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

Franck Aby, Louis-Etienne Lorenzo, Zoé Grivet, Rabia Bouali-Benazzouz, Hugo Martin, Stéphane Valerio, Sara Whitestone, Dominique Isabel, Walid Idi, Otmane Bouchatta, Philippe De Deurwaerdere, Antoine G. Godin, Cyril Herry, Xavier Fioramonti, Marc Landry, Yves De Koninck, Pascal Fossat
Sci. Adv.. 2022-07-29; 8(30):
DOI: 10.1126/sciadv.abo0689

PubMed
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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 naïve 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.

Auteurs Bordeaux Neurocampus