Efeito sinérgico da associação entre L-triptofano e analgésicos não-opióides em modelos de nocicepção experimental em camundongos

• Autor(a) principal: Rocha, Nayrton Flávio Moura
• Data de Publicação: 2013
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
• Texto Completo: http://www.repositorio.ufc.br/handle/riufc/15738
• topic: Triptofano; Serotonina; Dipirona

The drug combination to reach greater clinical outcomes or reduce side effects is usual practice in the managing of several morbid conditions. The current painkillers have side effects potentially dangerous that should be monitoring during its utilization. Objective: to study the interaction between L-tryptophan and non-opioids analgesics dipyrone, ketoprofen or paracetamol, by oral or intraperitoneal route, in models of nociception in mice, including the investigation about the importance of blockage of serotonergic neurotransmission as well as alfa-2, melatonin and ATP-dependent potassium channel. The interaction with kynurenic acid was analyzed too. Results: The L-tryptophan (p.o. or i.p) does not possess antinociceptive activity as solely agent but it is capable to increase central 5-HT amount. The ED50 for antinociceptive effect of dipyrone or paracetamol were ED50=128,7 mg/kg (92,78-178,6 mg/kg) e ED50=281 mg/kg (204,1 – 387,0 mg/kg), respectively. The oral co-treatment (on the same administration) with L-triptophan in the proportion (weight/weight) 1:1,4 with dipyrone and 1:1,5 with paracetamol decrease with significance the ED50 to 33,30 mg/kg (28,05 – 39,54 mg/kg)* and 50,99 mg/kg (41,96 – 61,96 mg/kg)*, respectively. The previous intraperitoneal treatment with L-tryptophan (defined here as combined treatment) reduces the ED50 for analgesic effect of dipyrone (in the proportions of 1:1 and 1:2), paracetamol (1:4,12) or ketoprofen (5,7:1), to 30,90 mg/kg (23.10-43,56 mg/kg)* e 18,07 mg/kg (13,25- 24,67 mg/kg )*, 47,30 mg/kg (34.00 - 65.82 mg/kg)* e 2,09 mg/kg (1,355-3,224 mg/kg)*, respectively compared to solely treatment with dipyrone ED50=91,20 mg/kg (77.39 - 95.78 mg/kg ), Paracetamol ED50=96,18 mg/kg (76.23 - 121.3 mg/kg) or Cetoprofeno= 10,25 mg/kg (6,729 to 15,61mg/kg) on the abdominal writhing test induced by acetic acid. The treatment with L-tryptophan increases the central concentration of serotonin, but not influence the concentrations of noradrenaline or dopamine. L-tryptophan 25 or 50 mg/kg does not influence the concentration of cortical amount of glutamate. However, the combined treatment i.p. with non-effective doses of dipyrone and paracetamol reduces the concentration of this neurotransmitter. The combined treatment of L-tryptophan with non antinociceptive doses (i.g.) dipyrone and paracetamol exhibited antinociceptive effect in the formalin-induced licking test in both phases. The combination of L-tryptophan and dipyrone (i.p.) was effective when tested against the test nociception induced by capsaicin, but the association with paracetamol failed this test. Blockage of 5-HT synthesis by treatment with the inhibitor PCPA (p-chlorophenylalanine) antagonizes the synergistic effect of the L-tryptophan association with dipyrone in the writhing test. Kynurenic acid exerts a synergistic effect with dipyrone and paracetamol in the writhing test. The blockage of 5-HT2 and 5-HT3 receptor have no influence on the synergism of L-tryptophan and dipyrone, ketoprofen, paracetamol or writhing model. The 5-HT1 receptor blockage seems to be important for the synergistic effect of L-tryptophan ketoprofen with paracetamol and not having an effect on the synergism and dipyrone. The blockage of the α2 adrenergic receptor channels influences the synergism of L-tryptophan with paracetamol. The synergistic interaction with dipyrone is attenuated by blocking melatonin receptors. Conclusion: Our results showed that there is a synergistic relationship between L-tryptophan and antinociceptive activity of ketoprofen, paracetamol and dipyrone. The mechanism underlying this interaction appears to be different for dipyrone in relation to this mechanistic effect on ketoprofen and paracetamol, although in both cases it seems important the metabolism of L-tryptophan to serotonin and, possibly, kynurenic acid.