title: Inhibition of fatty acid amide hydrolase by URB597 attenuates the anxiolytic-like effect of acetaminophen in the mouse elevated plus-maze test.
abstract: Acetaminophen is the most widely used analgesic/antipyretic drug. It is metabolized into N-arachidonoylphenolamine (AM404), which inhibits the reuptake of anandamide. In view of the role of endocannabinoids in the effect of acetaminophen, we tested its anxiolytic-like effect by observing the behavior of mice using the elevated plus-maze test. The results indicated that acetaminophen [100 and 200 mg/kg, intraperitoneally (i.p.)] exerted an anxiolytic-like effect that was represented by higher percentage open-arm time, percentage open-arm entries, and total number of head dips compared with the vehicle control (P<0.05). Inhibition of fatty acid amide hydrolase, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, using URB597 (0.07 mg/kg, i.p.), attenuated the anxiolytic-like effect of acetaminophen. Pretreatment with the cannabinoid type-1 receptor antagonist rimonabant (1 mg/kg, i.p.) antagonized the effect of acetaminophen. Remarkably, the selected doses of rimonabant or URB597 did not themselves induce any anxiolytic-like effect. Furthermore, the selected doses of acetaminophen (25, 50, 100, and 200 mg/kg, i.p.) did not significantly alter the locomotor activity of mice in the open-field test. In conclusion, these findings confirmed that acetaminophen shows an anxiolytic-like effect in mice that involves, at least in part, AM404-mediated accumulation of anandamide in the brain and consequent activation of cannabinoid type-1 receptors.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia. sawsan_zaytoon@pharm.suez.edu.eg
authors: Sawsan A
authors: SA
authors: Zaitone
authors: Ahmed F
authors: AF
authors: El-Wakeil
authors: Soad H
authors: SH
authors: Abou-El-Ela
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000082:Acetaminophen; D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C107594:N-(4-hydroxyphenyl)arachidonylamide