Involvement of α-Melanocyte-Stimulating Hormone-Thromboxane A₂ System on Itching in Atopic Dermatitis

α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. α-MSH elicits itch-related responses in mice. We, therefore, investigated whether α-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, α-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, melanocortin receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion of mice with dermatitis, mRNAs encoding MC1R, MC3R, and MC5R were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal α-MSH elicited itch-associated responses, which were inhibited by thromboxane (TX) A₂ receptor antagonist ONO-3708. In mouse keratinocytes, α-MSH increased the production of TXA₂, which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca²⁺ chelator EGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, α-MSH-induced TXA₂ production was decreased. α-MSH increased intracellular Ca²⁺ ion concentration in dorsal root ganglion neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA₂ production by keratinocytes.