itch [32], and increased epidermal nerve density has been frequently reported in humans with chronic itch conditions, including psoriasis [12; 18; 29–32], with some exceptions [19; 24]. Nociceptive fibers are expressed throughout the epidermis and often categorized as peptidergic or nonpeptidergic fibers [7]. The former contain the neuropeptides calcitonin gene–related peptide (CGRP) and/or substance P, whereas the latter express the purinergic receptor P2X3 and isolectin B4. Ablation of the peptidergic or non-peptidergic subset of fibers produces modality-specific deficits in response to heat and mechanical stimuli, respectively [8; 40]. Enhanced intraepidermal nonpeptidergic nerve density has been reported previously in animal models of dry skin itch [25; 34]. The majority of nonpeptidergic sensory neurons express glial cell line-derived neurotrophic factor (GDNF) family receptor (GFR)α-1 and/or GFRα-2, which show preferential binding for GDNF and neurturin (NRTN), respectively [36]. These neurotrophic growth factors are important for the development and maintenance of nonpeptidergic sensory neurons [5; 9; 13; 15; 35; 41]. As such, overexpression of these growth factors could lead to increased nonpeptidergic nerve density, possibly leading to increased itch. We have reported that the imiquimod-induced psoriasis mouse model is useful for the investigation of chronic itch in psoriasis [23]. Utilizing this model, we presently investigated whether the epidermal density of nonpeptidergic nerves and the expression of their neurotrophic growth factors (GDNF and NRTN) are increased in psoriasis-like skin. Because this model exhibits spontaneous scratching that is histamine-dependent in the early phase (Day 2) and histamine-independent in the late phase (Day 7), we measured nerve fiber density at these time points. In addition, we tested whether inhibition of NRTN could affect the density of intraepidermal fibers and spontaneous scratching behavior.

STUDY QUESTION Do cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA), testosterone (T) and estradiol (E2) differ in women with polycystic ovary syndrome (PCOS) as compared to eumenorrheic, ovulatory women (EW)? SUMMARY ANSWER Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW. WHAT IS KNOWN ALREADY The chronic anovulation characteristic of PCOS has been attributed to increased central GnRH drive and resulting gonadotropin aberrations. Androgens are thought to regulate GABA, which in turn regulates the neural cascade that modulates GnRH drive. STUDY DESIGN, SIZE, DURATION This cross-sectional observational study included 15 EW and 12 non-obese women with PCOS who consented to a lumbar puncture in addition to 24 h of serum blood collection at 15-min intervals. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 27 women were studied at a the General Clinical Research Center (GCRC) at the University of Pittsburgh. Serum analytes included T, E2 and androstenedione. CSF analytes included GABA, glutamate, glucose, T and E2. MAIN RESULTS AND THE ROLE OF CHANCE Women with PCOS had higher CSF GABA as compared to EW (9.04 versus 7.04 μmol/L, P < 0.05). CSF glucose and glutamate concentrations were similar between the two groups. CSF T was 52% higher (P = 0.1) and CSF E2 was 30% higher (P < 0.01) in women with PCOS compared to EW. Circulating T was 122% higher (P < 0.01) and circulating E2 was 75% higher (P < 0.01) in women with PCOS than in EW. LIMITATIONS REASONS FOR CAUTION The study is limited by its small sample size and the technical limitations of measuring CSF analytes that are pulsatile and have short half-lives. WIDER IMPLICATIONS OF THE FINDINGS Women with PCOS displayed significantly higher circulating levels of T and E2, significantly higher CSF levels of E2, and higher levels of CSF testosterone, although the latter was not statistically significant. A better understanding of the central milieu informs our understanding of the mechanisms mediating increased the GnRH drive in PCOS and lends a new perspective for understanding the presentation, pathogenesis and potential health consequences of PCOS, including gender identity issues. STUDY FUNDING/COMPETING INTEREST(S) No conflicts of interest. The study was funded by NIH grants to SLB (RO1-MH50748, U54-HD08610) and NIH RR-00056 to the General Clinical Research Center of the University of Pittsburgh. TRIAL REGISTRATION NUMBER NCT01674426.

