title: NMDA-receptor regulation of substance P release from primary afferent nociceptors.
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 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.
authors.affiliation: Department of Anatomy, University of California San Francisco, 94143, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: P W
authors.initials: PW
authors.lastname: Mantyh
authors.forename: A I
authors.initials: AI
authors.lastname: Basbaum
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D007278:Injections, Spinal; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D009475:Neurons, Afferent / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D017661:Receptors, Presynaptic; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure; D013373:Substance P / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; D017661:Receptors, Presynaptic; D013373:Substance P; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate