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

Nature volume 386, pages 721–724 (1997)Cite this article

Abstract

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 cord1. 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 injury2, 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.

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Authors and Affiliations

  1. Departments of Anatomy and Physiology, and W. M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California, 94143, USA

    Hantao Liu & Allan I. Basbaum

  2. Molecular Neurobiology Laboratory, Veterans Administration Medical Center, University of Minnesota, Minneapolis, Minnesota, 55417, USA

    Patrick W. Mantyh

  3. Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, 55417, USA

    Patrick W. Mantyh

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  1. Hantao Liu
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  2. Patrick W. Mantyh
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  3. Allan I. Basbaum
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Liu, H., Mantyh, P. & Basbaum, A. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386, 721–724 (1997). https://doi.org/10.1038/386721a0

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