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

Ann N Y Acad Sci. 2010 Jun:1198:168-72. doi: 10.1111/j.1749-6632.2010.05462.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bumetanide / pharmacology
  • Chronic Disease
  • Hyperalgesia / physiopathology*
  • Inflammation / physiopathology
  • K Cl- Cotransporters
  • Pain / physiopathology*
  • Rats
  • Sodium Potassium Chloride Symporter Inhibitors / pharmacology
  • Sodium-Potassium-Chloride Symporters / drug effects
  • Sodium-Potassium-Chloride Symporters / genetics
  • Sodium-Potassium-Chloride Symporters / physiology*
  • Solute Carrier Family 12, Member 2
  • Spinal Cord Injuries / complications
  • Spinal Cord Injuries / physiopathology*
  • Symporters / genetics
  • Symporters / physiology*
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / physiology
  • gamma-Aminobutyric Acid / physiology


  • Slc12a2 protein, rat
  • Sodium Potassium Chloride Symporter Inhibitors
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
  • Symporters
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Bumetanide
  • gamma-Aminobutyric Acid