Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice

Abstract Fatty acid amide hydrolase (FAAH) is the primary degradative enzyme of the endocannabinoid anandamide ( N -arachidonoylethanolamine), which activates cannabinoid CB 1 and CB 2 receptors. FAAH disruption reduces nociception in a variety of acute rodent models of inflammatory pain. The present study investigated whether these actions extend to the chronic, collagen-induced arthritis (CIA) model. We investigated the anti-arthritic and anti-hyperalgesic effects of genetic deletion or pharmacological inhibition of FAAH in the CIA model. FAAH (−/−) mice, and FAAH-NS mice that express FAAH exclusively in nervous tissue, displayed decreased severity of CIA and associated hyperalgesia. These phenotypic anti-arthritic effects were prevented by repeated daily injections of the CB 2 receptor antagonist, SR144528, but not the CB 1 receptor antagonist rimonabant. Similarly, repeated administration of the FAAH inhibitor URB597 reduced CIA severity, and acute administration of rimonabant, but not SR144528, blocked the anti-hyperalgesic effects of prolonged FAAH inhibition, suggesting that prolonged CB 2 receptor activation reduces the severity of CIA, whereas acute CB 1 receptor activation reduces CIA-induced hyperalgesia. In contrast, acute administration of URB597 elicited a CB 1 receptor-dependent anti-hyperalgesic effect. The observed anti-arthritic and anti-hyperalgesic properties of FAAH inhibition, coupled with a lack of apparent behavioral alterations, suggest that endocannabinoid modulating enzymes offer a promising therapeutic target for the development of novel pharmacological approaches to treat rheumatoid arthritis and associated hyperalgesia.