Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia

Abstract

Although the N-arachidonoyl ethanolamine (anandamide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by fatty acid amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid. In order to test whether anandamide and other non-cannabinoid fatty amides modulate nociception, we compared FAAH (+/+) and (−/−) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (−/−) mice exhibited a CB 1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests. These mice also exhibited CB 1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB 1 or CB 2 antagonists. Additionally, FAAH (−/−) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB 2, but not CB 1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI, which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (−/−) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals. Collectively, these findings demonstrate a cannabinoid receptor-mediated analgesic phenotype in FAAH (−/−) mice. In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.