Itch Sensation Research Articles

Mas-Related G Protein-Coupled Receptors and the Biology of Itch Sensation.

Chronic, persistent itch is a devastating symptom that causes much suffering. In recent years, there has been great progress made in understanding the molecules, cells, and circuits underlying itch sensation. Once thought to be carried by pain-sensing neurons, itch is now believed to be capable of being transmitted by dedicated sensory labeled lines. Members of the Mas-related G protein-coupled receptor (Mrgpr) family demarcate an itch-specific labeled line in the peripheral nervous system. In the spinal cord, the expression of other proteins identifies additional populations of itch-dedicated sensory neurons. However, as evidence for labeled-line coding has mounted, studies promoting alternative itch-coding strategies have emerged, complicating our understanding of the neural basis of itch. In this review, we cover the molecules, cells, and circuits related to understanding the neural basis of itch, with a focus on the role of Mrgprs in mediating itch sensation.

A pivotal role for the activation of TRPV3 channel in itch sensations induced by the natural skin sensitizer carvacrol.

Itching is an intricate, common symptom of dermatologic and systemic diseases, and both TRPV3 and TRPA1 channels have been suggested to function as downstream effector targets. But the relative contributions of TRPV3 and TRPA1 to itch sensation in vivo remain unclear. To dissect the role of TRPA1 or TRPV3 in the cutaneous sensation of itching, we took the advantage of a natural compound carvacrol from oregano, and examined its effect on the induction of scratching behavior in mice. We showed that the intradermal injection of carvacrol (0.01%, 0.1% and 1%, 50 μL) induced scratching in a concentration-dependent manner. But in TRPV3-knockout mice, the scratching induced by carvacrol (1%, 50 μL) was markedly decreased by approximately 64% (from 275 scratching bouts down to 90) within 60 min. Further analysis revealed that TRPV3-knockout caused a reduction of scratching bouts for approximately 40% in the first 20 min (the initial phase), whereas the scratching bouts were reduced by approximately 90% in the last 40 min (the sustained phase). These results were in consistence with those in our whole-cell recordings in HEK-293T cells expressing either TRPA1 or TRPV3: carvacrol exhibited similar potencies in activating either TRPA1 or TRPV3, but carvacrol-activated TRPA1 current showed a rapid desensitization, which was reduced by approximately 90% within 5 min before a complete washout, whereas carvacrol-induced TRPV3 current showed a slow desensitization that caused less than 30% of current reduction in 10 min and left a significant residual TRPV3 current after washout. Our results demonstrate that carvacrol from plant oregano is a skin sensitizer or allergen; TRPV3 is involved in the initial phase and the sustained phase of pruritus, whereas TRPA1 likely contributes to the initial phase.

Nocebo-induced modulation of cerebral itch processing – An fMRI study

It has been shown repeatedly that perceiving itch-related pictures or listening to a lecture on itch can enhance itch sensation and scratching behaviour (Niemeier and Gieler, 2000; Holle et al., 2012; Lloyd et al., 2013), indicating that itch is strongly influenced by expectations. Using fMRI, we investigated the neural correlates of the itch-related nocebo effect in healthy male and female human subjects. Itch sensation on the left forearm was induced by cutaneous histamine application and thermally modulated, with cooling leading to higher itch. Nocebo-induced aggravation of histaminergic itch was achieved by ostensibly treating volunteers with “transcutaneous electrical nerve stimulation (TENS)” about which subjects were instructed that it would increase itch. During a conditioning phase subjects indeed experienced stronger itch due to slightly altered cooling and histamine concentrations, but attributed it to the alleged “TENS stimulation”. Importantly, in the subsequent test phase where no “TENS” or electrical stimulation was applied, volunteers significantly reported stronger itch during the nocebo as compared to the control condition.Comparing BOLD responses during nocebo in contrast to control, we observed increased activity in contralateral (right) rolandic operculum. Opercular involvement was repeatedly reported in studies related to the expectation of stimulus intensification and might thus represent an early area integrating expectation information with somatosensory information. Finally, functional coupling between the insula and the periaqueductal gray (PAG) was enhanced specifically in the nocebo condition. This cortex-PAG interaction indicates that context-dependent top-down modulation during itch might represent a shared mechanism with other modalities such as pain.

