Histamine Released from Epidermal Keratinocytes Plays a Role in a-MelanocyteeStimulating Hormone-Induced Itching in Mice
Kyoko Shimizu,* Tsugunobu Andoh,y Yoko Yoshihisa,* and Tadamichi Shimizu*
From the Departments of Dermatology* and Applied Pharmacology,y Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Accepted for publication July 14, 2015.
Address correspondence to Tadamichi Shimizu, Depart- ment of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Japan. E-mail: shimizut@med.u- toyama.ac.jp.
Sunburn, wound repair, and chronic renal failure with hemodialysis are usually accompanied by both pigmentation and itching. Proopiomelanocortin-derived a-melanocyteestimulating hormone (a-MSH) is produced in response to external stimuli, such as UV irradiation, and is involved in cutaneous pigmen- tation. However, it is unclear whether a-MSH is also involved in the itching. We therefore investigated whether a-MSH elicited itch-related responses in mice. We found that an intradermal injection of a-MSH induced hind-paw scratching, an itch-related response, in mice. The a-MSHeinduced scratching was inhibited by the m-opioid receptor antagonist naltrexone and the H1 histamine receptor antagonist terfenadine. In mast cell-deficient mice, a-MSH also elicited scratching, which was inhibited by terfe- nadine. The immunoreactivity for L-histidine decarboxylase, a key enzyme required for the production of histamine, histamine, and the melanocortin 1 and 5 receptors were shown in not only mast cells but also keratinocytes in murine skin. In addition to the expression of L-histidine decarboxylase and melanocortin 1 and 5 receptors, the mouse keratinocyte cell lines (Pam212) also showed immunoreactivity for L-his- tidine decarboxylase, histamine, and melanocortin 1 and 5 receptors. The application of a-MSH induced the release of histamine from Pam212 cells. These findings indicate that a-MSH may play an important role in the itching associated with pigmented cutaneous lesions and that the histamine released from keratinocytes is involved in this a-MSHeinduced itching. (Am J Pathol 2015, -: 1e8; http://dx.doi.org/ 10.1016/j.ajpath.2015.07.015)