Introduction La gale touche environ 175 millions de personnes/an (maladie tropicale negligee reconnue par l’OMS en 2017). La morbidite est populationnelle (epidemies, endemies) et individuelle, i.e. prurit et complications, y compris impetigo et nephrite post- streptococcique. Les therapeutiques proposees sont suboptimales : topiques difficiles d’utilisation et souvent mal toleres, ivermectine orale disponible mais sans activite absolue, demi-vie courte, non ovicide. L’objectif etait d’utiliser le modele animal experimental porcin pour evaluer/optimiser in vitro/ex vivo et in vivo les strategies therapeutiques. Materiel et methodes Le modele experimental porcin a ete developpe en Australie et mis en place en France il y a 5 ans. Un projet collaboratif a evalue : – l’efficacite et la pharmacologie plasmatique et cutanee de deux specialites veterinaires, – la moxidectine (famille des lactones macrocycliques) ou l’afoxolaner (isoxazolines), – l’activite ovicide de differentes molecules deja disponibles ou en developpement, – les mecanismes moleculaires impliques dans la physiopathologie du prurit associe a la gale, – les mesures permettant d’eradiquer les œufs et les sarcoptes de l’environnement. Ces travaux ont recu l’autorisation ethique des comites franco-australien et ont ete finances en partie par des AO de la SFD. Resultats Quatre etudes ont ete realisees : – 2 essais therapeutiques precliniques ont montre que la moxidectine (0,3 mg/kg) ou l’afoxolaner (2,5 mg/kg) a dose orale unique etaient plus efficaces que 2 × 0,2 mg/kg d’ivermectine, – une vaste etude in vitro a evalue les activites ovicides de plusieurs acaricides et avons constate que la plupart des molecules avaient une activite ovicide faible ou nulle, – une etude analysant des biopsies cutanees des porcs infestes montrait que les mediateurs non-histaminergiques du prurit (TRPV1, TRPA1, PAR-2) etaient considerablement plus nombreux que chez les temoins, – une etude comparant l’elimination des acariens et des œufs dans les textiles montrait que les meilleures conditions etaient le lavage en machine (cycle court, 50 °C), seche-linge (10 min), congelation (5 h), ou l’isolement dans des sacs en plastique (nombre de jours dependant de l’humidite et de la temperature). Discussion Grâce a ces travaux, des etudes complementaires vont pouvoir etre developpees : essais therapeutiques chez l’homme (phase II moxidectine NCT03905265 , evaluation ivermectine double dose essai controle NCT02841215 avec etude porcine parallele prevue), etude de pharmacologie cutanee dans le modele porcin ; pistes ouvertes pour la prise en charge du prurit (inhibiteur de PAR-2) et des recommandations environnementales adaptees aux conditions socio-economiques et climatiques. Conclusion Le modele experimental de gale porcine permet d’obtenir des donnees essentielles pour ameliorer le controle de la gale humaine.

Itch is a common sensation that drives an intense urge to scratch. Itch and scratching have persisted in humans and many other species, suggesting that they play an important role in survival. This commentary discusses the function of itch as a danger signal, why itch feels unpleasant and why we feel relief and pleasure when we scratch an itch. In addition, we explore the ways that this system becomes dysfunctional in conditions of chronic itch and important implications for treatment.

