Role of peripheral 5-HT1D, 5-HT3 and 5-HT7 receptors in the mechanical allodynia induced by serotonin in mice

Serotonin (5-HT) acts as a neurotransmitter in the central nervous system (CNS) and as a mediator released by enterochromaffin cells to regulate intestinal motility. However, this amine also plays an important role as an inflammatory mediator and induces phenotypic changes of nociceptors. Despite the wide knowledge of the role of 5-HT in nociception, most studies have focused on its role in the CNS, while a clear information about its role in peripheral tissues is still lacking. In the present study, we investigated the role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan in mice by using antagonists that target different 5-HT receptors. Mechanical nociceptive threshold was measured with an analgesimeter and evaluated after intraplantar (i.pl.) injection of 5-HT or carrageenan. 5-HT antagonists were injected via the i.pl. route. 5-HT (10, 20, 40 or 80 μg/paw) or carrageenan (100 μg/paw) induced mechanical allodynia. Pretreatment with isamoltane (5 μg; 5-HT1B antagonist) or ketanserine (1 μg; 5-HT2A antagonist) did not affect the mechanical allodynia induced by 5-HT. This response was inhibited by BRL 15572 (10 μg; 5-HT1D antagonist) or SB 269970 (25 μg; 5-HT7 antagonist). On the other hand, mechanical allodynia induced by 5-HT or carrageenan was exacerbated by ondansetron (10, 20 or 40 μg; 5-HT3 antagonist). The results indicate that activation of 5-HT1D and 5-HT7 receptors plays a role in the mechanical allodynia induced by 5-HT in mice. This study also demonstrates the inhibitory role of peripheral 5-HT3 receptors in the nociceptive response induced by 5-HT or carrageenan.