LB964 Inhibition of TSLP, inflammatory cytokines, and tissue damage in a reconstructed human epidermis model mimicking atopic dermatitis

Thymic stromal lymphopoietin (TSLP) is highly expressed by keratinocytes in atopic dermatitis (AD) in which TSLP drives immune dysregulation, barrier alternations, and triggers itch sensation. Several reports demonstrated that keratinocyte and reconstructed human epidermis (RHE) when treated with an inflammatory cocktail, comprised of a TLR3 agonist, Th2 cytokines and TNF-a, exhibited key aspects of AD-related phenotype including increased release of TSLP, cytokines, spongiosis, and disrupted skin barrier. The objective of this study was to develop this AD model and evaluate its utility for assessing topical actives in suppressing inflammation responses triggered by the AD inflammatory cocktail. Hydrocortisone was utilized for the initial evaluation of this AD model. Treatment of inflammatory cocktails comprised of different concentrations of poly I:C, IL-4, IL-13 and TNF-a resulted in a dose and time-dependent increased expression and release of inflammatory mediators (e.g., TSLP, COX-2, LTB4, and various cytokines) in RHE. The inflammatory cocktails also led to differing extents of tissue damage including spongiosis, reduced keratinocyte proliferation, differentiation, and tissue integrity. Topical treatment with hydrocortisone inhibited the inflammatory cocktail-induced TSLP, and cytokines. Histology analyses demonstrated that topical hydrocortisone alleviated the cocktail-induced tissue damage, and altered cell proliferation. Topical treatment with hydrocortisone, when applied prior to, simultaneously, or post-inflammatory cocktail treatment, resulted in differing degrees of protection against the inflammatory cocktail-induced TSLP, cytokines, and tissue damage, with the highest level of inhibition associated with application before cocktail treatment. In conclusion, this report suggests that the AD RHE model system could be a useful in vitro tool for the screening of therapeutic agents which target TSLP expression, as demonstrated by the results with hydrocortisone.

Efficacy and tolerability of liposomal polyvinylpyrrolidone-iodine hydrogel for the localized treatment of chronic infective, inflammatory, dermatoses: an uncontrolled pilot study.

Infection is common in many chronic, inflammatory skin conditions but is often difficult to treat, in part due to growing bacterial resistance to antibiotics. Liposomal polyvinyl-pyrrolidone (PVP)-iodine hydrogel has a unique mode of action, combining the antiseptic and anti-inflammatory actions of PVP-iodine with the drug delivery and moisturizing properties of liposomes. We investigated the utility of liposomal PVP-iodine to treat infective dermatoses. In this prospective, single-arm (uncontrolled), open-label Phase II pilot study, patients with acne vulgaris (n=30), atopic dermatitis (n=20), impetigo contagiosa (n=10), and rosacea (n=10) received PVP-iodine (3%) hydrogel for ≤4 weeks. Global Clinical Severity score improved for all dermatoses (range: 0.5 for acne vulgaris [p<0.001] to 1.0 for impetigo contagiosa [p=0.011]). Improvements in pain, quality of life, (Freiburg Life Quality Assessment), and Eczema Area and Severity Index scores were also seen. Treatment was well tolerated; most frequent adverse events were burning (14%) or itching (9%) sensations. Thus, liposomal PVP-iodine hydrogel has potential utility as an effective treatment for inflammatory skin conditions associated with bacterial colonization.

