Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury

Accumulating evidence suggests that cannabinoids can produce antinociception through peripheral mechanisms. In the present study, we determined whether cannabinoids attenuated existing hyperalgesia produced by a mild heat injury to the glabrous hindpaw and whether the antihyperalgesia was receptor-mediated. Anesthetized rats received a mild heat injury (55 degreesC for 30 s) to one hindpaw. Fifteen Minutes after injury, animals exhibited hyperalgesia as evidenced by lowered withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey monofilament (200 mN force) delivered to the injured hindpaw. Separate groups of animals were then treated with an intraplantar (i.pl.) injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, or 30 mug in 100 mul. WIN 55,212-2 attenuated both heat and mechanical hyperalgesia. dose-dependently. The inactive enantiomer WIN 55,212-3 did not alter mechanical or heat hyperalgesia, suggesting the effects of WIN 55,212-2 were receptor-mediated. The CB I receptor antagonist AM 251 (30 mug) co-injected with WIN 55,212-2 (30 mug) attenuated the antihyperalgesic effects of WIN 55,212-2. The CB2 receptor antagonist AM 630 (30 mug) co-injected with WIN 55,212-2 attenuated only the early antihyperalgesic effects of WIN 55,212-2. I.pl. injection of WIN 55,212-2 into the contralateral paw did not alter the heat-injury induced hyperalgesia, suggesting that the antihyperalgesia occurred through a peripheral mechanism. These data demonstrate that cannabinoids primarily activate peripheral CB 1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CBI receptors. (C) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.