Selective monoacylglycerol lipase inhibitors: Antinociceptive vs. cannabimimetic effects in mice.

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiological processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. Here, we tested JZL184 and MJN110, MAGL inhibitor that possesses increased selectivity and potency, in mouse behavioral assays of neuropathic pain (chronic constrictive injury of the sciatic nerve; CCI), interoceptive cannabimimetic effects (drug discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid, but did not affect anandamide (AEA) in whole brain. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% CL) values in mg/kg: MJN110 (0.43 (0.30-0.63) > JZL184 (17.8 (11.6-27.4))], and also substituted for the potent cannabinoid receptor agonist CP55,940 in the drug discrimination paradigm [ED50 (95% CL) values in mg/kg: MJN110 (0.84 (0.69-1.02)) > JZL184 (24.9 (14.6-42.5))]. However, these compounds elicited differential effects on locomotor behavior. Similar to CB1 receptor agonists, JZL184 produced hypomotility, while MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although these results suggest that MAGL inhibitors hold promise for the treatment of neuropathic pain, their substitution for CP55,940 in the drug discrimination assay may not be desirable for a therapeutic drug. Nonetheless, in contrast to CB1 receptor agonists, each MAGL inhibitor tested elicited few or no pharmacological effects in other standard assays used to infer cannabimimetic activity.
The American Society for Pharmacology and Experimental Therapeutics.