Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects.
The monoacylglycerol lipase (MAGL) inhibitor 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 CB(1) receptor downregulation and desensitization. This functional CB(1) 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 constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal CB(1) 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 (THC). This same pattern of effects was found in a rimonabant-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 CB(1) receptor tachyphylaxsis/tolerance or cannabinoid dependence.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
monoacylglycerol JZL184 JZL184 JZL184 [(3)H]SR141716A CP55,940 (35)S Monoacylglycerol JZL184 CB(1) JZL184 MAGL CB(1) cannabinoid receptor MAGL CB(1) CB(1) monoacylglycerol lipase MAGL CB(1) Monoacylglycerol Lipase JZL184 CB1 JZL184 JZL184 JZL184 Δ(9)-tetrahydrocannabinol JZL184 THC rimonabant