PT  - JOURNAL ARTICLE
AU  - Toshio Ohta
AU  - Toshiaki Imagawa
AU  - Shigeo Ito
TI  - Involvement of Transient Receptor Potential Vanilloid Subtype 1 in Analgesic Action of Methylsalicylate
AID  - 10.1124/mol.108.051292
DP  - 2009 Feb 01
TA  - Molecular Pharmacology
PG  - 307--317
VI  - 75
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/75/2/307.short
4100  - http://molpharm.aspetjournals.org/content/75/2/307.full
SO  - Mol Pharmacol2009 Feb 01; 75
AB  - Methylsalicylate (MS) is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite the common use of MS as a pain reliever, the underlying molecular mechanism is not fully understood. Here we characterize the action of MS on transient receptor potential V1 (TRPV1). In human embryonic kidney 293 cells expressing human TRPV1 (hTRPV1), MS evoked increases of [Ca2+]i, which declined regardless of its continuous presence, indicative of marked desensitization. TRPV1 antagonists dose-dependently suppressed the MS-induced [Ca2+]i increase. MS simultaneously elicited an inward current and increase of [Ca2+]i in the voltage-clamped cells, suggesting that MS promoted Ca2+ influx through the activation of TRPV1 channels. MS reversibly inhibited hTRPV1 activation by polymodal stimuli such as capsaicin, protons, heat, anandamide, and 2-aminoethoxydiphenyl borate. Because both the stimulatory and inhibitory actions of MS were exhibited in capsaicin- and allicin-insensitive mutant channels, MS-induced hTRPV1 activation was mediated by distinct channel regions from capsaicin and allicin. In cultured rat sensory neurons, MS elicited a [Ca2+]i increase in cells responding to capsaicin. MS significantly suppressed nocifensive behavior induced by intraplantar capsaicin in rats. The present data indicate that MS has both stimulatory and inhibitory actions on TRPV1 channels and suggest that the latter action may partly underlie the analgesic effects of MS independent of inhibition of cyclooxygenases in vivo. The American Society for Pharmacology and Experimental Therapeutics