Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 2010 Sep;13(9):1113-9
Date
08/24/2010Pubmed ID
20729846Pubmed Central ID
PMC2928870DOI
10.1038/nn.2616Scopus ID
2-s2.0-77956181836 (requires institutional sign-in at Scopus site) 515 CitationsAbstract
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.
Author List
Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BFAuthor
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmidohydrolasesAnalgesics
Animals
Benzodioxoles
Brain
Cannabinoid Receptor Modulators
Endocannabinoids
Enzyme Inhibitors
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Models, Animal
Monoacylglycerol Lipases
Neuronal Plasticity
Pain
Piperidines
Receptor, Cannabinoid, CB1
Synapses
