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

Abstract

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.(ABSTRACT TRUNCATED AT 400 WORDS)

Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus

“…These results are consistent with evidence in vitro (46,47) and in vivo (48,49) that SP and neurokinin A release glutamate and aspartate from the spinal cord. SE and neuronal death often result from excess release of glutamate (50)(51)(52).…”

Brain microdialysis of GABA and glutamate: What does it signify?

“…The increase in glutamate was characterized by a considerable variability in the magnitude of the response and was TTX-independent (Skilling et al, 1988;Sorkin and McAdoo, 1993). The glutamate changes were hypothesized to be secondary to an initial rise in substance P, as infusion of 0.5 mmol substance P (SP5-11) into the spinal cord increased extracellular glutamate in a way similar to that during noxious stimulation (Skilling et al, 1988(Skilling et al, , 1990. Since the latter effect was enhanced by TTX the authors concluded that ''the formalin-induced release of glutamate could reflect the inability of our model to distinguish between simultaneous metabolic and neuronal changes in glutamate.''…”

“…For instance, the rises in glutamate during noxious stimuli (Skilling et al, 1988(Skilling et al, , 1990 were TTX-insensitive. During stress, glutamate in dialysates was only partly inhibited during blockade of sodium-channels.…”

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

“…Consequently, involvement of 5␣-DHP and 3␣,5␣-THP biosynthetic pathways in the regulation of nociception needs to be considered in regard to various neurobiological mechanisms occurring in both acute and chronic phases of pain, even though in vivo studies have shown that 3␣,5␣-THP and its synthetic analogs induce antinociceptive effects in rats and humans (40-43). It is also important to recall that rNK1-mediated hyperalgesia seems to be an extremely complex mechanism involving the release of prostanoids (44,45) and glutamate (46,47), and the phosphorylation of NMDA receptor through a protein kinase C transduction process (48,49). Therefore, we suggest here an hypothetical model to recapitulate and clarify neurochemical events that may occur in spinal Values are the mean Ϯ SEM of four independent experiments.…”