Title page Regulation of Inflammatory Pain by Inhibition of Fatty Acid Amide Hydrolase (FAAH)

Abstract Although cannabinoids are efficacious in laboratory animal models of inflammatory pain, their established cannabimimetic actions diminish enthusiasm for their therapeutic development. Conversely, fatty acid amide hydrolase (FAAH), the chief catabolic enzyme regulating the endogenous cannabinoid N-arachidonoylethanolamine (anandamide), has emerged as an attractive target to treat pain and other conditions. Here, we tested WIN55,212-2, a cannabinoid receptor agonist, as well as genetic deletion or pharmacological inhibition of FAAH in the lipopolysaccharide (LPS) mouse model of inflammatory pain. WIN55,212 significantly reduced edema and hotplate hyperalgesia caused by LPS infusion into the hind paws, though the mice also displayed analgesia and other CNS effects. FAAH (-/-) mice exhibited reduced paw edema and hyperalgesia in this model, without apparent cannabimimetic effects. Transgenic mice expressing FAAH exclusively on neurons continued to display the anti-edematous, but not the anti-hyperalgesic, phenotype. The CB 2 receptor antagonist, SR144528, blocked this non-neuronal, anti-inflammatory phenotype, and the CB 1 receptor antagonist, rimonabant, blocked the anti-hyperalgesic phenotype. The FAAH inhibitor, URB597 attenuated the development of LPS-induced paw edema and reversed LPS-induced hyperalgesia through respective CB 2 and CB 1 receptor mechanisms of action. However, the TRPV1 receptor antagonist, capsazepine, did not affect either the anti-hyperalgesic or antiedematous effects of URB597. Finally, URB597 attenuated levels of the pro-inflammatory cytokines IL-1β and TNF-α in LPS-treated paws. These findings demonstrate that simultaneous elevations in non-neuronal and neuronal endocannabinoid signaling are possible through inhibition of a single enzymatic target, thereby offering a potentially powerful strategy to treat chronic inflammatory pain syndromes that operate at multiple levels of anatomical integration