Abstract: The modulatory effect of substance P (SP) on strychnine-sensitive glycine (Gly) response was examined in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using nystatin perforated patch recording configuration under voltage-clamp conditions. Application of SP potentiated 30 μmol/L Gly-activated chloride current (IGly) in a concentration-dependent manner over the range of 1 nmol/L to 1 μmol/L at a holding potential of -40 mV. SP neither changed the reversal potential of Gly response nor affected the affinity of Gly to its receptor. The SP potentiation effect could be blocked by spantide as well as a selective NK1 receptor antagonist, L-668,169, but not by NK2 receptor antagonist, L-659,877. The facilitatory action of SP on IGly could also be abolished by pretreatment with chelerythrine or KN-62 in different neurons, a finding suggesting that protein kinase C (PKC) or Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) possibly contributes to an intracellular pathway of SP in the augmentation of IGly. The results imply that SP may suppress nociception in the spinal cord by potentiating Gly response.