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

  • Author(s): Guindon, J
  • Guijarro, A
  • Piomelli, D
  • Hohmann, AG
  • et al.
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. © 2011 The British Pharmacological Society.

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