Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

Joel E. Schlosburg, Jacqueline L. Blankman, Jonathan Z. Long, Daniel K. Nomura, Bin Pan, Steven G. Kinsey, Peter T. Nguyen, Divya Ramesh, Lamont Booker, James J. Burston, Elizabeth A. Thomas, Dana E. Selley, Laura J. Sim-Selley, Qing Song Liu, Aron H. Lichtman, Benjamin F. Cravatt

Research output: Contribution to journalArticlepeer-review

520 Scopus citations

Abstract

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 CB 1 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.

Original languageEnglish (US)
Pages (from-to)1113-1119
Number of pages7
JournalNature Neuroscience
Volume13
Issue number9
DOIs
StatePublished - Sep 2010
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience

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