Targeting FAAH and COX to Treat Visceral Pain

Abstract

Genetic deletion or pharmacological inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for catabolism of the endogenous cannabinoid anandamide, leads to a CB1 receptor mediated decrease in nociceptive behavior in a variety of inflammatory and neuropathic pain models. However, there are presently no published reports that have evaluated whether FAAH blockade reduces nociception in visceral pain, though direct‐acting CB1 receptor agonists as well as cyclooxygenase (COX) inhibitors are highly effective in visceral pain assays. Therefore, in the present study we evaluated whether FAAH blockade will block nociceptive behavior in the mouse acetic acid writhing model. Additionally, we examined whether co‐administration of a FAAH inhibitor and COX inhibitor would synergize to block visceral pain. FAAH (‐/‐) mice as well as wild type mice treated with FAAH inhibitors (i.e., URB597 and OL‐135) or the non‐selective COX inhibitor diclofenac displayed a decrease in acetic acid‐induced writhing. URB597 (1–10 mg/kg; ED50 = 2.1 mg/kg) and diclofenac (3–30 mg/kg; ED50 = 9.8 mg/kg) produced dose‐dependent antinociception in the writhing test. The CB1 receptor antagonist rimonabant blocked the analgesic effects in the FAAH‐compromised mice, but failed to attenuate the actions of diclofenac. Interactions between URB597 and diclofenac were analyzed using an isobolographic approach. Combined administration of URB59597 and diclofenac in ratios of 1:1 [ED50s = 0.24 and 1.18 mg/kg], 1:3 [ED50s = 0.28 and 4.30 mg/kg], or 3:1 yielded [ED50s = 0.44 and 0.72 mg/kg] yielded synergistic interactions. Taken together, the results of the present study suggest that FAAH represents a promising target to treat visceral pain and combination of FAAH inhibitors and NSAIDs may have greater therapeutic utility than either class of drug given alone.