Differential effects of C- and N-terminal substance p metabolites on the release of amino acid neurotransmitters from the spinal cord: Potential role in nociception

Extensive evidence implicates Substance P [SP(1-11)] as a primary afferent neurotransmitter or modulator of nociceptive information, and there is increasing evidence that the excitatory amino acids aspartate (Asp) and glutamate (Glu) may also act as nociceptive neurotransmitters. We have previously demonstrated that nociceptive stimulation (metatarsal injection of formalin) caused a tetrodotoxin (TTX)-sensitive release of Asp and a TTX-insensitive release of Glu from the dorsal spinal cord. We have also shown release of Asp and Glu following the direct infusion of SP(1-11), suggesting that formalin-induced Asp or Glu changes could be secondary to an initial release of SP(1-11). In contrast to nociception, pretreatment with TTX, reported here, had no effect on the SP(1-11)-induced release of Asp, suggesting a presynaptic mechanism. Behavioral experiments, in both our laboratory, and others, now suggest that the N-terminal products of SP metabolism play a distinct role in the modulation of SP( 1-11) nociception, possibly through an interaction with an opiate receptor. To test the hypothesis that N- and C-terminal fragments of SP produce opposite effects on biochemical events potentially involved in nociception, we compared the effects of infusion of the N-terminal metabolite SP( 1 -7) and the C-terminal metabolite SP(5-11) on changes in the ECF concentration of amino acids in the spinal cord as a measure of their apparent release, using microdialysis. Intradiaylsate infusion of SP(5-11) increased the release of Asp, Glu, asparagine (Asn), glycine (Gly), and taurine (Tau). The changes in Asp, Glu, and Tau were similar in direction and magnitude to changes produced by SP(1-11) or formalin injection, further supporting the hypothesis that the C-terminal is responsible for the nociceptive effects of SP(1-11). in contrast, infusion of SP(1-7) significantly decreased the release of Asn, Tau, Glu, and Gly. This inhibition of amino acid release is consistent with the hypothesis that N-terminal metabolites produce opposite effects to those of C-terminal metabolites of SP(1-11). The decreases in Glu, Asn, Gly, and Tau following SP(1-7) infusion were significantly reduced by i.p. or intradialysate naloxone. Systemic naloxone had no significant effects on the SP(5-11)-induced amino acid changes; however, it did inhibit the SP(1-11)-induced increase in Asp and Glu. Intradialysate naloxone had no effect on the SP(1-11)-induced increases. These results support the hypothesis that N-terminal fragments of SP, generated by SP(1-11) metabolism in vivo, may be responsible for the naloxone-reversible analgesic effects of SP( 1-11) while the nociceptive actions of SP( 1-11) may be mediated through its C-terminal end.