Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury

Neuropathic pain is a common problem following spinal cord injury (SCI). Effective analgesic therapy has been hampered by the lack of knowledge about the mechanisms underlying post-SCI neuropathic pain. Current evidence suggests GABAergic spinal nociceptive processing is a critical functional node in this complex phenotype, representing a potential target for therapeutic intervention. Normal GABA neurotransmission is dependent on precise regulation of the level of intracellular chloride, which is determined by the coordinated activities of two cation/chloride cotransporters (CCCs) in the SLC12 family: the inwardly directed Na+-K+-Cl- cotransporter isoform 1 (NKCC1) and outwardly directed K+-Cl- cotransporter isoform 2 (KCC2). Inhibition of NKCC1 with its potent antagonist bumetanide reduces pain behavior in rats following SCI. Moreover, the injured spinal cord tissues exhibit a significant transient upregulation of NKCC1 protein and a concurrent downregulation of KCC2 protein. Thus, imbalanced function of NKCC1 and KCC2 may contribute to the induction and maintenance of the chronic neuropathic pain following SCI.