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.
Department of Neurosurgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Tera
T
Hasbargen
Mostafa M
MM
Ahmed
Gurwattan
G
Miranpuri
Lin
L
Li
Kristopher T
KT
Kahle
Daniel
D
Resnick
Dandan
D
Sun
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