That substance P (SP) contributes in some way to spinal nociceptive processing has been known for many years. However, the contribution of SP and NK-1 receptors to the generation and maintenance of inflammatory hyperalgesia or persistent chemical hyperalgesia is not clear. The purpose of this study was to test the hypothesis that SP contributes to the generation but not maintenance of hyperalgesia using two models of inflammatory pain: carrageenan, which allows for testing of acute noxious thermal and mechanical stimuli, and formalin, a model of spontaneous pain. Intrathecal pretreatment with the NK-1 receptor antagonist CP-96,345 (100, 50, 25 nmol) dose-dependently attenuated the thermal (46%, 27% and 16%, respectively) and mechanical (66%, 37% and 3%, respectively) hyperalgesia produced by 2 mg carrageenan, but not 6 mg carrageenan, 3 h after the induction of inflammation. The attenuation was still apparent at 5 h for the greatest dose, but at 7 h the magnitude of hyperalgesia was equal to rats pretreated with saline. Posttreatment with 100 nmol CP-96,345 following the establishment of hyperalgesia had no effect. Intrathecal pretreatment with 125 nmol CP-96,345 prior to formalin (1% or 5%) injection into the hindpaw produced an overall 29% or 23% attenuation, respectively, of the nociceptive behavior during the 1-h observation period. For both 1% and 5% formalin injections, the phase 2 response, but not the phase 1 response, was significantly lower than that from rats pretreated both saline. Pretreatment with 100 or 125 nmol of the inactive enantiomer, CP-96,344, was no different than pretreatment with saline. A dose of 250 nmol CP-96,345 produced voluntary paralysis yet the flexion reflex to noxious pinch remained. These results support the hypothesis that SP contributes to the generation of inflammatory hyperalgesia but once established, the contribution of SP to maintaining the state of hyperalgesia is reduced. The interaction of SP, NK-1 receptors and spinal NMDA receptors in relation to inflammatory pain is discussed.