Itch is a major indicator of psoriasis, but the underlying mechanisms behind this symptom are largely unknown. To investigate the neuronal mechanisms of psoriatic itch, we tested whether mice subjected to the imiquimod-induced psoriasis model exhibit itch-associated behaviors. Mice received daily topical applications of imiquimod to the rostral back skin for 7 days. Imiquimod-treated mice exhibited a significant increase in spontaneous scratching behavior directed to the treated area as well as touch-evoked scratching (alloknesis). To characterize this model, we measured the mRNA expression levels of pruritogens and itch-relevant receptors/channels using real-time reverse transcription PCR. The mRNA expression of MrgprA3, MrgprC11, and MrgprD decreased gradually over time in the dorsal root ganglion (DRG) cells. There was no significant change in the mRNA expression of TRPV1 or TRPA1 in DRG cells. TRPV4 mRNA expression was transiently increased in the DRG cells, whereas TRPM8 mRNA was significantly decreased. The mRNA expression levels of histidine decarboxylase and tryptophan hydroxylase 1, as well as the intensity of histamine and serotonin immunoreactivity, were transiently increased in the skin on day 2, returning to baseline by day 7. Histamine H1-receptor antagonists, chlorpheniramine and olopatadine, significantly inhibited spontaneous scratching on day 2, but not day 7. Neither chlorpheniramine nor olopatadine affected alloknesis on day 2 or day 7. These results may reflect the limited antipruritic effects of histamine H1-receptor antagonists on human psoriasis. The imiquimod-induced psoriasis model seems to be useful for the investigation of itch and its sensitization in psoriasis.

Itch consists of both sensory and affective components. For chronic itch patients, the affective component of itch affects both quality of life (leading to psychological comorbidities) and disease prognosis (by promoting scratching of itchy skin). We found that acute itch stimuli, such as histamine, induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice. Itch stimuli also increased activity in projection areas to the amygdala, suggesting that these regions form a circuit for affective itch processing. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling. Selective optogenetic activation of histamine-responsive amygdala neurons in adult male and female Fos:CreERT2;R26Ai14mice using the Targeted Recombination in Active Populations system enhanced both scratching and anxiety-like behavior. These results highlight the importance of itch-responsive amygdala neurons in modulating itch-related affect and behavior.SIGNIFICANCE STATEMENTThe sensation of itch includes an affective component that leads to stress and anxiety in chronic itch patients. We investigated the neuronal basis of affective itch in mice, with a focus on the amygdala, the key brain region for the generation of anxiety. A subpopulation of amygdala neurons responded to itch stimuli such as histamine. Optogenetic activation of histamine-responsive amygdala neurons affected both scratching and anxiety-like behavior. Therefore, this population appears to be important for mediating the affective component of itch.

Introduction Le prurit, souvent intolerable et insomniant, est un des symptomes les plus frequents de la gale. Il peut etre familial et est alors une aide precieuse au diagnostic. Il peut aussi persister plusieurs semaines apres le traitement et etre responsable de complications notamment infectieuses secondaires au grattage. Son impact sur la qualite de vie est important : perte du sommeil, troubles de la concentration, absenteisme scolaire ou au travail, voire decompensation de pathologie psychiatrique. Bien que tres souvent prescrits, les antihistaminiques anti-H1 semblent peu efficaces en dehors de leur utilite sedative. De facon generale, la symptomatologie prurigineuse est consideree comme liee a une liberation de mediateurs stimulant des recepteurs specifiques au niveau des fibres sensorielles epidermiques. Ce mecanisme n’a jamais ete explore de facon specifique dans la gale. Materiel et methodes Les niveaux d’expression de mediateurs du prurit : histamine, TRPV1, TRPA1 (transient receptor potential vanilloid 1 and ankyrin 1), tryptase, PAR-2 (protease-activated receptor 2) et b-tubuline etaient mesures dans des biopsies cutanees provenant de patients humains infestes par la gale (n = 6) ; de temoins sains (n = 4) et du modele experimental porcin (n = 3). Une analyse immunohistochimique etait realisee. Les niveaux d’expression des mediateurs etaient mesures par l’intensite de la fluorescence dans l’epiderme. L’analyse des lames etait faite en aveugle. Un t-test etait utilise pour l’analyse statistique. L’etude etait acceptee par les comites d’ethique americain et francais. Resultats Les taux de PAR2, TRPA1 et TRPV1 etaient statistiquement plus eleves dans l’epiderme des tissus infestes par la gale, humains (p = 0,01 ; 0,027 ; 0,002) et porcins (p = 0,001 ; Fig. 1 et 2 ). Discussion L’expression de la tryptase, de son recepteur PAR-2 et des canaux ioniques TRPA1 et TRPV1 etait elevee dans les tissus infestes par la gale alors que l’histamine n’etait pas augmentee. Ces resultats suggerent que le prurit associe a l’infestation par la gale est induit par une voie independante de l’histamine. Des etudes similaires ont pu montrer que cette voie etait aussi impliquee dans le prurit de la dermatite atopique. Conclusion Ces mediateurs non histaminergiques pourraient servir de cibles antiprurigineuses, offrant de nouvelles perspectives de recherche pour le traitement du prurit de la gale.

