title: Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice.
abstract: There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CB1 receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. Electronic address: chihiron@uni-bonn.de.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Nozaki
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Markert
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism; D005996:Nitroglycerin; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant; D014110:Touch; D014278:Trigeminal Nuclei / Q000187:drug effects* / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D005996:Nitroglycerin; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C578453:CNR1 protein, mouse; C571431:Cnr2 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide
keywords: CB1 receptor; Endocannabinoid; FAAH; Headache; Migraine; Nitroglycerin