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 responses 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 AM251, but not with the CB₂ receptor antagonist AM630. ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 hours 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.