Synergistic effect of the L-tryptophan and kynurenic acid with dipyrone or paracetamol in mice

Abstract

Purpose: Our great interest in this work was study the synergism between L-tryptophan and dipyrone or paracetamol as well as the interaction of kynurenic acid (L-tryptophan metabolite) and these analgesics agents utilizing a robust methodology. Methods: We performed the writhing test induced by acetic acid in mice to evaluate the antinociceptive effect of the treatments isolated and combined (p.o. and i.p.). Dose–response curves were constructed and the values of ED50 for treatment alone and combined were statistically compared. In addition, isobolographic analysis was performed and the experimental values were compared with the theoretical values for simple additive effect. Results: The combined treatment with L-tryptophan and dipyrone or paracetamol reduced significantly the ED50 of these analgesics when compared to the isolated treatments. L-tryptophan alone has no antinociceptive effect. L-Tryptophan increases the central amount of 5-HT and the synergism with dipyrone is antagonized by the 5-HT depletion. The kyna has an antinociceptive dose-related effect and a synergistic interaction with dipyrone and paracetamol verified by isobolographic analyses and confirmed by experimental values of ED50 of combined treatments were statistically lower than theoretical calculated values for simple additive effect. Melatonin antagonist receptor attenuates the antinociceptive synergism between L-tryptophan and dipyrone. Conclusion: Our results demonstrate that the increased 5-HT amount on the central nervous system is not per se capable to induce antinociception. The L-tryptophan interacts synergistically with dipyrone and paracetamol both orally and by i.p. route. This effect is dependent on the biotransformation of L-tryptophan to 5-HT and involves kynurenic acid and melatonin receptors.