Although it is well known that cannabinoids produce antinociception in acute pain models, there is less information on the ability of cannabinoids to alleviate hyperalgesia. In the present study, we determined whether cannabinoids attenuated the development of hyperalgesia produced by intraplantar injection of capsaicin in rats. In normal, untreated animals, intraplantar injection of 10 microg capsaicin produces nocifensive behavior (elevation of the injected paw) suggestive of pain, an increase in the frequency of withdrawal from punctate mechanical stimuli applied to the paw (mechanical hyperalgesia) and a decrease in the latency of withdrawal from noxious heat (heat hyperalgesia). Separate groups of animals were pretreated intravenously with vehicle, the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, 100 or 200 microg/kg, or the enantiomer WIN 55,212-3 (100 microg/kg) 5 min before intraplantar injection of capsaicin into one paw. The duration of nocifensive behavior was measured during the first 5 min after capsaicin injection. Withdrawal responses to mechanical and heat stimuli applied to the plantar surface of both hindpaws were measured before and at 5 and 30 min after capsaicin. Pretreatment with WIN 55,212-2 produced a dose-dependent decrease in nocifensive behavior and in hyperalgesia to mechanical and heat stimuli produced by capsaicin, as compared with vehicle pretreatment. Doses of 100 and 200 microg/kg WIN 55,212-2 completely blocked the development of hyperalgesia to mechanical and heat stimuli without altering withdrawal responses on the contralateral control paw. Furthermore, these doses of WIN 55,212-2 had no effect on basal withdrawal responses to heat in animals that did not receive capsaicin. The inactive enantiomer WIN 55,212-3 did not alter the development of capsaicin-evoked pain or hyperalgesia. These data suggest that low doses of cannabinoids, which do not produce analgesia or impair motor function, attenuate chemogenic pain and possess antihyperalgesic properties.