Functional hypothalamic amenorrhea is characterized by anovulation caused by reduced gonadotropin-releasing hormone drive and is associated with hypercortisolemia that has been linked to heightened hypothalamic-pituitary-adrenal reactivity to common psychological and metabolic challenges.We hypothesized that women with functional hypothalamic amenorrhea would display greater cortisol responses to exercise challenge than ovulatory women with eumenorrhea.We completed a cross-sectional comparison of 9 women with functional hypothalamic amenorrhea and 11 women with eumenorrhea who were of reproductive age, who weighed 90-110% ideal body weight, who did not exercise excessively, and who had no formal psychiatric diagnosis. Subjects completed a 20-minute submaximal exercise challenge using a cycle ergometer in a research exercise laboratory. Heart rate and circulatory cortisol, glucose, and lactate were measured at 10-minute intervals before, during, and after the exercise challenge.Baseline (t= -10 minutes) cortisol, glucose, lactate, and heart rate were comparable between groups. Glucose levels rose modestly during exercise by 2.9% in women with eumenorrhea (P=.4) but declined by 10.6% in functional hypothalamic amenorrhea (P.03). The nadir in glucose levels in functional hypothalamic amenorrhea occurred at the end of the 20-minute exercise challenge (t= +20 min). Lactate levels rose comparably in both groups (P.01). Heart rate increased significantly with exercise in both groups (P.01), but the increase was smaller in subjects with functional hypothalamic amenorrhea (P.01). Cortisol levels increased during the exercise challenge in both groups (P.01) and peaked 10 minutes after the exercise ended (t= +30 min). At peak, subjects with functional hypothalamic amenorrhea displayed higher cortisol levels (147±22 [standard error of the mean] ng/mL) than women with eumenorrhea (96±12 ng/mL; P=.05). The mean percent increase over baseline was 62% in women with eumenorrhea and 92% in functional hypothalamic amenorrhea.The heightened cortisol response to exercise in women with functional hypothalamic amenorrhea was associated with a decline in blood glucose level that was not observed in women with eumenorrhea. Women with functional hypothalamic amenorrhea appear to be more reactive at the endocrine level to the metabolic demand of exercise. Submaximal challenge unmasks underlying stress sensitivity in women with functional hypothalamic amenorrhea and highlights the importance of the use of psychological interventions for stress reduction in this population.

To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and nonitchy, nonlesional skin biopsies from 25 patients with atopic dermatitis and 25 patients with psoriasis and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared with healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and nonitchy skin in atopic and psoriatic subjects. Overexpression of several genes, such as phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1, in itchy skin was positively correlated with itch intensity ratings in both atopic dermatitis and psoriasis. Cytokines such as IL-17A, IL-23A, and IL-31 had elevated gene transcript levels in both itchy atopic and psoriatic skin. However, expression of genes for TRP vanilloid 2, TRP ankyrin 1, protease-activated receptor 2, protease-activated receptor 4, and IL-10 was found to be increased only in pruritic atopic skin, whereas expression of genes for TRP melastatin 8, TRP vanilloid 3, phospholipase C, and IL-36α/γ was elevated only in pruritic psoriatic skin. This "itchscriptome" analysis will lead to an increased understanding of the molecular mechanisms of chronic pruritus and provide targets for itch treatment irrespective of disease state.

