Peripheral antinociceptive effects of inhibitors of monoacylglycerol lipase in a rat model of inflammatory pain

• Published in: British journal of pharmacology Vol. 163; no. 7; pp. 1464 - 1478
• Main Authors: Guindon, Josée, Guijarro, Ana, Piomelli, Daniele, Hohmann, Andrea G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2011
• Subjects: 2‐arachidonoylglycerol; Amidohydrolases - metabolism; anandamide; Animals; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Benzodioxoles - pharmacology; Biphenyl Compounds - pharmacology; cannabinoid antagonists; Cannabinoid Receptor Modulators - metabolism; Drug Interactions; Drug Therapy, Combination; endocannabinoid levels; Endocannabinoids; formalin; Glycerides - metabolism; Glycerides - pharmacology; hind paw; inflammatory pain; JZL184; Male; MGL; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - metabolism; Pain - drug therapy; Pain - metabolism; Pain Measurement - drug effects; Phospholipase D - metabolism; Piperidines - pharmacology; Polyunsaturated Alkamides - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Research Papers; URB602
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01192.x

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 (ED50), 2‐AG + JZL184 (at their ED50), 2‐AG + URB602 (at their ED50), 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 (ED50 Phase 1: 0.06 ± 0.028; Phase 2: 0.03 ± 0.011 µg) produced greater antinociception than URB602 (ED50 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 (CB1) and cannabinoid receptor 2 (CB2) 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 CB1 and CB2 receptor mechanisms. MGL inhibition increased paw skin 2‐AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7