Synergy between Enzyme Inhibitors of Fatty Acid Amide Hydrolase and Cyclooxygenase in Visceral Nociception

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Abstract
The present study investigated whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide catabolism, produces antinociception in the acetic acid-induced abdominal stretching model of visceral nociception. Genetic deletion or pharmacological inhibition of FAAH reduced acetic acid-induced abdominal stretching. Transgenic mice that express FAAH exclusively in the nervous system displayed the antinociceptive phenotype, indicating the involvement of peripheral fatty acid amides. The cannabinoid receptor 1 (CB1) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB2) receptor antagonist, SR144528, blocked the antinociceptive phenotype of FAAH(-/-) mice and the analgesic effects of URB597 (3′-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) or OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane), respective irreversible and reversible FAAH inhibitors, administered to C57BL/6 mice. The opioid receptor antagonist, naltrexone, did not block the analgesic effects of either FAAH inhibitor. URB597, ED50 [95% confidence interval (CI) = 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED50 (95% CI) = 9.8 (8.2-11.7) mg/kg], dose-dependently inhibited acetic acid-induced abdominal stretching. Combinations of URB597 and diclofenac yielded synergistic analgesic interactions according to isobolographic analysis. It is important that FAAH(-/-) mice and URB597-treated mice displayed significant reductions in the severity of gastric irritation caused by diclofenac. URB597 lost its gastroprotective effects in CB1(-/-) mice, whereas it maintained its efficacy in CB2(-/-) mice, indicating a CB1 mechanism of action. Taken together, the results of the present study suggest that FAAH represents a promising target for the treatment of visceral pain, and a combination of FAAH inhibitors and NSAIDs may have great utility to treat visceral pain, with reduced gastric toxicity.

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