Gene therapy approaches to restore chloride homeostasis for treating neuropathic pain

Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Intracellular chloride homeostasis in mature neurons is critical for normal synaptic inhibition by GABA and glycine, and chloride dysregulation in primary sensory neurons and spinal dorsal horn neurons is closely involved in neuropathic pain. In this chapter, we review the function of two cation-chloride cotransporters, Na⁺-K⁺-Cl^- cotransporter 1 (NKCC1) and K⁺-Cl^- cotransporter 2 (KCC2), expressed in the spinal cord and their involvement in the diminished synaptic inhibition at the spinal cord level in neuropathic pain. We describe the contribution of NMDA receptor-calpain signaling to nerve injury-induced KCC2 proteolysis and downregulation in the spinal dorsal horn in neuropathic pain. We also discuss the therapeutic potential of intrathecal delivery of the KCC2 gene using viral vectors for restoring chloride homeostasis and for treating neuropathic pain.