NMDA receptor activation modulates evoked release of substance P from rat spinal cord

The possible modulation exerted by glutamate on substance P (SP) release fr om the rat spinal cord has been investigated. The N-methyl-D-aspartate (NMD A) receptor agonist, NMDA (1 mu M), increased SP basal outflow by 46.5 +/- 10.9% (n = 3, P<0.01) without changing the evoked release of the peptide. C onversely, NMDA antagonists but not 6-cyano-7-nitroquinoxaline-2,3-dione (C NQX) inhibited both electrically-evoked and capsaicin-induced release of SP . In particular, D-2-amino-5-phosphonopentanoate (D-APS; 50 mu M) inhibited electrically-evoked and capsaicin-induced release of SP by 93+/-2.4% and 9 3.2+/-3.8% (n=12, P<0.01), respectively. Functional pharmacological evidenc e is provided for glutamate exerting a positive feedback on SP release evok ed by C fibre stimulation via NMDA receptor activation.