Substance P is involved in nociception in both the peripheral nervous system and the CNS and has been documented to play a crucial role in the complex regional pain syndrome (CRPS). So far, however, most experimental animal models are restricted to the effect of neurokinin-1 receptor blockers to inhibit substance P and do not directly evaluate its action. Thus, this study was conducted to test the hypothesis that local application of substance P causes signs and symptoms of CRPS. For this purpose rats received a continuous infusion of either substance P or saline over 24 h delivered by a mini-osmotic pump connected to an intrafemoral catheter. Animals were analyzed at either day 1 (n=6, each group) or day 4 (n=5, each group) after start of infusion. Substance P application caused a significant and long-lasting decrease in paw withdrawal thresholds upon mechanical stimulation, while animals did not present with thermal allodynia at days 1 and 4 after onset of infusion. In addition, severe s.c. edema was observed in all animals receiving substance P. In vivo fluorescence microscopy of the extensor digitorum longus muscle of the affected hind paw revealed enhanced leukocyte-endothelial cell interaction with a significant rise in the number of leukocytes both rolling along and firmly adhering to the wall of postcapillary venules, while saline-exposed animals were free of this local inflammatory response. Muscle cell apoptosis, as assessed by in vivo bisbenzimide staining, terminal deoxynucleotidyl transferase nick end labeling analysis and caspase 3-cleavage, could not be observed in either of the animals. In summary, the present study indicates that substance P is responsible for neurogenic inflammation, including local cell response, edema formation and mechanical pain, while it seems not to contribute to the generation of thermal allodynia.