Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Summary: 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. : Li et al. find that spinal KCC2 gene transfer induces sustained KCC2 expression and restores chloride homeostasis disrupted by nerve injury in both dorsal horn and primary sensory neurons. KCC2 gene transfer completely and persistently eliminates neuropathic pain and normalizes pre- and postsynaptic NMDA receptor activity increased by nerve injury. Keywords: neuropathic pain, cation-chloride cotransporters, gene therapy, synaptic transmission, synaptic plasticit