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

Abstract

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.

Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice

“…This is in accordance with previous studies in both rats and mice showing increased WDR hyperexcitability in pathological model of persistent pain. 26 , 39 This hyperexcitability was consistent across both male and female mice. By contrast, no changes in the WDR threshold following C-fiber stimulation were observed after SNI in P2X4KO mice or myeloid P2X4KO mice of both sexes, demonstrating the involvement of P2X4 in myeloid cells in dorsal horn neuron hyperexcitability.…”

Analgesic effects of oral Yokukansan on acute postoperative pain and involvement of the serotonin nervous system: a mouse model study

“…A recent study revealed that the serotonergic descending pain inhibitory system changes to pain facilitatory properties in neuropathic pain model mice due to a reduction in KCC2 ion transporter (K-Cl cotransporter) expression in the spinal dorsal horn neurons. In this way, serotonergic neuronal transmission is converted from being inhibitory to being excitatory [ 27 ]. However, acute pain due to tissue injury (intraplantar injection of formalin) reportedly stimulates serotonin secretion in the spinal cord more rapidly than does noradrenaline [ 28 ].…”

Analgesic effects of oral Yokukansan on acute postoperative pain and involvement of the serotonin nervous system: A mouse model study

“…A recent study revealed that the serotonergic descending pain inhibitory system changes to pain facilitatory properties in neuropathic pain model mice due to a reduction in KCC2 ion transporter (K-Cl cotransporter) expression in the spinal dorsal horn neurons. In this way, serotonergic neuronal transmission is converted from being inhibitory to being excitatory [19].…”