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 microg) 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 microg 2-PMPA selectively inhibited noxious-evoked activity (input, post-discharge and C- and Adelta-fibre-evoked responses), and not low threshold Abeta-fibre-evoked responses. After
carrageenan inflammation, the lower dose of 100 microg 2-PMPA inhibited input, post-discharge, C- and Adelta-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.