TY - JOUR T1 - Desensitization of TRPA1 by the TRPV1-selective cannabinoid arachidonoly-2 chloroethanolamine (ACEA) JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.068940 SP - mol.110.068940 AU - Nikita B. Ruparel AU - Amol M. Patwardhan AU - Armen N. Akopian AU - Kenneth M. Hargreaves Y1 - 2011/03/25 UR - http://molpharm.aspetjournals.org/content/early/2011/03/25/mol.110.068940.abstract N2 - Recent studies on cannabinoid-induced analgesia implicate certain transient receptor potential (TRP) channels as a therapeutic target along with metabotropic cannabinoid receptors. While TRPA1-selective cannabinoids such as Win 55,212 are effective at desensitizing TRPA1 and TRPV1, there is a gap in knowledge in understanding the opposite situation, namely whether TRPV1-selective cannabinoids desensitize TRPA1. We selected the TRPV1-specific synthetic cannabinoid, arachidonoly-2 chloroethanolamine (ACEA) to study peripheral antihyperalgesic properties since ACEA is known to activate TRPV1. Hence, using in vitro as well as in vivo assays, we evaluated: 1) the effects of ACEA on the TRPA1 selective agonist, mustard oil (MO), for CGRP release from rat hindpaw skin in vitro; 2) the effects of a peripherally-selective dose of ACEA on MO-induced nocifensive behavior in vivo; and 3) the effects of five ACEA-insensitive TRPV1 mutations on ACEA-inhibition of MO-evoked calcium accumulation using a CHO cell expression system. Our results demonstrate that 1) ACEA significantly attenuated (~ 40%) MO-evoked CGRP release from rat hindpaw skin and this effect was not antagonized by the TRPV1 antagonist, capsazepine; 2) ACEA significantly inhibited (~ 40%) MO-induced nocifensive behavior in WT, but not in TRPV1 knockout mice; and 3) all TRPV1 mutations insensitive to ACEA lacked the ability to inhibit MO-evoked calcium accumulation in CHO cells transfected with both TRPV1 and TRPA1. Collectively, the results indicate that a TRPV1-selective cannabinoid, ACEA, inhibits MO-evoked responses via a TRPV1-dependent mechanism. This study strengthens the hypothesis that cannabinoids mediate their peripheral analgesic properties, at least in part, via the TRP channels. ER -