Monoacylglycerol lipase activity is a critical modulator of the tone and integrity of the endocannabinoid system.
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.
Chanda
Pranab K
PK
Neuroscience Research Unit, Pfizer Global Research, Princeton, New Jersey, USA.
Gao
Ying
Y
Mark
Lilly
L
Btesh
Joan
J
Strassle
Brian W
BW
Lu
Peimin
P
Piesla
Michael J
MJ
Zhang
Mei-Yi
MY
Bingham
Brendan
B
Uveges
Albert
A
Kowal
Dianne
D
Garbe
David
D
Kouranova
Evguenia V
EV
Ring
Robert H
RH
Bates
Brian
B
Pangalos
Menelas N
MN
Kennedy
Jeffrey D
JD
Whiteside
Garth T
GT
Samad
Tarek A
TA
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*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D008994:Monoacylglycerol Lipases