Interactions between keratinocytes, immune cells, and sensory nerve endings strongly influence the sensation of itch. Mast cells, eosinophils, and T cells are commonly mentioned as immune cells involved in itch, meanwhile the role of neutrophils in pruritus is rarely discussed. However, neutrophils

Dear Editor, Although dry skin and barrier impairment are key drivers for itch induction in atopic dermatitis (AD), many other factors can impact itch intensity. In particular, AD patients often report that autologous sweating aggravates their itch1. Indeed, AD lesions are characteristically distributed in regions where sweat glands are prominent, such as the neck, face, wrists, and cubital and popliteal fossae. Additionally, sweat is known to influence the pH of skin, which plays a crucial role in the pathogenesis of skin dermatoses such as AD2. The association between perspiration and pruritus is of great clinical importance, yet no experimental model has been developed to assess this relationship. To address this issue, we conducted a controlled-cohort study to evaluate the effects of localized, cholinergically induced perspiration on the intensity of non-histaminergic induced itch (see Supplement). In the baseline sweat condition, sweat was induced by pilocarpine iontophoresis on healthy (n=10) and AD (n=10) subjects’ forearms. Sweat was collected for 30 minutes, and activated sweat glands (ASG) were counted after sweat collection. In the baseline itch condition, itch was induced using cowhage, which activates PAR2 receptors3, which have been shown to play a role in the itch of AD4. Subjects rated itch intensity using a visual analogue scale (VAS) for the duration of the itch sensation. In the combined sweat and itch condition, itch was induced immediately following sweat induction. Sweat was collected and itch intensity was rated as before. We hypothesized that sweating would increase itch intensity in both AD and healthy subjects. The average VAS itch for the AD subjects for two weeks before the experiment was 5.5 ± 2.3, while the average Eczema Area and Severity Index score was 21.2 ± 20.1. AD subjects reported that the forearm and thigh areas itched most often and that their pruritus-related QOL was most affected by “temperature or seasonal changes,” with an average frequency score of 4.13 ± 0.38. Of note, 60% of subjects reported that sweat exacerbated their itch. In the baseline sweat condition, healthy and AD subjects produced statistically similar amounts of sweat (0.48 ± 0.2 g vs. 0.42 ± 0.15 g). AD subjects produced less sweat when itch and sweat were induced together (0.22 ± 0.03 g) compared to baseline sweat alone (p=0.02). Healthy subjects did not significantly differ in sweat production during the sweat and itch condition (0.36 ± 0.18 g) compared to baseline sweat. Furthermore, AD subjects produced significantly less sweat than healthy controls during the combined itch and sweat condition (p=0.04; Fig. 1A). Although some prior reports have shown a reduced sweat response in AD subjects upon cholinergic stimulation5–7, another study found no difference in the volume of sweat produced by AD and healthy subjects with either pilocarpine-induced sweat or emotional sweat8. The amount of sweat collected from AD subjects was significantly decreased during the combined itch and sweat condition compared to baseline sweat. However, ASG counts were statistically similar in all conditions (Fig. 1B–D), suggesting that they were not responsible for the change in sweat production. Figure 1 (a) The amount of sweat produced did not differ between healthy and AD subjects. However, AD subjects produced less sweat while itching compared to their sweat baseline and compared to healthy subjects during sweat and itch (*p

Chronic itch is a significant health burden with few effective treatments. As such, itch researchers seek to understand the mechanisms behind itch and to find potential targets for treatment. The field of itch research is dynamic, and many advances have been made so far this decade. In particular, major steps forward include the identification of new peripheral and central itch mediators and modulators, the discovery of greater roles for immune cells and glia in itch transmission, and a focus on the brain processing of itching and scratching. Finally, several new therapeutic interventions for itch have shown success in clinical trials.

Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE) - Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG), suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.