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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Appleton, I. (1997). Non-steroidal anti-inflammatory drugs and pain, in: The Pharmacology of Pain - Handbook of Experimental Pharmacology, Vol. 130, Dickenson, A. and Besson, J. M. (Eds), pp. 44–60. Springer-Verlag, Berlin.
Badawy, A. A. B. and Morgan, C. J. (1982). Tryptophan and tryptophan pyrrolase in haem regulation, Biochem. J. 206, 451–460.
Brown, R. R. (1994). Tryptophan metabolism: a review, in: L-Tryptophan: Current Prospects in Medicine and Drug Safety, Kochen, W. and Steinhart, H. (Eds.), pp. 17–30. De Gruyter, Berlin.
Carlton, S. M. and Coggeshall, R. E. (1999). Inflammation-induced changes in peripheral glutamate receptor populations, Brain Res. 820, 63–70.
Carpenedo, R., Pittaluga, A., Cozzi, A., et al. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release, Eur. J. Neurosci. 13, 2141–2147.
Chiarugi, A., Carpenedo, R., Molina, M. T., et al. (1995). Comparison of the neurochemical and behavioural effects resulting from the inhibition of kynurenine hydroxylase and/ or kyureninase, J. Neurochem. 65, 1176–1183.
Connick, J. H., Heywood, G. C., Sills, G. J., et al. (1992). Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity, Gen. Pharmacol. 23, 235–239.
Davidson, E. M. and Carlton, S. M. (1998). Intraplantar injection of dextrorphan, ketamine, or memantine attenuates formalin-inducedbehaviours, Brain Res. 78, 136–142.
Davies, N. M. and Anderson, K. E. (1997). Clinical pharmacokinetics of diclofenac: therapeutic insights and pitfalls, Clin. Pharmacokinet. 33, 185–213.
Dickenson, A. H. (1990). A cure for wind up: NMDA receptor antagonists as potential analgesics, Trends Pharmacol. Sci. 11, 307–309.
Edwards, S. R., Mather, L. E., Lin, Y., et al. (2000). Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac, J. Pharm. Pharmacol. 52, 59–66.
Fukui, S., Schwarcz, R., Rapoport, S. I., et al. (1991). Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism, J. Neurochem. 56, 2007–2017.
Grace, R. F., Edwards, S. R., Mather, L. E., et al. (2000). Central and peripheral tissue distribution of diclofenac after subcutaneous injection in the rat, Inflammopharmacology 8, 43–54.
Holmes, E. W. (1988). Determination of serum kynurenine and hepatic tryptophan dioxygenase activity by high-performance liquid chromatography, Anal. Biochem. 172, 518–525.
Kessler, M., Terramani, T., Lynch, G., et al. (1989). A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists, J. Neurochem. 52, 1319–1328.
Lou, G. L., Pinsky, C. and Sitar, D. S. (1994). Kynurenic acid distribution into brain and peripheral tissues of mice, Can. J. Physiol. Pharmacol. 72, 161–167.
McCormack, K. (1994). The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects, Drugs 47 (Suppl. 5), 28–45.
Moroni, F., Russi, P., Lombardi, G., et al. (1988). Presence of kynurenic acid in the mammalian brain, J. Neurochem. 51, 177–180.
Russi, P., Alesiani, M., Lombardi, G., et al. (1992). Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions, J. Neurochem. 59, 2076–2080.
Smith, Q. R., Momma, S., Aoagi, M., et al. (1987). Kinetics of neutral amino acid transport across the blood-brain barrier, J. Neurochem. 49, 1651–1658.
Stone, T. W. (1993). Neuropharmacology of quinolinic and kynurenic acids, Pharmacol. Rev. 45, 310–367.
Swartz, K. J., Matson, W. R., MacGarvey, U., et al. (1990). Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric elecrode array detection, Anal. Biochem. 185, 363–376.
Takeuchi, F. and Shibata, Y. (1984). Kynurenine metabolism in vitamin-B-6-defficient rat liver after tryptophan injection, Biochem. J. 220, 693–699.
Urenjak, J. and Obrenovitch, T. P. (2000). Neuroprotective potency of kynurenic acid against excitotoxicity, Neuroreport. 27, 1341–1344.
Widner, B., Werner, E. R., Schennach, H., et al. (1999). An HPLC method to determine tryptophan and kynurenine in serum simultaneously, Adv. Exp. Med. Biol. 467, 827–832.
Wong, E. and Kemp, J. A. (1991). Sites for antagonism on the N-methyl-D-aspartate receptor channel complex, Annu. Rev. Pharmacol. Toxicol. 31, 401–425.
Yeh, J. K. and Brown, R. R. (1977). Effects of vitamin B-6 defficiency and tryptophan loading on urinary excretion of tryptophan metabolites in mammals, J. Nutr. 107, 261–271.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Edwards, S.R., Mather, L.E. Diclofenac increases the accumulation of kynurenate following tryptophan pretreatment in the rat: a possible factor contributing to its antihyperalgesic effect. Inflammopharmacology 11, 277–292 (2003). https://doi.org/10.1163/156856003322315622
Issue Date:
DOI: https://doi.org/10.1163/156856003322315622