Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

Nat Neurosci. 2010 Sep;13(9):1113-9. doi: 10.1038/nn.2616. Epub 2010 Aug 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Analgesics / administration & dosage
  • Analgesics / pharmacology
  • Animals
  • Benzodioxoles / administration & dosage
  • Benzodioxoles / pharmacology
  • Brain / drug effects
  • Brain / physiology
  • Cannabinoid Receptor Modulators / antagonists & inhibitors
  • Cannabinoid Receptor Modulators / metabolism*
  • Endocannabinoids*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Animal
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / genetics
  • Monoacylglycerol Lipases / metabolism*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Pain / drug therapy
  • Pain / metabolism
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism
  • Synapses / drug effects
  • Synapses / physiology

Substances

  • Analgesics
  • Benzodioxoles
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Enzyme Inhibitors
  • JZL 184
  • Piperidines
  • Receptor, Cannabinoid, CB1
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase