Role of the Na+-K+-2Cl- cotransporter in the development of capsaicin-induced neurogenic inflammation

J Neurophysiol. 2006 Jun;95(6):3553-61. doi: 10.1152/jn.01091.2005.


Recent behavioral and electrophysiological studies have attributed an important role to dorsal root reflexes (DRRs) in the initiation and development of neurogenic inflammation produced by intradermal capsaicin (CAP). The DRRs can occur in peptidergic fibers, resulting in peripheral release of neuromediators that produce vasodilation, plasma extravasation and subsequently hyperalgesia and allodynia. In this study, we have evaluated the effect of spinal administration of bumetanide (a blocker of the Na+-K+-2Cl- cotransporter, NKCC) on DRR activity, changes in cutaneous blood flow (vasodilation), hindpaw edema, mechanical allodynia, and hyperalgesia induced by intradermal injection of 1% CAP in Sprague-Dawley rats. Vasodilation was monitored using laser Doppler flowmetry, neurogenic edema was evaluated by measurements of hindpaw volume, and secondary mechanical allodynia and hyperalesia were tested using von Frey filaments (10 and 200 mN) applied to the plantar surface of the paw. Changes in the blood flow were blocked significantly by intrathecal bumetanide at 10 and 100 microM in both pre- and posttreatment studies. Spinal bumetanide at 10 and 100 microM blocked neurogenic edema when it was administered before CAP injection, but only bumetanide at 100 microM administered after CAP injection reduced the paw edema significantly. Furthermore, the administration of bumetanide onto the spinal cord reduced the increment in DRR activity produced by CAP. Finally, both secondary mechanical allodynia and hyperalesia were reduced by bumetanide at 1, 10, and 100 microM. Taken together these results suggest that NKCC is involved in the increases in DRR activity, neurogenic inflammation and hyperalgesia and allodynia induced by intradermal CAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bumetanide / pharmacology
  • Capsaicin
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiopathology*
  • Hyperalgesia / chemically induced
  • Hyperalgesia / physiopathology*
  • Inflammation / chemically induced
  • Inflammation / physiopathology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reflex*
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Vasodilation*


  • Sodium-Potassium-Chloride Symporters
  • Bumetanide
  • Capsaicin