Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
| Autor: | Dana E. Selley, Bin Pan, Aron H. Lichtman, Elizabeth A. Thomas, Qing-song Liu, Daniel K. Nomura, Benjamin F. Cravatt, Steven G. Kinsey, Jacqueline L. Blankman, Peter T. Nguyen, Divya Ramesh, Joel E. Schlosburg, Lamont Booker, Laura J. Sim-Selley, Jonathan Z. Long, James J. Burston |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cannabinoid receptor medicine.medical_treatment 2-Arachidonoylglycerol Pain Mice Transgenic Pharmacology Article Amidohydrolases Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines Receptor Cannabinoid CB1 Cannabinoid Receptor Modulators medicine Animals Benzodioxoles Enzyme Inhibitors JZL184 030304 developmental biology Mice Knockout Analgesics 0303 health sciences Neuronal Plasticity musculoskeletal neural and ocular physiology General Neuroscience Brain Anandamide ABHD6 Endocannabinoid system Monoacylglycerol Lipases 3. Good health Mice Inbred C57BL Monoacylglycerol lipase nervous system chemistry Models Animal Synapses Female lipids (amino acids peptides and proteins) Cannabinoid psychological phenomena and processes 030217 neurology & neurosurgery Endocannabinoids |
| Zdroj: | Nature neuroscience |
| ISSN: | 1546-1726 1097-6256 |
| Popis: | Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. Here we show that a similar form of functional antagonism is produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). 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 MAGL. Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity, and desensitization of brain CB1 receptors. These data contrasted with blockade of fatty acid amide hydrolase (FAAH), 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. |
| Databáze: | OpenAIRE |
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