title: Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception.
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 (CB(1)) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB(2)) 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, ED(50) [95% confidence interval (CI) = 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED(50) (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 CB(1)(-/-) mice, whereas it maintained its efficacy in CB(2)(-/-) mice, indicating a CB(1) 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA.
authors.forename: Pattipati S
authors.initials: PS
authors.lastname: Naidu
authors.forename: Lamont
authors.initials: L
authors.lastname: Booker
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D019342:Acetic Acid; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004008:Diclofenac / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy*; D020011:Protective Agents; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D019342:Acetic Acid; D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D004791:Enzyme Inhibitors; D009271:Naltrexone; D009292:Narcotic Antagonists; D020011:Protective Agents; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester