AN N-TERMINAL FRAGMENT OF SUBSTANCE-P, SUBSTANCE P(1-7), DOWN-REGULATES NEUROKININ-1 BINDING IN THE MOUSE SPINAL-CORD

Injected intrathecally, substance P (SP) down-regulates neurokinin-1 ( NK-1) binding in the spinal cord and desensitizes rats to the behavior al effect of SP. N-terminal fragments of SP, such as SP(1-7), induce a ntinociception and play a role in desensitization to SP in mice. The g oal of this study was to assess the abilities of N- and C-terminal fra gments of SP to down-regulate NK-1 binding. Binding of [H-3]SP to mous e spinal cord membranes was inhibited-by SP, CP-96,345, and to a lesse r extent by SP(5-11), but not SP(1-7), consistent with these binding s ites being NK-1 receptors. Injection of SP(5-11) intrathecally did not affect the affinity (K-d) or concentration (B-max) of[H-3]SP binding. However, injection of 1 nmol of SP(1-7) decreased the B-max of [3H]SP binding in the spinal cord at 6 h after its injection just as this do se of SP decreased the B-max at 24 h. These data suggest that the N-te rminus of SP is responsible for down-regulation of NK-1 binding As SP( 5-11) did not down-regulate NK-1 binding, activation of NK-1 sites doe s not appear necessary or sufficient for down-regulation of SP binding . In contrast, SP(1-7), in spite of its inability to interact with NK- 1 sites, did down-regulate SP binding suggesting an indirect mechanism dissociated from NK-1-receptors.