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Itch induces conditioned place aversion in mice

Itch sensation consists of both sensory and emotional components. The molecular and cellular mechanisms underlying the transduction and transmission of itch sensation have been studied extensively in rodents. However, whether itch induces emotional responses in mice still remains unknown. We found that pruritogens induced conditioned place aversion (CPA) in mice, and that the CPA lasted for at least two weeks. Disruption of itch signal transmission by depletion of peripheral sensory fibers expressing TRPV1 (transient receptor potential vanilloid subfamily, member 1) attenuated chloroquine-induced CPA. Consistently, ablation of itch-specific neurons that express gastrin-releasing peptide receptor in the spinal cord also abolished itch-induced CPA, confirming that itch-induced CPA is dependent on the spinal itch circuit. Thus, these results demonstrate that itch can induce CPA in mice, which requires peripheral itch signal inputs.

A central neural circuit for itch sensation.

Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing.

The effect of UVB-induced skin inflammation on histaminergic and non-histaminergic evoked itch and pain

Abstract Aims Itch often occurs in cutaneous conditions characterized by some degree of inflammation, e.g. atopic dermatitis, psoriasis or urticaria. It is unclear to which extent cutaneous inflammation causes sensitization of pruriceptive primary afferent C-fibers. The aim of this study was to explore if inflammation induced by UVB (B-ultraviolet rays) modify neurogenic inflammation and itch associated with experimental itch provocations. Methods Twenty healthy volunteers (10F/10M, 26.2 ± 1.6 years) were included. Eight circles (diameter=2cm), four on each volar forearm were studied. Two spots were irradiated with 0.5 × Minimal Erythema Dose (MED), two with 1× MED and two with 2× MED, and two acted as controls. Itch provocations were conducted using histamine (1%) percutaneously introduced and 35–45 cowhage spicules (non-histaminergic itch). The duration and intensity of itch and pain, sensitivity to touch-evoked itch (STI), mechanical pain thresholds (MPT) and sensitivity (MPS), and superficial blood perfusion where measured in UVB-irradiated- and control areas 24-h after UVB-irradiation and following each itch provocation. Results UVB induced dose-dependent hyperalgesia validated by decreased MPT, increased MPS and neurogenic inflammation (all P &lt; 0.01). UVB-induced inflammation did not increase the magnitude of itch reported following any itch provocation. However, cowhage was associated with more pain in UVB-irradiated areas and the proportional ratings of the mixed itch and pain sensation was shifted towards increased pain dominance (P &lt; 0.01). Itch provocations did not increase the mechanical hyperalgesia induced by UVB, whereas it provoked an increase in superficial blood perfusion compared to UVB alone (P &lt; 0.05). Conclusions (1) The UVB model induces sensitization to pain but not itch stimuli and independently increases the nociceptive sensations associated with non-histaminergic itch provocation. (2) The inflammatory UVB-perturbation does not mimic the sensitization associated with inflammatory dermatoses where lesioned skin is more receptive to pruritogens, suggesting that more specific or prolonged inflammatory processes are involved in clinical itch conditions.

COX-2-selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels.

The transient receptor potential vanilloid 3 (TRPV3) channel is a heat-sensitive ion channel, which is predominantly expressed in keratinocytes. TRPV3 channels are involved in numerous physiological and pathophysiological processes within the skin, including cutaneous nociception, temperature sensation and development of itch. The role of TRPV3 channels in such processes is poorly understood; therefore, the establishment of selective modulators of TRPV3 channels is highly desirable. Novel TRPV3-modulating compounds were identified using fluorometric intracellular Ca2+ assays and further evaluated with electrophysiological techniques. TRPV3 activity, elicited by 2-aminoethoxydiphenyl borate (2-APB), was efficaciously enhanced by deracoxib and celecoxib, two COX-2-selective inhibitors. They exerted their potentiating effect via a direct interaction with TRPV3 as evident from excised inside-out recordings. Structurally-related COX-2 inhibitors affected TRPV3 channel gating to a much lesser degree. Similar results were obtained in HEK293 cells stably expressing cyan fluorescent protein-tagged mouse TRPV3 channels and in a mouse keratinocyte cell line, endogenously expressing TRPV3. The effects of celecoxib and deracoxib on TRPV3 were dependent on the stimulus used to activate TRPV3. While 2-APB and heat-activated TRPV3 channels were potentiated by celecoxib, carvacrol-activated channels were inhibited by celecoxib. We identified a new class of drugs that modulate TRPV3 channels. The most potent compound celecoxib is an approved analgesic and anti-inflammatory drug, which is currently being investigated for its topical application in the treatment of skin cancer. As TRPV3 is highly expressed in skin, celecoxib might affect TRPV3 activity in vivo when used at high local concentrations.

