Progesterone- and deoxycorticosterone-derived GABAergic neurosteroids induce itch-related scratching behavior in...

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_A 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.