1. Academic Validation
  2. The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

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

  • J Pharmacol Exp Ther. 2016 Apr;357(1):145-56. doi: 10.1124/jpet.115.229971.
Jenny L Wilkerson 1 Micah J Niphakis 2 Travis W Grim 2 Mohammed A Mustafa 2 Rehab A Abdullah 2 Justin L Poklis 2 William L Dewey 2 Hamid Akbarali 2 Matthew L Banks 2 Laura E Wise 2 Benjamin F Cravatt 2 Aron H Lichtman 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (J.L.W., T.W.G., M.A.M., R.A.A., J.L.P., W.L.D., H.A., M.L.B., L.E.W., A.H.L.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.) [email protected].
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (J.L.W., T.W.G., M.A.M., R.A.A., J.L.P., W.L.D., H.A., M.L.B., L.E.W., A.H.L.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).
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 (Δ(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 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 these drugs in combination revealed synergistic antiallodynic 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 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.

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