title: Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model.
abstract: The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.
authors.affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: wayne.anderson@sydney.edu.au.
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Anderson
authors.affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gould
authors.affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Romeo D
authors.initials: RD
authors.lastname: Torres
authors.affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Mitchell
authors.affiliation: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Vaughan
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000150:complications*; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000627:therapeutic use; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement; D010879:Piperazines / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D001549:Benzamides; D048588:Benzoxazines; D002219:Carbamates; D009025:Morpholines; D009281:Naphthalenes; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D000099252:Fatty Acid Amide Hydrolases; C000592052:JZL195; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Cannabinoid receptors; Fatty acid amide hydrolase; Inflammation; Monoacylglycerol lipase; Pain