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: Josée Guindon, Ana Guijarro, Daniele Piomelli, Andrea G Hohmann
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 7 Pg. 1464-78 (Aug 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21198549 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Arachidonic Acids
• Benzodioxoles
• Biphenyl Compounds
• Cannabinoid Receptor Modulators
• Endocannabinoids
• Glycerides
• JZL 184
• Piperidines
• Polyunsaturated Alkamides
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• URB602
• glyceryl 2-arachidonate
• Monoacylglycerol Lipases
• Napepld protein, rat
• Phospholipase D
• Amidohydrolases
• fatty-acid amide hydrolase
• anandamide

Topics

• Amidohydrolases (metabolism)
• Animals
• Arachidonic Acids (metabolism, pharmacology)
• Benzodioxoles (pharmacology)
• Biphenyl Compounds (pharmacology)
• Cannabinoid Receptor Modulators (metabolism)
• Drug Interactions
• Drug Therapy, Combination
• Endocannabinoids
• Glycerides (metabolism, pharmacology)
• Male
• Monoacylglycerol Lipases (antagonists & inhibitors, metabolism)
• Pain (drug therapy, metabolism)
• Pain Measurement (drug effects)
• Phospholipase D (metabolism)
• Piperidines (pharmacology)
• Polyunsaturated Alkamides (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
• Receptor, Cannabinoid, CB2 (antagonists & inhibitors, metabolism)