Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain

Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naive mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Automated summary

Research has shown that serotonin (5-HT) neurons have a pain-relieving effect in mice who have not experienced pain before, but become pain-promoting in neuropathic pain models. An imbalance in spinal KCC2 function turns this pain relief into pain promotion, but KCC2 enhancers can restore the pain-relieving effect. Additionally, combining selective serotonin reuptake inhibitors (SSRIs) with KCC2 enhancers can effectively relieve pain hypersensitivity caused by nerve injury.