Endogenous cannabinoid receptor agonist anandamide induces peripheral antinociception by activation of ATP-sensitive K+ channels.

AIMS: The effects of several potassium (K(+)) channel blockers were studied to determine which K(+) channels are involved in peripheral antinociception induced by the cannabinoid receptor agonist, anandamide. MAIN METHODS: Hyperalgesia was induced by subcutaneous injection of 250 µg carrageenan into the plantar surface of the hind paw of rats. The extent of hyperalgesia was measured using a paw pressure test 3 h following carrageenan injection. The weight in grams (g) that elicited a nociceptive response, paw flexion, during the paw pressure test was used as the nociceptive response threshold. KEY FINDINGS: Doses of 50, 75, and 100 ng of anandamide elicited a dose-dependent antinociceptive effect. Following a 100 ng dose of anandamide no antinociception was observed in the paw that was contralateral to the anandamide injection site, which shows that anandamide has a peripheral site of action. Pretreatment with 20, 40 and 80 µg AM251, a CB(1) receptor antagonist, caused a dose-dependent decrease in anandamide-induced antinociception, suggesting that the CB(1) receptor is directly involved in anandamide effect. Treatment with 40, 80 and 160 µg glibenclamide, an ATP-sensitive K(+) channel blocker, caused a dose-dependent reversal of anandamide-induced peripheral antinociception. Treatment with other K(+) channel antagonists, tetraethylammonium (30 µg), paxilline (10 µg) and dequalinium (50 µg), had no effect on the induction of peripheral antinociception by anandamide. SIGNIFICANCE: This study provides evidence that the peripheral antinociceptive effect of the cannabinoid receptor agonist, anandamide, is primarily caused by activation of ATP-sensitive K(+) channels and does not involve other potassium channels.