Previous studies in our laboratory have demonstrated that cannabinoids administered intravenously attenuate the duration of nocifensive behavior and block the development of hyperalgesia produced by intraplantar injection of capsaicin. In the present study, we extended these observations and determined whether cannabinoids attenuate capsaicin-evoked pain and hyperalgesia through spinal and peripheral mechanisms, and whether the antihyperalgesia was receptor mediated. Separate groups of rats were pretreated 7 min before capsaicin with an intrathecal injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 0.1, 1.0 or 10 microg in 10 microl. Although the intrathecal application of WIN 55,212-2 did not alter nocifensive behavior following capsaicin, it produced a dose-dependent decrease in hyperalgesia to heat and mechanical stimuli. Intrathecal pretreatment with the CB1 receptor antagonist SR141716A (10 microg) blocked the antihyperalgesia produced by WIN 55,212-2. The ability of intrathecal administration of WIN 55,212-2 to attenuate hyperalgesia was not due to motor deficits since the highest dose of WIN 55,212-2 did not alter performance on the rota-rod test. To investigate whether cannabinoids attenuated capsaicin-evoked hyperalgesia through peripheral mechanisms, separate groups of rats were pretreated with an intraplantar injection of WIN 55,212-2 at doses of 0.1, 1.0, 10 or 30 microg in 100 microl 5 min before capsaicin. Intraplantar pretreatment with WIN 55,212-2 produced a dose-dependent attenuation of hyperalgesia to heat, but did not attenuate mechanical hyperalgesia or the duration of nocifensive behavior. The inactive enantiomer WIN 55,212-3 did not alter the development of hyperalgesia. SR141716A (100 microg) co-injected with WIN 55,212-2 (30 microg) partially attenuated the effects of WIN 55,212-2 on hyperalgesia to heat. Intraplantar injection of the highest dose of WIN 55,212-2 did not interfere with the development of hyperalgesia following capsaicin injection into the contralateral paw. These data show that cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are capable of acting at both spinal and peripheral sites.