title: Diclofenac increases the accumulation of kynurenate following tryptophan pretreatment in the rat: a possible factor contributing to its antihyperalgesic effect.
abstract: Kynurenate, a metabolite of tryptophan formed serially from kynurenine, inhibits N-methyl-D-aspartate (NMDA) receptor responses. Non-steroidal anti-inflammatory drugs (NSAIDs) may produce anti-hyperalgesic effects by altering tryptophan metabolism to increase kynurenate concentrations. We examined whether the NSAID diclofenac (40 mg/kg, s.c.) or saline (control) increased kynurenine and kynurenate accumulation in tissues following pretreatment with tryptophan (200 mg/kg, i.p., 150 min before tissue harvesting). Significantly larger increases in kynurenine and kynurenate concentrations occurred when diclofenac followed tryptophan pretreatment (maximal, 60 min: plasma: by 58% and 49%; kidney: by 205% and 203%) when compared to control. Brain and spinal cord kynurenine concentrations increased maximally (120 min: by 39% and 95%) when diclofenac challenge followed tryptophan pretreatment. In brain, diclofenac increased kynurenate concentrations (20 min: by 274%). Diclofenac facilitated kynurenine and kynurenate accumulation in plasma and kidney, apparently by inhibiting renal elimination. This raises the possibility that (some) NSAIDs could act indirectly, with central and/or peripheral NMDA receptors contributing to their antihyperalgesic effects.
authors.affiliation: Centre for Anaesthesia and Pain Management Research, University of Sydney at Royal North Shore Hospital, St Leonard's, NSW 2065, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Edwards
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Mather