Tlx3 Function in the Dorsal Root Ganglion is Pivotal to Itch and Pain Sensations.

Itch, a sensation eliciting a desire to scratch, is distinct from but not completely independent of pain. Inspiring achievements have been made in the characterization of itch-related receptors and neurotransmitters, but the molecular mechanisms controlling the development of pruriceptors remain poorly understood. Here, our RNAseq and in situ hybridization data show that the transcription factor Tlx3 is required for the expression of a majority of itch-related molecules in the dorsal root ganglion (DRG). As a result, Tlx3F/F;Nav1.8-cre mice exhibit significantly attenuated acute and dry skin-induced chronic itch. Furthermore, our study indicates that TRPV1 plays a pivotal role in the chronic itch evoked by dry skin and allergic contact dermatitis (ACD). The mutants also display impaired response to cold and inflammatory pain and elevated response to capsaicin, whereas the responses to acute mechanical, thermal stimuli and neuropathic pain remain normal. In Tlx3F/F;Nav1.8-cre mice, TRPV1 is derepressed and expands predominantly into IB4+ non-peptidergic (NP) neurons. Collectively, our data reveal a molecular mechanism in regulating the development of pruriceptors and controlling itch and pain sensations.

Thymic stromal lymphopoietin is expressed in human corneal stromal cells and secreted upon protease-activated receptor 1 activation.

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine that triggers inflammatory responses through activating dendritic cell. It is demonstrated to be involved in a number of disorders, including cancer, gastrointestinal diseases, and autoimmune diseases. In addition, TSLP is also found to be able to induce itch sensation by directly activating the itch sensory neurons. The expression of human TSLP is detected in various tissues such as heart, liver, testis, and prostate. In this study, we report that TSLP was expressed in the human corneal stromal cells, the highly specialized cells that are critical for the function of the cornea. Furthermore, we found that activation of the protease-activated receptor 1 (PAR1) induced secretion of TSLP by the corneal stromal cells. Beside the canonical activator thrombin, PAR1 can also be activated by a few matrix metalloproteases (MMPs) such as MMP1 and MMP13. Since MMPs including MMP1 and MMP13 are upregulated in many corneal diseases as well as the corneal wound healing process, we proposed that TSLP might function as the link between increased protease activity and inflammatory responses or itch sensation in the corneas. © 2017 IUBMB Life, 69(8):606-610, 2017.

Cynomolgus monkey model of interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor A by a humanized monoclonal antibody.

Scratching is an important factor exacerbating skin lesions through the so-called itch-scratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)-31 and its receptor IL-31 receptor A (IL-31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL-31 in primates. We showed that administration of cynomolgus IL-31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1mg/kg nemolizumab, a humanized anti-human IL-31RA monoclonal antibody that also neutralizes cynomolgus IL-31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL-31-induced scratching for about 2months. These results suggest that the IL-31 axis and IL-31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL-31 signalling by an anti-human IL-31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials.

