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NEUROPHARMACOLOGY

The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3'-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice

Department of Experimental Pharmacology, University of Naples, Italy (R.R., G.L., A.C.); Department of Pharmacology and Center for Drug Discovery, University of California, Irvine, Irvine, California (J.L., D.P.); Kadmus Pharmaceuticals Inc., Irvine, California (T.C., J.P.); Institute of Medicinal Chemistry, University of Urbino "Carlo Bo," Urbino, Italy (A.D., A.T., G.T.); and Pharmaceutical Department, University of Parma, Parma, Italy (M.M.)

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB₁ receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB₂ antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.

Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625. E-mail: piomelli{at}uci.edu

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