Um estudo sobre os mecanismos antinociceptivos periféricos induzidos pela serotonina

Abstract

Serotonin (5-HT) is a biogenic amine with important functions in the central nervous system, such as behavior, mood, sleep and appetite, and is part of the descending inhibitory pain pathway. So far, only its pro-nociceptive role was described at the peripheral level. Therefore, we set out to verify that serotonin could be linked to a nociceptive effect at peripheral level, as well as the selectivity of its receptors in this event, and the participation of opioidergic, canabinoidergic, nitrergic systems and potassium channels in this mechanism. The mouse paw pressure model was used to test in animals that had increased sensitivity to intraplantar injection of PGE2 (2 µ g), being used for statistical analysis to analysis of variance ANOVA followed by Bonferroni post test. To check the selectivity of receptors in event, selective serotonergic receptors antagonists (isamoltan 5-HT1B, BRL 15572 5-HT1D, ketanserin 5-HT2A, ondansetron 5-HT3 e SB-269970 5-HT7) were used. Serotonin administered on right hind paw (62,5, 125, 250 and 500 ng and 1 µ g) produced antinociceptive effect manifested in a dose-dependent. Selective antagonists for the 5-HT1B ,5-HT2A and 5-HT3 receptors, in doses of 100 ng, 1 µg and 10 µg, reversed the antinociceptive effect induced by serotonin at the dose of 250 ng. Also, selective antagonists for the 5-HT1D and 5-HT7 receptors (10 µg) were unable to reverse the antinociceptive effect induced by serotonin. In order to evaluate the participation of the opioidergic system, use the selective antagonist for opioid receptors µ, and clocinnamox (10, 20 and 40 µg), naltrindole (60 µg) and nor-binaltorfimina (200 µg) respectively, which reversed the antinociceptive effect induced by serotonin (250 ng). Bestatin (400 µ g), an encefalinases inhibitor that degrade peptides, opioids increased the antinociceptive effect induced by serotonin (lowest dose 62,5 ng). To assess the participation of the canabinoidergic system, selective antagonists for the CB1 and CB2 receptors, AM251 (20, 40 and 80 µ g) and AM630 (25, 50 and 100 µ g) respectively, were used and they reversed the antinociceptive effect induced by serotonin. In addition, MAFP (0,5 µg), an inhibitor of the FAAH enzyme which breaks down anandamide, JZL184 (3,75 µg), an inhibitor of MAGL enzyme that degrades the 2-AG, and the VDM11 (2,5 µ g), an inhibitor of anandamide uptake, have strengthened the antinociceptive effect induced by serotonin (lowest dose 62,5 ng). Also, tests to verify the participation of nitrergic system and channels for potassium, serotonin antinociceptive effect was reversed, so dose dependent, by non-selective inhibitor of isoforms of the us, L-NOArg (12,5, 25 and 50 µ g), by selective inhibitor for neuronal isoform LNPA (24 µ g) and the soluble guanylate cyclase inhibitor, ODQ (25, 50 and 100 µ g). Additionally, glyburide (20, 40 and 80 µ g), potassium channel ATP-sensitive blocker, reversed the effect of serotonin. Also the potassium channel blocker, voltage-sensitive tetraetilamônio (30 µ g), and potassium channel blockers calcium-activated high and low conductance, dequalínio (50 µ g) and paxilina (50 µ g), respectively, not reversed the effect of serotonin. In addition, the administration of serotonin intraplantar (250 ng) induced a significant increase in levels of nitrite in the homogenate of mice's foot plantar surface. Our data suggest, for the first time, the peripheral antinociceptive action induced by serotonin, and provide evidence that there is participation of the opoidergic and canabinoidergic systems in the action, with subsequent activation of the NO/GMPc/KATP pathway.