The NH₂-terminus of substance P modulates NMDA-induced activity in the mouse spinal cord

Excitatory amino acids (EAAs) and substance P are believed to transmit nociceptive information in the spinal cord. As substance P NH₂-terminal fragments can modulate non-NMDA EAA-mediated activity, we examined the effects of substance P fragments to ascertain whether the COOH- or NH₂- terminus of substance P modulates the actions of NMDA in the spinal cord. NMDA activity was measured by the intensity of behaviors produced by NMDA (0.2 nmol) administered intrathecally in the mouse. The NMDA response was attenuated after pretreatment with either substance P (22.5 pmol, 30 min) or the NH₂-terminal fragment of substance P, SP-(1-7). Pretreatment with the COOH-terminal fragment SP-(5-11) (22.5 pmol, 30 min), a neurokinin ligand, had no effect on NMDA-induced behaviors, suggesting that the inhibitory effect of substance P is caused by the NH₂-terminus. Pretreatment with D- Pro²,D-Phe⁷ substance P-(1-7), a SP-(1-7) antagonist, potentiated NMDA activity, suggesting a tonic inhibitory effect of the substance P NH₂- terminus. Desensitization to NMDA typically develops when NMDA is injected at 2 min intervals. While pretreatment with SP-(1-7) inhibited NMDA coadministration of SP-(1-7) (22.5 pmol), with the first of four injections of NMDA, first inhibited but then potentiated responses to each challenge with NMDA. Coadministration of the same dose of SP-(1-7) with the fourth injection of NMDA immediately potentiated the response to NMDA. D-Pro²,D- Phe⁷ substance P-(1-7) blocked the inhibition but not the potentiation of NMDA by SP-(1-7) whereas DPDT-SP, a neurokinin receptor antagonist, failed to alter either effect of SP-(1-7). These data support the novel hypothesis that substance P inhibits phasic but potentiates tonic NMDA activity in the spinal cord by an action of its NH₂-terminus on two distinct non-neurokinin receptor populations.