Opioid receptor and NO/cGMP pathway as a mechanism of peripheral antinociceptive action of the cannabinoid receptor agonist anandamide

AimsIn this study, we investigated whether the opioid system and the nitric oxide pathway were involved in the peripheral antinociception induced by a cannabinoid receptor agonist anandamide.Main methodsHyperalgesia was induced by a subcutaneous injection of carrageenan (250 μg) into the plantar surface of the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams (g) required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold.Key findingsAnandamide elicited a dose-dependent (50, 75, and 100 ng per paw) antinociceptive effect. The highest dose of anandamide did not produce antihyperalgesia in the contralateral paw, indicating a peripheral site of action. The CB1 receptor antagonist AM251 (20, 40, 80 and 160 μg per paw) antagonized peripheral antihyperalgesia induced by anandamide (100 ng), in a dose-dependent manner, suggesting CB1 receptor activation. Anandamide-induced peripheral antihyperalgesia was reverted by blockers of the l-arginine/NO/cGMP pathway NG-nitro-l-arginine (NOARG; 24, 36 and 48 μg per paw) and 1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 25, 50 and 100 μg per paw), in a dose-dependent manner. Furthermore, opioid receptor antagonist naloxone (12.5, 25 and 50 μg per paw) antagonized the peripheral antihyperalgesia induced by anandamide.SignificanceThis study provides evidence that the peripheral antinociceptive effect of the cannabinoid receptor agonist anandamide may result from l-arginine/NO/cGMP pathway activation and that the opioid system is also involved.