title: Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons.
abstract: Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic compounds 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 Ca(2+) response revealed 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 receptor 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 neurons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ.
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Se-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Goon Ho
authors.initials: GH
authors.lastname: Park
authors.forename: Donghoon
authors.initials: D
authors.lastname: Kim
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Lee
authors.forename: Hyejung
authors.initials: H
authors.lastname: Min
authors.forename: Estelle
authors.initials: E
authors.lastname: Wall
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Han
mesh_terms: D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D000077271:Imiquimod; D007369:Interferon Inducers; D051379:Mice; D009474:Neurons / Q000737:chemistry*; D011537:Pruritus / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000032:analysis*
chemical_list: D000634:Aminoquinolines; D007369:Interferon Inducers; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D006632:Histamine; D002738:Chloroquine; D000077271:Imiquimod