J Pharmacol Exp Ther. 2016 Jan 20. pii: jpet.115.229971. [Epub ahead of print]
The selective monoacylglycerol lipase inhibitor MJN110 produces opioid sparing effects in a mouse neuropathic pain model.
Wilkerson JL1, Niphakis MJ2, Grim TW3, Mustafa MA4, Abdullah RA5, Poklis JL5, Dewey WL4, Akbarali HI4, Banks ML4, Wise LE4, Cravatt BF6, Lichtman AH4.
Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis, ?9-tetrahydrocannabinol, produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonylglycerol (2-AG) through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate, (MJN110) were tested alone and in combination at an equally effective ratio in reversing CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of equally effective dose combinations of these drugs revealed synergistic anti-allodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required µ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly, (i.e., twice a day for six days) continued to produce anti-allodynic effects with no evidence of tolerance. These findings, taken together, suggest that MAGL inhibition produces opiate sparing events with diminished tolerance, constipation, and cannabimemetic side effects. |
