Role of serotonin receptors in inflammatory pain

The role of serotonin (5-HT) as a mediator of the pain system has been investigatedover the last 5 decades. Here a subset of studies that used behavioral,immunohistochemical, electrophysiological as well as molecular biology techniques tostudy the receptors mediating the peripheral and spinal effects of 5-HT in inflammatorypain are reviewed. The 5-HT1 receptor subfamily consists of 5 members, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. Despite some controversy about its localization indorsal root ganglion (DRG) neurons, experiments from our laboratory suggest thatperipheral activation, by selective subtype receptor agonists, of 5-HT1 receptors inducesantinociception and selective antagonists of each receptor dose-dependently block thiseffect. At the spinal cord, activation of 5-HT1A/1B/1D produces antinociception orpronociception by direct or indirect actions, respectively. There are no reports about thespinal effects of 5-HT1E/1F. On the other hand, it has been shown the presence of 5-HT5receptors in rat DRG neurons. Since 5-HT5, like 5-HT1, receptors are negatively coupledto adenylyl cyclase, it is suggested that its activation would lead to antinociception.However, so far there are still no data on this point. Contrariwise, activation of 5-HT2receptors mediates excitatory effects. The 5-HT2 receptor subfamily consists of threemembers, 5-HT2A, 5-HT2B, and 5-HT2C. The presence of mRNA as well as the protein of 5-HT2A and 5-HT2C in the spinal cord has been demonstrated. At the periphery, activation of these receptors induces nociception, whereas that in the spinal cord it mayproduce nociception or antinociception. 5-HT3 receptors behave in a similar way withthe difference that these are cationic channels. 5-HT4 receptors are found in primaryafferent neurons in the periphery and central sites. Activation of 5-HT4 receptors leads topronociception in the periphery whereas in the spinal cord produces antinociception.Experiments in our laboratory indicate that peripheral or intrathecal activation of 5-HT6or 5-HT7 receptors leads to an increase of nociceptive behavior in the formalin test. Inline with this, selective 5-HT6 or 5-HT7 receptor antagonists blocks formalin-inducednociception suggesting a pronociceptive role for these receptors. Accordingly, 5-HT6/7receptors are observed in DRG neurons. Thus, data suggest that 5-HT2/3/4/6/7 receptorsplay a pronociceptive role at peripheral sites. On the contrary, 5-HT1, and probably 5-HT5, receptors play an antinociceptive role on this site. The observed effects in the spinalcord will also depend of specific localization of receptors in the dorsal horn. 5-HTreceptors are key components of serotonergic signaling, thus investigation of their effectsand action sites and the conditions under which they work could yield valuable insights.In addition, selective drugs with agonist or antagonist properties for the differentsubtypes of 5-HT receptors may constitute a new therapeutic opportunity forinflammatory pain.