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 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.
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Acknowledgements
We thank S. Niessen and H. Hoover for assistance with proteomics studies, I. Beletskaya and R. Abdullah for technical support and the Cravatt and Lichtman laboratories for critical reading of the manuscript. This work was supported by the US National Institutes of Health (grants DA017259, DA009789, DA025285, DA005274, DA015683, DA03672, DA005274, DA07027, DA014277, DA023758 and DA024741), Ruth L. Kirschstein US National Institutes of Health Predoctoral Fellowships (DA026261 to J.L.B., DA026279 to J.E.S., DA028333 to L.B. and DA023758 to P.T.N.), the American Cancer Society (D.K.N.) and the Skaggs Institute for Chemical Biology.
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J.E.S. performed behavioral and receptor adaptation experiments. J.L.B. performed the metabolic biochemistry, proteomic and in situ hybridization experiments and contributed to behavioral experiments. J.Z.L. contributed to metabolic biochemistry and behavioral experiments. D.K.N., S.G.K., D.R. and L.B. contributed to behavioral experiments. B.P. performed the electrophysiology experiments. P.T.N. and J.J.B. contributed to receptor adaptation experiments. E.A.T. contributed to the design and interpretation of in situ hybridization experiments. D.E.S and L.J.S.-S. contributed to the design and interpretation of receptor adaptation experiments. Q.-s.L. contributed to the design and interpretation of electrophysiology experiments. A.H.L. and B.F.C. supervised the design, execution and interpretation of the experiments and wrote the manuscript.
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Schlosburg, J., Blankman, J., Long, J. et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 13, 1113–1119 (2010). https://doi.org/10.1038/nn.2616
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DOI: https://doi.org/10.1038/nn.2616
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