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Chronic neuropathic pain is a debilitating condition that remains difficult to treat.
Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR)
activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain.
However, the reciprocal relationship between synaptic inhibition and excitation in
neuropathic pain is unclear. Here, we show that intrathecal delivery of K(+)-Cl(-)
cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting
reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores
Cl(-) homeostasis disrupted by nerve injury in both spinal dorsal horn and primary
sensory neurons. Remarkably, restoring Cl(-) homeostasis normalizes both presynaptic
and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn.
Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways
through the disruption of Cl(-) homeostasis in spinal dorsal horn and primary sensory
neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for
the treatment of neuropathic pain.