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.
Hasbargen
Tera
T
Department of Neurosurgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Ahmed
Mostafa M
MM
Miranpuri
Gurwattan
G
Li
Lin
L
Kahle
Kristopher T
KT
Resnick
Daniel
D
Sun
Dandan
D
D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002908:Chronic Disease; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2; D013119:Spinal Cord Injuries / Q000150:complications / Q000503:physiopathology*; D027981:Symporters / Q000235:genetics / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000096922:K Cl- Cotransporters
D002034:Bumetanide; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D050916:TRPV Cation Channels; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578879:Slc12a2 protein, rat; C493922:Trpv1 protein, rat