Comelli_2007_Br.J.Pharmacol_152_787

BACKGROUND AND PURPOSE: 2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain. EXPERIMENTAL APPROACH: Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602. KEY
RESULTS: Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease. CONCLUSIONS AND IMPLICATIONS: The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.