title: Peripheral antinociceptive effects of inhibitors of monoacylglycerol lipase in a rat model of inflammatory pain.
abstract: BACKGROUND AND PURPOSE The endocannabinoid 2-arachidonoylglycerol (2-AG) is degraded primarily by monoacylglycerol lipase (MGL). We compared peripheral antinociceptive effects of JZL184, a novel irreversible MGL inhibitor, with the reversible MGL-preferring inhibitor URB602 and exogenous 2-AG in rats. EXPERIMENTAL APPROACH Nociception in the formalin test was assessed in groups receiving dorsal paw injections of vehicle, JZL184 (0.001-300 µg), URB602 (0.001-600 µg), 2-AG (ED(50)), 2-AG + JZL184 (at their ED(50)), 2-AG + URB602 (at their ED(50)), AM251 (80 µg), AM251 + JZL184 (10 µg), AM630 (25 µg) or AM630 + JZL184 (10 µg). Effects of MGL inhibitors on endocannabinoid accumulation and on activities of endocannabinoid-metabolizing enzymes were assessed. KEY RESULTS Intra-paw administration of JZL184, URB602 and 2-AG suppressed early and late phases of formalin pain. JZL184 and URB602 acted through a common mechanism. JZL184 (ED(50) Phase 1: 0.06 ± 0.028; Phase 2: 0.03 ± 0.011 µg) produced greater antinociception than URB602 (ED(50) Phase 1: 120 ± 51.3; Phase 2: 66 ± 23.9 µg) or 2-AG. Both MGL inhibitors produced additive antinociceptive effects when combined with 2-AG. Antinociceptive effects of JZL184, like those of URB602, were blocked by cannabinoid receptor 1 (CB(1)) and cannabinoid receptor 2 (CB(2)) antagonists. JZL184 suppressed MGL but not fatty-acid amide hydrolase or N-arachidonoyl-phosphatidylethanolamine phospholipase D activities ex vivo. URB602 increased hind paw 2-AG without altering anandamide levels. CONCLUSIONS AND IMPLICATIONS MGL inhibitors suppressed formalin-induced pain through peripheral CB(1) and CB(2) receptor mechanisms. MGL inhibition increased paw skin 2-AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain.
authors.affiliation: Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA, USA.
authors.forename: Josée
authors.initials: J
authors.lastname: Guindon
authors.forename: Ana
authors.initials: A
authors.lastname: Guijarro
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010739:Phospholipase D / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D052117:Benzodioxoles; D001713:Biphenyl Compounds; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D010739:Phospholipase D; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C501835:URB602; C094503:glyceryl 2-arachidonate; C527163:Napepld protein, rat; C078814:anandamide