2% Crisaborole topical ointment for the treatment of mild-to-moderate atopic dermatitis

ABSTRACTIntroduction: Crisaborole 2% topical ointment is an anti-inflammatory, non-steroidal phosphodiesterase 4 inhibitor which is currently under investigation for its potential role in the treatment of atopic dermatitis and psoriasis.Areas covered: So far, 7 trials have been completed in atopic dermatitis. The 2% strength appeared to be the superior dosing regimen. Pruritus improved significantly within one week. The improvements in objective efficacy assessments in crisaborole-treated patients were also statistically significant compared to the vehicle.Expert commentary: Crisaborole has several key features in its mode of action which distinguish it from existing treatments for atopic dermatitis (AD), notably its activity against the phosphodiesterase E4 (PDE4) pathway, regulating cyclic AMP (cAMP) levels. This is less immunosuppressive than other pathways and has no effect on skin thinning. The pathway interrupts the itch sensation (pruritus) which means that the itch-scratch cycle, the bane in the life of patients with AD, is interrupted, usually as early as a few days into treatment. Hence, with the promising safety profile demonstrated, early treatment of mild to moderate AD patients might help to control AD better and improve quality of life for patients.

Critical Role of R7 Binding Protein in the Sensation of Acute and Pathologic Itch

Itch is a common irritating sensation, which triggers a desire to scratch. Itch sensation could be triggered due to potentially harmful agents such as insects, parasites and certain plant alkaloids or in a variety of diseases conditions such as eczema, dry skin itch or jaundice or peripheral neuropathies.In the present study we identified R7BP, a palmitoylated membrane anchoring protein that facilitates Gαi/o –mediated GTPase activating protein (GAP) activity, diminishes scratching in response to a number of pruritogens administerd either intradermally in the nape of the neck or in the central nervous system by lumbar puncture. However, when tested to a number of sensory nociceptive modalities which included mechanical, heat and chemically induced pain, the R7BP KO mice did not show any significant changes except in response to the heat induced pain. The pruriceptive defect in R7bp KO was reversed in a double knock out mice also lacking OPRK1, encoding the Gαi/o coupled kappa opioid receptor.A similar pruriceptive phenotype was observed in a knock‐in of GAP‐insensitive mutant mice with a Gαo (Gnao1 G184s/+) mutation. Further in a model of atopic dermatitis, R7BP KO mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists as compared to wild type littermates.Based on our observations, R7BP has an important role to play in somatosensory itch sensation and probably it functions by modulating the kappa opioid receptor. Our findings also suggest that Gαo has a significant role in itch perception and it could be involved regulation of kappa opioid receptor activity to modulate itch sensation.Taken together, our results indicate that R7BP is a key regulator of itch sensation and suggest that the potential targeting of R7BP – dependent GAP activity as a novel therapeutic strategy for pathologic itch.Support or Funding InformationThis research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Dental and Craniofacial Research

Psychological traits of skin picking disorder and psychogenic itch

IntroductionDespite the intense discussion of psychiatric comorbidity in psychodermatology, research on psychological components of skin picking and psychogenic itch is limited, especially when it concerns patients’ representation of skin perception and their attitude towards disease.ObjectivesTo characterize psychological traits of skin picking and psychogenic itch disorder by comparing aspects of bodily experience.AimsTo reveal internal relations of different components of bodily experience in skin picking and psychogenic itch.MethodsThirty patients with skin picking disorder (L98.1) and 18 patients with psychogenic itch (F45.8) participated in the study. The psychosemantic method “Classification of sensations” was used to assess bodily experience. It includes estimation of 80 descriptors from 6 classes of bodily sensations: skin (ex. “itch”), inner body (ex. “sickness”), receptor (ex. “sticky”), emotional (ex. “anxiety”), dynamics (ex. “exhaustion”) and attitudinal descriptors (ex. “bad”). Cluster and factor analysis were performed.ResultsThe most significant aspect of bodily experience in skin picking was its dynamics as a transition from irritation to calmness connected with the sensation of itch opposed to all other sensations (there were opposite signs of factor loadings of these variables and they were included in the factor explaining 45% of total variance). In contrast, in psychogenic itch these relations are diffuse and consist of connections between skin sensations and inner bodily sensations and descriptors of emotions reflecting functional origin of disorder.ConclusionTraits of psychological components in skin picking disorder and psychogenic itch should be concerned in the complex (psychiatric, psychological and dermatological) treatment of these disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1.

