Tanaka Rina, Tanaka Satoshi, Fujii Masanori
Laboratory of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
Department of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 2. doi: 10.1007/s00210-025-04306-5.
Patients with atopic dermatitis (AD) are prone to itching, possibly due to central nervous system effects; However, the mediators remain largely unknown. 3α,5α-tetrahydroprogesterone (allopregnanolone, Allo-P), a neurosteroid produced from progesterone (PROG) via 5α-reductase and 3α-hydroxysteroid dehydrogenase, is a positive GABA receptor modulator. We previously showed that Allo-P administration into the brains of mice chronically suffering from AD markedly increased itch-related scratching behavior. However, the involvement of neurosteroids other than Allo-P in itching in AD has not yet been investigated. The present study aimed to investigate whether other neurosteroids with effects similar to those of Allo-P could induce itching in AD mice. Furthermore, sex differences in the effects of neurosteroids on itching behavior between female and male AD mice were examined. Hairless mice were fed a custom diet lacking polyunsaturated fatty acids and starch to induce AD symptoms. Neurosteroids were intracisternally administered, and scratching behavior was measured. In female mice with AD, pregnanolone, produced from PROG by 5β-reductase, markedly increased scratching behavior, similar to that of Allo-P. Deoxycorticosterone (DOC)-derived neurosteroids, including 3α,5α- and 3α,5β-tetrahydrodeoxycorticosterone, significantly but weakly increased scratching behavior, whereas 3α,5α-androstanediol (5α-Adiol), produced from testosterone, did not. Allo-P, but not 5α-Adiol, increased scratching behavior equivalently in both female and male AD mice, suggesting no significant sex differences in the responsiveness of neurosteroid-induced itching in AD mice. Our findings demonstrate for the first time that PROG- and DOC-derived GABAergic neurosteroids increase scratching behavior in an AD mouse model. These neurosteroids may mediate central itching in AD.
特应性皮炎（AD）患者容易出现瘙痒，这可能是由于中枢神经系统的影响；然而，其介导因子在很大程度上仍不明确。3α,5α-四氢孕酮（别孕烯醇酮，Allo-P）是一种通过5α-还原酶和3α-羟基类固醇脱氢酶由孕酮（PROG）产生的神经甾体，是一种阳性GABA受体调节剂。我们之前的研究表明，向长期患有AD的小鼠脑内注射Allo-P会显著增加与瘙痒相关的抓挠行为。然而，除Allo-P之外的神经甾体在AD瘙痒中的作用尚未得到研究。本研究旨在调查其他具有与Allo-P相似作用的神经甾体是否能在AD小鼠中诱发瘙痒。此外，还研究了神经甾体对雌性和雄性AD小鼠瘙痒行为影响的性别差异。给无毛小鼠喂食缺乏多不饱和脂肪酸和淀粉的定制饮食以诱发AD症状。通过脑池内给药神经甾体，并测量抓挠行为。在患有AD的雌性小鼠中，由PROG通过5β-还原酶产生的孕烷醇酮显著增加抓挠行为，与Allo-P相似。由脱氧皮质酮（DOC）衍生的神经甾体，包括3α,5α-和3α,5β-四氢脱氧皮质酮，显著但微弱地增加抓挠行为，而由睾酮产生的3α,5α-雄甾二醇（5α-Adiol）则没有。Allo-P而非5α-Adiol在雌性和雄性AD小鼠中同等程度地增加抓挠行为，这表明AD小鼠中神经甾体诱发瘙痒的反应性不存在显著性别差异。我们的研究结果首次证明，源自PROG和DOC的GABA能神经甾体在AD小鼠模型中会增加抓挠行为。这些神经甾体可能介导AD中的中枢性瘙痒。
