title: Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice.
abstract: The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiologic 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. In this study, we tested JZL184 [4-nitrophenyl 4-[bis(2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate] and MJN110 [2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate], MAGL inhibitors that possess increased selectivity and potency, in mouse behavioral assays of neuropathic pain [chronic constriction injury (CCI) of the sciatic nerve], 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 in whole brains. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% confidence limit [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 [2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol] 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 cannabinoid 1 (CB1) receptor agonists, JZL184 produced hypomotility, whereas MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although both drugs substituted for CP55,940 in the drug discrimination assay, MJN110 was more potent in reversing allodynia in the CCI model than in producing CP55,940-like effects. Overall, these results suggest that MAGL inhibition may alleviate neuropathic pain, while displaying limited cannabimimetic effects compared with direct CB1 receptor agonists.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.) bogna.ignatowska@gmail.com.
authors.forename: Bogna
authors.initials: B
authors.lastname: Ignatowska-Jankowska
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wilkerson
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Mohammed
authors.initials: M
authors.lastname: Mustafa
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Rehab
authors.initials: R
authors.lastname: Abdullah
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Micah
authors.initials: M
authors.lastname: Niphakis
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.I.-J., J.L.Wilk., M.M., R.A., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.N., B.F.C.); and Research Triangle Institute, Research Triangle Park, North Carolina (J.L.Wile.).
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D040761:Biomimetic Materials / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use; D003250:Constriction; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D013388:Succinimides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D052117:Benzodioxoles; D002186:Cannabinoids; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; C534333:JZL 184; C587715:MJN110; D010880:Piperidines; D013388:Succinimides; D008994:Monoacylglycerol Lipases