title: Augmented tonic pain-related behavior in knockout mice lacking monoacylglycerol lipase, a major degrading enzyme for the endocannabinoid 2-arachidonoylglycerol.
abstract: Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8510, Japan. Electronic address: abpetr@med.niigata-u.ac.jp.
authors.forename: Andrey B
authors.initials: AB
authors.lastname: Petrenko
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Baba
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C094503:glyceryl 2-arachidonate; D017853:Phosphotransferases (Alcohol Group Acceptor); C025944:acylglycerol kinase
keywords: Acetic acid test; CB(1) receptor desensitization; Formalin test; Monoacylglycerol lipase knockout mice; Proalgesic effect; Tonic pain