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Cannabinoid Modulation of Cutaneous A Nociceptors During Inflammation

¹Departments of Diagnostic and Biological Sciences, ²Veterinary and Biomedical Sciences, and ³Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota

Submitted 25 July 2008; accepted in final form 4 September 2008

Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB₁ and CB₂). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2'-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of A nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB₁ receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB₂ receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous A nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of A nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB₁ receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of A nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB₁ receptors during inflammation.