Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice
| Autor: | Divya Ramesh, Dana E. Selley, Lamont Booker, Benjamin F. Cravatt, Jonathan Z. Long, Rehab A. Abdullah, Joel E. Schlosburg, Steven G. Kinsey, Bogna M. Ignatowska-Jankowska, Qing Tao, Aron H. Lichtman |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cannabinoid receptor medicine.medical_treatment Pharmacology Amidohydrolases chemistry.chemical_compound Mice Piperidines Receptor Cannabinoid CB1 Fatty acid amide hydrolase Cannabinoid receptor type 1 medicine Animals Benzodioxoles Dronabinol Receptor JZL184 Mice Knockout Endocannabinoid system Adaptation Physiological Monoacylglycerol Lipases Monoacylglycerol lipase Mice Inbred C57BL chemistry nervous system Behavioral Pharmacology Molecular Medicine lipids (amino acids peptides and proteins) Cannabinoid Endocannabinoids |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 350(2) |
| ISSN: | 1521-0103 |
| Popis: | Complementary genetic and pharmacological approaches to inhibit monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, enable the exploration of potential therapeutic applications and physiologic roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of a high dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate; 40 mg/kg] given acutely or for 6 days in FAAH(-/-) and (+/+) mice. While acute administration of JZL184 to FAAH(-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ(9)-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence. |
| Databáze: | OpenAIRE |
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