Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
By J. Schlosburg, Jacqueline L. Blankman, Jonathan Z. Long, Daniel K. Nomura, Bin Pan, S. Kinsey, Peter T. Nguyen, Divya Ramesh, L. Booker, J. Burston and 6 more. Nature Neuroscience, 2010
617 citations recorded by the source corpus.
Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.
Subfields: Cognitive Neuroscience, Pharmacology, Toxicology
View Paper: https://www.semanticscholar.org/paper/b61b66b5ff097fb140090e4a1417a635ac83aeff
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Citations in the corpus
- Neurobiological Interactions Between Stress and the Endocannabinoid System (2016, background): “…problematic, as unlike the fact that chronic elevations in AEA do not seem to modulate CB1 receptor function (Lichtman et al, 2002), chronic elevations in 2-AG signaling, through administration of high doses of MAGL inhibitors, seem to clearly desensitize the CB1 receptor (Schlosburg et al, 2010).”
- Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight (2010, result): “That these two mediators are not merely redundant agonists at the same receptors is strongly supported not only by the finding of their interconnected biosynthetic routes and of potential alternative targets for anandamide, but also by the recent demonstration, obtained by comparing the phenotypes o”
- Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System (2018, background): “Abbreviations THC ∆9-tetrahydrocannabinol CBR Cannabinoid receptor AEA N-arachidonoyl-ethanolamine 2-AG 2-arachidonoylglycerol CBD Cannabidiol GPCR G protein-coupled receptor TRPV1 Transient receptor potential cation channel subfamily V member 1 NAPE N-acyl-phosphatidylethanolamine NAPE-PLD NAPE-spe”
- Lipolysis – A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores (2011, background): “Yet, in MGL-deficient mice elevated levels of various MAG species have been described in the brain [23].”