title: Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects.
abstract: The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB1) downregulation and desensitization. This functional CB1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 (≥16 mg/kg) for 6 days displayed decreased CB1 receptor density and function in the brain, as assessed in [(3)H]SR141716A binding and CP55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, respectively. In contrast, normal CB1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB1 receptor tachyphylaxis/tolerance or cannabinoid dependence.
authors: Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
authors: Steven G
authors: SG
authors: Kinsey
authors: Laura E
authors: LE
authors: Wise
authors: Divya
authors: D
authors: Ramesh
authors: Rehab
authors: R
authors: Abdullah
authors: Dana E
authors: DE
authors: Selley
authors: Benjamin F
authors: BF
authors: Cravatt
authors: Aron H
authors: AH
authors: Lichtman
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology; D004008:Diclofenac; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D004361:Drug Tolerance; D063388:Endocannabinoids / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis / Q000187:drug effects*; D000077285:Rimonabant; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D004008:Diclofenac; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D000077285:Rimonabant