title: Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice.
abstract: Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states with minimal cannabimimetic effects.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kinsey
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Qing-Song
authors.initials: QS
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Lenka
authors.initials: L
authors.lastname: Hruba
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Lance R
authors.initials: LR
authors.lastname: McMahon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Travis W
authors.initials: TW
authors.lastname: Grim
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Christina R
authors.initials: CR
authors.lastname: Merritt
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Rehab A
authors.initials: RA
authors.lastname: Abdullah
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.).
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (S.G., T.W.G., C.R.M., L.E.W., R.A.A., D.E.S., L.J.S.-S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin (Q.L.); Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (L.H., L.R.M.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (B.F.C.) alichtma@vcu.edu.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage*; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D052117:Benzodioxoles; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C557973:PF 3845