Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: An electrophysiological study in the rat

Katherine J. Carpenter, Sayen Sen, Elizabeth A. Matthews, Sarah L. Flatters, Krystyna M. Wozniak, Barbara S. Slusher, Anthony H. Dickenson

Research output: Contribution to journalArticlepeer-review

Abstract

N-Acetylaspartylglutamate (NAAG) is a peptide neurotransmitter present in the brain and spinal cord. It is hydrolysed by glutamate carboxypeptidase II (GCPII); thus, the GCP-II inhibitor 2-[phosphono-methyl]-pentanedioic acid (2-PMPA) protects endogenous NAAG from degradation, allowing its effects to be studied in vivo. We recorded the effect of spinal 2-PMPA (50-1000 μg) on the electrical-evoked activity of dorsal horn neurones in normal and carrageenan-inflamed animals, and in the spinal nerve ligation (SNL) model of neuropathy and sham-operated animals. In normal animals, 1000 μg 2-PMPA selectively inhibited noxious-evoked activity (input, post-discharge and C- and Aδ-fibre-evoked responses), and not low threshold Aβ-fibre-evoked responses. After carrageenan inflammation, the lower dose of 100 μg 2-PMPA inhibited input, post-discharge, C- and Aδ-fibre-evoked responses by a significantly greater amount than the same dose in normal animals. 2-PMPA inhibited neuronal responses less consistently in sham-operated and SNL animals, and effects were not significantly different from those seen in normal animals. NAAG is an agonist at the inhibitory metabotropic glutamate receptor mGluR3, and 2-PMPA may inhibit nociceptive transmission in normal animals by elevating synaptic NAAG levels, allowing it to activate mGluR3 and thus reducing transmitter release from afferent nerve terminals. mGluR3 expression in the superficial dorsal horn is upregulated after peripheral inflammation, perhaps explaining the greater inhibition of neuronal responses we observed after carrageenan inflammation. These results support an important role of endogenous NAAG in the spinal processing of noxious information.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalNeuropeptides
Volume37
Issue number5
DOIs
StatePublished - Oct 2003
Externally publishedYes

Keywords

  • Dorsal horn
  • GCP-II
  • Inflammation
  • Metabotropic glutamate receptor
  • NAAG
  • NAALADase
  • Neuropathy
  • Nociception

ASJC Scopus subject areas

  • Endocrinology
  • Neurology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

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