NMDA-receptor regulation of substance P release from primary afferent nociceptors

Nature. 1997 Apr 17;386(6626):721-4. doi: 10.1038/386721a0.


Severe or prolonged tissue or nerve injury can induce hyperexcitability of dorsal horn neurons of the spinal cord, resulting in persistent pain, an exacerbated response to noxious stimuli (hyperalgesia), and a lowered pain threshold (allodynia). These changes are mediated by NMDA (N-methyl-D-aspartate)-type glutamate receptors in the spinal cord. Here we report that activation of the NMDA receptor causes release of substance P, a peptide neurotransmitter made by small-diameter, primary, sensory 'pain' fibres. Injection of NMDA in the cerebrospinal fluid of the rat spinal cord mimicked the changes that occur with persistent injury, and produced not only pain, but also a large-scale internalization of the substance P receptor into dorsal horn neurons, as well as structural changes in their dendrites. Both the pain and the morphological changes produced by NMDA were significantly reduced by substance P-receptor antagonists or by elimination of substance P-containing primary afferent fibres with the neurotoxin capsaicin. We suggest that presynaptic NMDA receptors located on the terminals of small-diameter pain fibres facilitate and prolong the transmission of nociceptive messages, through the release of substance P and glutamate. Therapies directed at the presynaptic NMDA receptor could therefore ameliorate injury-evoked persistent pain states.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Injections, Spinal
  • N-Methylaspartate / administration & dosage
  • N-Methylaspartate / antagonists & inhibitors
  • Neurons, Afferent / metabolism
  • Nociceptors / metabolism*
  • Pain
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Neurokinin-1 / drug effects
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Presynaptic
  • Spinal Cord / metabolism
  • Spinal Cord / ultrastructure
  • Substance P / metabolism*


  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurokinin-1
  • Receptors, Presynaptic
  • Substance P
  • N-Methylaspartate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-Amino-5-phosphonovalerate