We have shown previously that the development of hyperalgesia and inflammation associated with knee joint arthritis depends on interactions among various receptors in the central and peripheral nervous system in addition to the contribution of blood borne inflammatory mediators. In the present study, the involvement of spinal nicotinic cholinergic receptors in the modulation of inflammatory pain was evaluated using a model of acute arthritis in rats. Epibatidine (EP), a potent agonist for neuronal nicotinic acetylcholine receptors sharing similar structural and functional characteristics with acetylcholine and nicotine, has been used in this study. The physiological effects of EP on pain-related behaviors and inflammation were tested after administration to the dorsal horn via a microdialysis fiber. Knee joint inflammation was induced in rats by injecting a mixture of kaolin and carrageenan into the knee joint. Paw withdrawal latency to radiant heat was measured before and at 4, 5, 6, 7 and 8 h after induction of inflammation. The decrease in PWL in this arthritis model is indicative of secondary hyperalgesia. The extent of peripheral inflammation was also assessed by measuring knee joint circumference and temperature. Treatment of the spinal cord of animals with EP prior to induction of arthritis attenuated the development of heat hyperalgesia and resulted in a significant improvement of the animals' spontaneous pain-related behaviors. More interestingly, the knee joint circumference and temperature of these animals were also significantly lower than those of the control animals when measured at 8 h. Likewise, spinal administration of epibatidine after the development of hyperalgesia not only significantly attenuated the decrease in PWL, but prevented further increases in knee joint swelling and temperature. The antinociceptive effect of epibatidine was selectively blocked by the nicotinic receptor antagonist, mecamylamine. Joint circumference and temperature were not selectively altered by mecamylamine suggesting another mechanism involving non-nicotinic receptors in the spinal regulation of joint inflammatory responses. Collectively, these findings provide considerable evidence to suggest an important role for central nicotinic cholinergic receptors in the modulation of persistent pain and neurogenic inflammation mediated by events in the dorsal horn.