Avaliação do papel da 5-hidroxitriptamina (5-HT) no processamento periférico da resposta nociceptiva

Abstract

5-Hydroxytryptamine (5-HT, serotonin) is a cell-derived vasoactive amine, released primarily by platelets (in humans), mast cells (in rodents) and endothelial cells. It is a regulator of smooth muscle in the cardiovascular and gastrointestinal systems, an enhancer of platelet aggregation, and a neurotransmitter in the central nervous system. Although 5-HT is implicated in the regulation of a number of physiological processes and their malfunction, including those related to inflammation, the exact sites and mechanisms of its action are poorly defined. Pharmacological as well as therapeutic tools have been discovered by selectively targeting 5-HT receptor subtypes, which have been described in different tissues and demonstrated to be involved in painful and inflammatory conditions. The aim of this study was to investigate the role played by 5-HT and its receptors in the peripheral processing of the nociceptive response of mice. Initially, 5-HT was found in peripheral tissues (hind paw) and mRNA for 5-HT1B, 5-HT1D, 5-HT2, 5-HT3 was found in the dorsal root ganglion, but not in the paw. Intraplantar (i.pl.) injections of 5-HT (10, 20 or 40 g/paw; 10 l) induced a nociceptive response in mice characterized by paw licking behavior. Pre-treatment (-10 min; 10 l; i.pl.) with cyproheptadine (0.5 or 5 g; 5-HT1, 5-HT2 antagonist), mianserine (0.1 g; 5-HT2, 5-HT6 antagonist), isamoltane (0.5 or 5 g; 5-HT1B antagonist) or ketanserine (0.1 or 1 g; 5-HT2A antagonist) significantly reduced the paw licking behavior induced by 5-HT. When injected at the contralateral paw, these antagonists did not reduce paw licking behavior induced by 5-HT, indicating that their effect results from local action. BRL 15572 (1 or 10 g; 5-HT1D antagonist), ondansetron (5 or 20 g; 5-HT3 antagonist) or SB 269970 (2.5 or 25 g; 5-HT7 antagonist) did not inhibit the nociceptive response induced by 5-HT. 5-HT (10, 20, 40, 80 g; 20 l; i.pl.) also induced mechanical allodynia. This response was inhibited by pre-treatment (-10 min; 20 l; i.pl.) with BRL 15572 (10 g) or SB 269970 (25 g), but not by isamoltane (5 g; 20 l; i.pl.) or ketanserine (1 g; 20 l; i.pl.). On the other hand, ondansetron (20 g; 20 l; i.pl.) increased mechanical allodynia induced by 5-HT. We also investigated the effects induced by these antagonists on the mechanical allodynia induced by carrageenan (100 g; 20 l; i.pl.). None of the antagonists inhibited this response. However, ondansetron (20 g; 20 l; i.pl.) increased mechanical allodynia induced by carrageenan. Our results provide support to the involvement of 5-HT in the peripheral nociceptive processing by demonstrating that (1) the amine is present in peripheral tissues; (2) mRNA for many of its receptors is found in the dorsal root ganglion and (3) antagonists inhibit or increases the response induced by 5-HT or carrageenan. Regarding the receptors involved, the results indicate an important excitatory role for 5-HT1, 5-HT2, 5-HT6 and 5-HT7 receptors, depending on the nociceptive model evaluated. Finally, our study provides the first evidence of the inhibitory role of 5-HT3 receptors at peripheral tissues in mice. KEYWORDS: Serotonin; 5-hydroxytryptamine; 5-HT; peripheral serotonergic receptors; pain; nociception; mice