Lysophosphatidic acid (LPA) is an itch mediator, but not a pain mediator by a cheek injection model. Dorsal root ganglion neurons directly respond to LPA depending on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1). LPA-induced itch-related behaviours are decreased in TRPA1-knockout (KO), TRPV1KO or TRPA1TRPV1 double KO mice. TRPA1 and TRPV1 channels are activated by intracellular LPA, but not by extracellular LPA following LPA5 receptor activation with an activity of Ca2+ -independent phospholipase A2 and phospholipase D. Intracellular LPA interaction sites of TRPA1 are KK672-673 and KR977-978 (K: lysine, R: arginine). Intractable and continuous itch sensations often accompany diseases such as atopic dermatitis, neurogenic lesions, uremia and cholestasis. Lysophosphatidic acid (LPA) is an itch mediator found in cholestatic itch patients and it induces acute itch and pain in experimental rodent models. However, the molecular mechanism by which LPA activates peripheral sensory neurons remains unknown. In this study, we used a cheek injection method in mice to reveal that LPA induced itch-related behaviours but not pain-related behaviours. The LPA-induced itch behaviour and cellular effects were dependent on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which are important for itch signal transduction. We also found that, among the six LPA receptors, the LPA5 receptor had the greatest involvement in itching. Furthermore, we demonstrated that phospholipase D (PLD) plays a critical role downstream of LPA5 and that LPA directly and intracellularly activates TRPA1 and TRPV1. These results suggest a unique mechanism by which cytoplasmic LPA produced de novo could activate TRPA1 and TRPV1. We conclude that LPA-induced itch is mediated by LPA5 , PLD, TRPA1 and TRPV1 signalling, and thus targeting TRPA1, TRPV1 or PLD could be effective for cholestatic itch interventions.

A central role for R7bp in the regulation of itch sensation.

Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gβ5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.

Distraction From Itch Shows Brainstem Activation Without Reduction in Experimental Itch Sensation.

The central processing of itch is not completely understood. This is the first study to use functional magnetic resonance imaging (fMRI) to examine the central modulation by distraction of experimentally induced itch. A total of 33 healthy volunteers were examined with fMRI. Periods of itch induction without distraction and itch with distraction by a Stroop task (psychological test, where the participants have to decide if the colour of the writing corresponds to the written word, for example if "red" is written in red or not) were counterbalanced during the scanning to examine task-specific changes in blood oxygenation level dependent-signal. The intensity of the subjects' itch sensation, desire to scratch and pain sensation were evaluated. Distraction by a Stroop task did not reduce itch intensity or urge to scratch. However, the Stroop task led to significantly higher activation of the left brainstem when it followed the "pure" itch sensation. Itch and pain seem to have similar inhibition pathways, particularly concerning brainstem activation during distraction. But as itch sensation, in contrast to pain, could not be sufficiently reduced by distraction, both entities might have different modulation systems.

Opioid Receptors in Psoriatic Skin: Relationship with Itch.

Psoriasis is an inflammatory immunogenetic skin disease, often accompanied by itch. Opioid receptors are known regulators of itch sensation in the central nervous system. In the brain, μ-opioid receptors may potentiate itch, while activation of κ-opioid receptors may reduce or even alleviate itch; however, the role of opioid receptors in itch perception in the skin is poorly understood. To further elucidate the role of opioid receptors in the neurobiology of psoriatic itch, punch biopsies of non-lesional and lesional skin of patients with psoriasis and healthy controls were studied. Real-time polymerase chain reaction and immunofluorescence microscopy were used to detect opioid receptor genes and protein expression, respectively. The OPRK1/κ-opioid receptor pathway was found to be downregulated in lesional skin of psoriasis, correlating positively with itch sensation. In contrast, the OPRM1/μ-opioid receptor system was uniformly expressed by epidermal keratinocytes in all analysed groups. These findings suggest that imbalance of epidermal opioid receptors may result in disordered neuroepidermal homeostasis in psoriasis, which could potentiate transmission of itch.