Nucleus raphe magnus serotonin neurons bidirectionally control spinal mechanical pain transmission

Background. Noxious stimuli are conveyed to and integrated in the dorsal horn of the spinal cord (DHSC) before being transmitted to supraspinal centers, where pain perception is generated. Descending pathways from the brainstem dynamically modulate this integration, either facilitating or inhibiting nociceptive information based on physiological, emotional, genetic and environmental factors. Serotonergic neurons in the nucleus raphe magnus (NRM), activating different spinal 5-HT receptors, exert bidirectional control, both facilitatory and inhibitory, but the underlying mechanisms of this control remain unclear. Methods. We investigated in adult mice, the NRM serotonergic modulation of nociception using imaging, behavioral, pharmacological, electrophysiological, chemogenetic and optogenetic approaches. Results. We have demonstrated that the action of serotonergic neurons in the NRM on spinal nociceptive transmission depends on their activation pattern, which targets different spinal 5-HT receptors likely associated with different spinal microcircuits. Serotonergic neurons of the NRM exert a tonic analgesic effect mediated by 5-HT2c receptor. Low increase in 5-HT activity leads to an increased analgesia through spinal inhibitory interneurons expressing 5-HT2c and 5-HT2A receptors. Finally, prolonged stimulation of serotonergic neurons led to hyperalgesia mediated by 5-HT3 receptor. Comparison of 5-HT receptors in spinal tissue from mice and human shows that 5-HT2c receptor has a very high expression level, comparable between both species. Conclusions. These results propose a model of bidirectional action of serotonin neurons on nociceptive transmission depending on their level of activity and show that 5-HT2c receptor is the main mediator of serotonin-induced analgesia.