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Assessment of the impact of sex in intensity, skin flares and central processing of histaminergic itch – a pilot study.

Itch is the commonest skin-related symptom and sex differences are increasingly recognised as important determinants in stratified medicine, but only little is known about sex differences in itch. Questionnaire-based studies indicated that women perceive itch as more intensive and bothersome in comparison to men. However, data of studies using standardised itch models to objectify sex differences are scarce and inconsistent. To determine sex differences in intensity, skin flares and central processing of histaminergic itch we compared 15 female and 15 male healthy subjects in a double-blinded, within-subject, placebo-controlled study using a histamine skin prick itch-model (histamine 1% applied onto the volar forearm) and functional MRI. We found trends in higher mean itch intensity (0.58 VAS, CI 95% 0.004-1.19, p=0.056) and maximum itch intensity (men 3.93 VAS ± 0.39 SD at 3 minutes, women 4.73 VAS ± 0.31 SD at 4 minutes, p=0.073) in women paralleled by a trend in a stronger positive correlation between itch intensity and blood oxygen level dependent (BOLD) activity in brain structures identified during itch in comparison to men (r in women: 0.46, p=0.08, r in men: 0.07, p=0.79). The erythema and wheal following histamine skin pricking were (non-significantly) larger in men indicating that higher mean itch intensities on the right volar forearm in women may not be explained by more intense flares. The comparison of the activation patterns between the sexes revealed increased activity in men compared to women in the left middle temporal gyrus (temporooccipital part)/lateral occipital cortex. Thus, our findings indicate that histaminergic itch perception and central itch processing differ between the sexes under standardised conditions.

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Why We Scratch: Function and Dysfunction.

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. This article is protected by copyright. All rights reserved.

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Itch sensitization? A systematic review of studies using quantitative sensory testing in patients with chronic itch.

As well-established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch.Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin-/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and non-lesional skin and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available.Of 4,667 identified papers, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis) were found more sensitive than the controls to histamine-evoked itch in lesional skin (SMD: 0.66 [CI: 0.16,1.15]), but not non-lesionally (SMD: -0.26 [CI: -0.58;0.06]). Cowhage did not evoke more itch in non-lesional skin of patients as compared to the controls (SMD: 0.38 [CI: -0.04,0.81]). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies.Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than atopic dermatitis are needed to establish whether sensitization is robustly present across chronic itch conditions.

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Switch to Itch-The many novel facets of pruritus research.

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What is new in the psychology of chronic itch?

Itch is often regarded as unpleasant or bothersome and is accompanied by symptoms of distress and impairments in daily life. The biopsychosocial model of chronic itch describes how psychological factors can contribute to the improvement or exacerbation of chronic itch and related scratching behavior. Recent research underlines the important role of cognitive-affective information processing, such as attention, affect, and expectancies. This may not only play a role for acute itch states, but may particularly apply to the process of itch chronification, e.g., due to the vicious cycle in which these factors shape the experience of itch. The present paper focuses on new insights into the relation between itch and the cognitive-affective factors of attention, affect, and expectancies. These factors are thought to play a possible aggravating role in itch in the long term and have received increasing attention in the recent empirical literature on maintaining and exacerbating factors for chronic physical symptoms. Possible psychophysiological and neurobiological pathways regarding these factors are discussed, as well as possible intervention methods. This article is protected by copyright. All rights reserved.

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Sensitive skin is a neuropathic disorder.

Sensitive skin is defined by the occurrence of unpleasant sensations such as tingling, burning, tautness, itching or pain. Mechanisms explaining sensitive skin are controversial, and many hypotheses have been proposed. Because sensitive skin is primarily characterized by a wide variety of neuropathic-like symptoms, it is highly likely that neurosensory dysfunction in the skin represents one of the pathological mechanisms of sensitive skin. This hypothesis does not exclude other explanations like role of keratinocyte, transient receptor potential channels, vasculature or environmental factors. Nevertheless, the role of the nervous system in the development of sensitive skin is crucial, and growing evidence supports this hypothesis. Pain and pruritus described by patients with sensitive skin corresponds to neuropathic component, and its assessment shows an increase of neuropathic measures (DN-4, Douleur Neuropathique-4) compared to control. These sensations are similar to the sensations observed in small-fiber neuropathy (SFN), which is a group of disorders that affect thin nerve fibers. One study on the pathophysiology of sensitive skin demonstrated that intraepidermal nerve fiber density, especially of peptidergic C-fibers, was lower in the sensitive skin group. A recent study showed a modification in heat-pain detection threshold in patients with sensitive skin. All these results indicate that C-fiber damage can help explain sensitive skin. Consequently, the role of the nervous system is increasingly obvious. Nevertheless, keratinocytes and other epidermal cells closely participate in sensory transduction. Therefore, the results of neurophysiological studies should be interpreted in the light of this information that the whole epidermis represents a huge polymodal nociceptor. This article is protected by copyright. All rights reserved.

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Shedding light on the itch of cholestasis.

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The pharmacology of itch.

The article has been co-published with permission in British Journal of Dermatology and British Journal of Pharmacology. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article.

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Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord.

It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.

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Are we facing a change in the treatment of chronic pruritus?

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