The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Abstract

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 (D 9 -tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol 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 equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED 50 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 these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required m-opioid, CB 1 , and CB 2 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 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

“…In contrast, there are no reports in the literature testing whether inhibitors of endocannabinoid metabolizing enzymes are beneficial adjutants to opioid therapy in chronic pain patients. The results of the present study taken together with other studies that report individual inhibition of either FAAH or MAGL also produces opioid sparing antinociceptive effects with no added side effects (Miller et al, 2012; Wilkerson et al, 2016) supports the idea to initiate clinical trials to test whether FAAH, MAGL, or simultaneous FAAH and MAGL inhibition is opioid-sparing.…”

“…These findings suggest that FAAH inhibition alone sufficiently augments morphine-induced antinociception and are consistent with the results of Miller et al (2012), who demonstrated that combination of the FAAH inhibitor URB597 and morphine produced additive antinociceptive effects in acetic acid-induced abdominal stretching and depression of wheel running in mice. In contrast combination of morphine and the MAGL inhibitor MJN110 produced synergistic antinociceptive effects in the CCI model (Wilkerson et al, 2016). Taken together, these results suggest that the endocannabinoid hydrolyzing enzyme inhibitors differentially interact with morphine in the CCI model of neuropathic pain, with FAAH inhibition producing additive antinociceptive effects and MAGL inhibition producing synergistic antinociceptive effects.…”

“…Specifically, combination of the FAAH inhibitor URB597 and morphine produces additive antinociceptive effects in the acetic acid model of visceral nociception (Miller et al, 2012). Additionally, co-administration of the MAGL inhibitor MJN110 and morphine produces synergistic anti-allodynic effects in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model (Wilkerson et al, 2016). Given the national crisis of clinical opioid misuse and abuse, therapeutic pain options that lessen the total opioid prescription burden, and limiting the overt abuse liability of opioids (e.g., morphine, oxycodone and heroin) are needed.…”

Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats

“…Interestingly, this compound can be used in combination with morphine to produce synergistic analgesia and even appears to alleviate tolerance to opioid analgesia. A similar effect has also been noted using low-dose MAGL inhibition via MJN110 in combination with morphine in a rodent model of neuropathic pain (Wilkerson et al, 2016b). In our pain model, EM-2 in combination with URB597 enhanced antinociceptive activity, confirming the synergistic effects of ECs and opioids in pain suppression, being an exciting avenue for future research.…”

The cannabinoid system and pain

“…Interestingly, this compound can be used in combination with morphine to produce synergistic analgesia, and even appears to alleviate tolerance to opioid analgesia. A similar effect has also been noted using low dose MAGL inhibition via MJN110 in combination with morphine in a rodent model of neuropathic pain (Wilkerson et al, 2016b), suggesting this is an exciting avenue for future research.…”