Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons
Se-Jeong Kima,b,1, Goon Ho Parka,1, Donghoon Kimb, Jaekwang Leec, Hyejung Mina, Estelle Walla, C. Justin Leec, Melvin I. Simona,2, Sung Joong Leeb,2, and Sang-Kyou Hana,2
aDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093; bDepartment of Neuroscience, Dental Research Institute, and Brain Korea21, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea; cCenter for Functional Connectomics, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
Contributed by Melvin I. Simon, January 5, 2011 (sent for review November 7, 2010)
Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic com- pounds offers insight into understanding the molecular and cellular basis of itch. Imiquimod (IQ) is an agonist of Toll-like receptor 7 (TLR7) used to treat various infectious skin diseases such as genital warts, keratosis, and basal cell carcinoma. Itch is reportedly one of the major side effects developed during IQ treatments. We found that IQ acts as a potent itch-evoking compound (pruritogen) in mice via direct excitation of sensory neurons. Combined studies of scratching behavior, patch-clamp recording, and Ca2+ response re- vealed the existence of a unique intracellular mechanism, which is independent of TLR7 as well as different from the mechanisms exploited by other well-characterized pruritogens. Nevertheless, as for other pruritogens, IQ requires the presence of transient re- ceptor potential vanilloid 1 (TRPV1)-expressing neurons for itch- associated responses. Our data provide evidence supporting the hypothesis that there is a specific subset of TRPV1-expressing neu- rons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ.
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Filename : pnas-201019755.pdf (828 KB)
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Filename : pnas-201019755si.pdf (378 KB)
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