title: 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 (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.
authors.affiliation: 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.) jenny.wilkerson@vcuhealth.org.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wilkerson
authors.affiliation: 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.).
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.affiliation: 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.).
authors.forename: Travis W
authors.initials: TW
authors.lastname: Grim
authors.affiliation: 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.).
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Mustafa
authors.affiliation: 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.).
authors.forename: Rehab A
authors.initials: RA
authors.lastname: Abdullah
authors.affiliation: 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.).
authors.forename: Justin L
authors.initials: JL
authors.lastname: Poklis
authors.affiliation: 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.).
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: 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.).
authors.forename: Hamid
authors.initials: H
authors.lastname: Akbarali
authors.affiliation: 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.).
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: 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.).
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.affiliation: 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.).
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: 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.).
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D003251:Constriction, Pathologic / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013388:Succinimides / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D001095:Arachidonic Acids; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C587715:MJN110; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D013388:Succinimides; D009020:Morphine; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases