Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P

A. Nazarian, G. Gu, N. G. Gracias, K. Wilkinson, X. Y. Hua, Michael Vasko, T. L. Yaksh

Research output: Contribution to journalArticle

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Abstract

Dorsal horn N-methyl-d-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with d-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with d-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists dl-2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalin-induced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.

Original languageEnglish
Pages (from-to)119-127
Number of pages9
JournalNeuroscience
Volume152
Issue number1
DOIs
StatePublished - Mar 3 2008

Fingerprint

Neurokinin-1 Receptors
Nociception
Substance P
Aspartic Acid
Formaldehyde
Dizocilpine Maleate
Capsaicin
Serine
Spinal Cord
Perfusion
2-Amino-5-phosphonovalerate
Pain
aspartic acid receptor
Calcitonin Gene-Related Peptide
Glycine
Axons
Peptides
Injections

Keywords

  • C-fiber
  • dorsal horn
  • glutamate
  • internalization
  • neurokinin 1 receptor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P. / Nazarian, A.; Gu, G.; Gracias, N. G.; Wilkinson, K.; Hua, X. Y.; Vasko, Michael; Yaksh, T. L.

In: Neuroscience, Vol. 152, No. 1, 03.03.2008, p. 119-127.

Research output: Contribution to journalArticle

Nazarian, A. ; Gu, G. ; Gracias, N. G. ; Wilkinson, K. ; Hua, X. Y. ; Vasko, Michael ; Yaksh, T. L. / Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P. In: Neuroscience. 2008 ; Vol. 152, No. 1. pp. 119-127.
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