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Brain allopregnanolone induces marked scratching behaviour in diet-induced atopic dermatitis mouse model.

ABSTRACT: Allopregnanolone (ALLO) is a neurosteroid produced in the brain, but so far, no study has explored its link with itching. Herein, we used a diet-induced atopic dermatitis mouse model to examine whether exogenously administered and endogenously produced ALLO contribute to inducing scratching. Systemic administration of ALLO elicited robust scratching in the atopic dermatitis model, while it did not affect spontaneous and pruritogen-induced scratching in normal mice. ALLO caused scratching when administered intracisternally, but not when administered intrathecally or intradermally, suggesting the involvement of supraspinal mechanisms. Pharmacological analyses suggested that both γ-aminobutyric acid type A receptor activation and serotonin type 3 receptor inhibition were involved in ALLO-induced scratching. We next examined whether endogenously produced ALLO is involved in ethanol-induced scratching in atopic dermatitis mice, because ethanol administration increases ALLO in rodent brain. Acute ethanol administration increased brain ALLO levels, which coincided with increased scratching. Pre-treatment with finasteride, a synthetic ALLO inhibitor, suppressed ethanol-induced scratching and ALLO production in the brain. Collectively, our results demonstrated for the first time that ALLO administration caused marked scratching in atopic dermatitis mice, and ethanol-induced scratching may be mediated through endogenously produced brain ALLO.

SUBMITTER: Fujii M

PROVIDER: S-EPMC6382911 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch-scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification.AimThe aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli.MethodsAnalyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch.ResultsAnalysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification.ConclusionOur results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch.

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Brain allopregnanolone induces marked scratching behaviour in diet-induced atopic dermatitis mouse model.

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