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 the 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) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central 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 (tail 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 nmolg(-1). The corresponding regional glutamate concentrations ranged between 4.8-10.6 micromol g(-1), and were significantly lower in the ischaemia group when compared with both control (15%, P < 0.05) and diclofenac-treated (19%, P < 0.002) groups. Kynurenate concentrations in these CNS regions ranged between 3.3-45.8 pmol g(-1). Pairwise comparisons between the control and diclofenac-treated groups found significant increases in kynurenate concentrations in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05). Noxious stimulation from tail ischaemia appeared to be associated with increased release of glutamate. Additionally, NSAIDs appeared to increase kynurenate concentrations in the spinal cord and diencephalon. Antagonism by kynurenate of glutamate effects at NMDA receptors may contribute to the antinociceptive effects of NSAIDs.
Edwards
S R
SR
Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia.
Mather
L E
LE
Lin
Y
Y
Power
I
I
Cousins
M J
MJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004008:Diclofenac / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D018698:Glutamic Acid / Q000378:metabolism*; D007279:Injections, Subcutaneous; D007511:Ischemia / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D010146:Pain / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013623:Tail / Q000098:blood supply*; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018691:Excitatory Amino Acid Antagonists; D004008:Diclofenac; D018698:Glutamic Acid; D007736:Kynurenic Acid