Nucleus raphe magnus serotonin neurones bidirectionally control spinal nociceptive transmission in mice.

Abstract

Noxious stimuli are conveyed to and integrated in the dorsal horn of the spinal cord before being transmitted to supraspinal centres, 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 neurones in the nucleus raphe magnus (NRM), activating different spinal 5-hydroxytryptamine (5-HT) receptors, exert bidirectional control, both facilitatory and inhibitory, but the underlying mechanisms of this control remain unclear. Serotonergic modulation by the NRM of nociception was investigated in adult mice using imaging, behavioural, pharmacological, electrophysiological, chemogenetic and optogenetic approaches. The action of serotonergic neurones 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 neurones of the NRM exert a tonic analgesic effect mediated by 5-HT_2c receptor. Low increases in 5-HT activity led to increased analgesia through spinal inhibitory interneurones expressing 5-HT_2c and 5-HT_2A receptors. Prolonged stimulation of serotonergic neurones led to hyperalgesia mediated by 5-HT₃ receptors. Comparison of 5-HT receptors in spinal tissue from mice and humans shows that 5-HT_2c receptors have high expression level, comparable between both species. These results propose a bidirectional model of action by serotonin neurones of nociceptive transmission depending on their level of activity and show that 5-HT_2c receptors mediate the serotonin-induced analgesia.