Glutamate and Kynurenate in the Rat Central Nervous System Following Treatments with Tail Ischaemia or Diclofenac

Abstract

Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-Daspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-in¯ammatory 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 À1 , 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 3Á0±3Á8 nmol g À1 . The corresponding regional glutamate concentrations ranged between 4Á8±10Á6 mmol g À1 , and were signi®cantly lower in the ischaemia group when compared with both control (15%, P`0Á05) and diclofenac-treated (19%, P`0Á002) groups. Kynurenate concentrations in these CNS regions ranged between 3Á3±45Á8 pmol g À1

The kynurenine pathway: a finger in every pie

“…Patients receiving low-dose aspirin, which preferentially inhibits COX-1, were significantly more likely to respond to treatment than placebo-treated subjects, suggesting that aspirin may be an efficacious adjunctive treatment for bipolar depression 176 . Interestingly, the COX-1 inhibitors, indometacin and diclofenac increased brain levels of KynA in the rat 177, 178 and KynA levels in both the plasma and the hippocampus were shown to be significantly increased one hour after a single dose of ibuprofen 179 . Whether the impact of COX inhibition on KynA is independent of its general anti-inflammatory effects remains to be determined but either way these data raise the possibility that changes in KP metabolism may contribute to the putative anti-depressant effects of COX inhibitors.…”

Synthesis and Pharmacological Evaluation of Some 4‐Oxo‐quinoline‐2‐carboxylic Acid Derivatives as Anti‐inflammatory and Analgesic Agents

“…Furthermore, it was proposed that increased brain formation of kynurenic acid (1,4‐dihydro‐4‐oxo‐quinoline‐2‐carboxylic acid (KYNA)) induced by NSAIDs, contributes to their analgesic efficacy probably through an inhibitory action on COX‐1 21. In fact, an increased formation of brain kynurenic acid (KYNA) has been suggested to contribute to the analgesic action of diclofenac, a relatively non‐selective COX‐inhibitor 22. KYNA is a metabolite of tryptophan and is synthesized in brain astrocytes.…”

Effect of Diclofenac with B Vitamins on the Treatment of Acute Pain Originated by Lower-Limb Fracture and Surgery

“…However, there is also evidence that diclofenac exhibits additional prostaglandin-independent properties that mediate its antinociceptive effects. For instance, diclofenac is able to inhibit H + -gated channels in sensory neurons, increase the concentration of kynurenate (an endogenous antagonist of NMDA receptors), stimulate the nitric oxide-cGMP-K + channels pathway, and activate metformin- and phenformin-dependent mechanisms to induce antinociception [19–23]. On the other hand, several studies demonstrated antinociceptive and antihyperalgesic effects with the mixture of thiamine, pyridoxine, and cyanocobalamin in the models of hyperalgesia induced by carrageenan, in the pressure testing of the tail, and in the formalin model [24, 25].…”