title: Systemic and spinal administration of FAAH, MAGL inhibitors and dual FAAH/MAGL inhibitors produce antipruritic effect in mice.
abstract: The increase of endocannabinoid tonus by inhibiting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) represents a promising therapeutic approach in a variety of disease to overcome serious central side effects of exocannabinoids. Recent studies reported that systemic administration of FAAH and MAGL inhibitors produce antipruritic action. Dual FAAH/MAGL inhibitors have also been described to get enhanced endocannabinoid therapeutic effect. In this study, we examined and compared dose-related antipruritic effects of systemic (intraperitoneal; ip) or intrathecal (it) administration of selective FAAH inhibitor PF-3845 (5, 10, and 20 mg/kg, i.p.; 1, 5, and 10 µg, i.t.), MAGL inhibitor JZL184 (4, 20, and 40 mg/kg, i.p.; 1, 5, and 10 µg, i.t.) and dual FAAH/MAGL inhibitor JZL195 (2, 5, and 20 mg/kg, i.p.; 1, 5, and 10 µg, i.t.) on serotonin (5-HT)-induced scratching model. Serotonin (25 μg) was injected intradermally in a volume of 50 μl into the rostral part of skin on the back of male Balb-C mice. Both systemic or intrathecal administration of PF-3845, JZL184 or JZL195 produced similar dose-dependent antipruritic effects. Our results suggest that endocannabinoid-degrading enzymes FAAH and MAGL are involved in pruritic process at spinal level. FAAH, MAGL or dual FAAH/MAGL inhibitors have promising antipruritic effects, at least, in part through spinal site of action.
authors.affiliation: Department of Pharmacology, Drug Discovery and Research Center, Gulhane Academy of Medicine, Etlik, 06018, Ankara, Turkey. oyesilyurt@gata.edu.tr.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Yesilyurt
authors.affiliation: Department of Dermatology, Mevki Military Hospital, 06018, Ankara, Turkey.
authors.forename: Mutlu
authors.initials: M
authors.lastname: Cayirli
authors.affiliation: Department of Gastroenterology, Gulhane Academy of Medicine, Etlik, 06018, Ankara, Turkey.
authors.forename: Yusuf Serdar
authors.initials: YS
authors.lastname: Sakin
authors.affiliation: Department of Pharmacology, Drug Discovery and Research Center, Gulhane Academy of Medicine, Etlik, 06018, Ankara, Turkey.
authors.forename: Melik
authors.initials: M
authors.lastname: Seyrek
authors.affiliation: Department of Dermatology, Gulhane Academy of Medicine, Etlik, 06018, Ankara, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Akar
authors.affiliation: Department of Pharmacology, Drug Discovery and Research Center, Gulhane Academy of Medicine, Etlik, 06018, Ankara, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogrul
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000982:Antipruritics / Q000008:administration & dosage / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000982:Antipruritics; D052117:Benzodioxoles; D002219:Carbamates; D063388:Endocannabinoids; D008994:Monoacylglycerol Lipases; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D012701:Serotonin; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C000592052:JZL195; C557973:PF 3845
keywords: Antipruritic effect; Endocannabinoid system; Fatty acid amide hydrolase; Monoacyglycerol lipase; Pruritis