title: Monoacylglycerol lipase activity is a critical modulator of the tone and integrity of the endocannabinoid system.
abstract: Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research, Princeton, New Jersey, USA.
authors.forename: Pranab K
authors.initials: PK
authors.lastname: Chanda
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.forename: Joan
authors.initials: J
authors.lastname: Btesh
authors.forename: Brian W
authors.initials: BW
authors.lastname: Strassle
authors.forename: Peimin
authors.initials: P
authors.lastname: Lu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Piesla
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Brendan
authors.initials: B
authors.lastname: Bingham
authors.forename: Albert
authors.initials: A
authors.lastname: Uveges
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: David
authors.initials: D
authors.lastname: Garbe
authors.forename: Evguenia V
authors.initials: EV
authors.lastname: Kouranova
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.forename: Brian
authors.initials: B
authors.lastname: Bates
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kennedy
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Samad
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008994:Monoacylglycerol Lipases / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D008994:Monoacylglycerol Lipases