ROLE OF SUBSTANCE-P IN THE MODULATION OF C-FIBER-EVOKED RESPONSES OF SPINAL DORSAL HORN NEURONS

Substance P (SP) as well as excitatory amino acids (EAAs) appear to be released in response to stimulation of primary afferent C-fibers. Act ivity at N-methyl-D-aspartate (NMDA) receptors is essential for wind-u p (the progressive potentiation of C-fiber-evoked responses of single neurons in response to an electrical stimulation), however, the role o f SP in wind-up is unclear. To address this, the effects of iontophore tically applied CP-99,994 (a NK-1 receptor antagonist), SP and SP(1-7) (an N-terminal breakdown product of SP), were compared on responses o f spinal dorsal horn wide dynamic range (WDR) neurons of the rat. Post -stimulus time histograms (PSTH) were summed over 12 responses to low frequency (0.5 Hz) electrical stimulation of the cutaneous receptive f ield. Changes in responses of dorsal horn neurons were evaluated by mo nitoring C-fiber input, wind-up, and the total number of spikes evoked by C-fiber activity in response to the 12 stimuli. The NK-1 receptor antagonist CP-99,994 significantly inhibited the total number of C-spi kes and caused a significant reduction in wind-up without changing the C-fiber input, indicating the involvement of NK-1 receptors in wind-u p. Application of SP led to an overall increase in the total number of C-fiber evoked responses of dorsal horn neurons and C-fiber input, ho wever, wind-up, as defined, was significantly decreased following SP. In contrast, substance P(1-7) evoked a long-lasting increase in the to tal number of C-fiber-related spikes which was initially sustained by a transient increase in the input followed by a longer tasting increas e in wind-up, an effect opposite that of CP-99,994. As NMDA activity h as been previously shown to be inhibited and then potentiated by SP N- terminal activity over a similar time interval, the present data are c onsistent with the mediation of wind-up by NMDA and its modulation by SP N-terminal activity. Release of SP in response to noxious stimulati on may, therefore, increase primary afferent C-fiber activity (input) whereas an accumulation of SP N-terminal metabolites appears to potent iate wind-up, perhaps via positive modulation of EAA activity.