Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac

Kynurenate is an endogenous antagonist at the allosteric glycine site on th e N-methyl-D-aspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) ar e mediated peripherally and possibly centrally through inhibition of prosta glandin synthesis, there is also evidence for centrally mediated prostaglan din-independent antinociceptive effects that may result from increased cent ral nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg(-1), s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (ta il ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions. Regional CNS tissue concentrations of diclofenac were between 3.0-3.8 nmol g(-1). The corresponding regional glutamate concentrations ranged between 4 .8-10.6 mu mol g(-1), and were significantly lower in the ischaemia group w hen compared with both control (15%, P < 0.05) and diclofenac-treated (19%, P < 0.002) groups. Kynurenate concentrations in these CNS regions ranged b etween 3.3-45.8 pmol g(-1). Pairwise comparisons between the control and di clofenac-treated groups found significant increases in kynurenate concentra tions in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05). Noxious stimulation from tail ischaemia appeared to be associated with incr eased release of glutamate. Additionally, NSAIDs appeared to increase kynur enate concentrations in the spinal cord and diencephalon. Antagonism by kyn urenate of glutamate effects at NMDA receptors may contribute to the antino ciceptive effects of NSAIDs.