The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury
Altered Cl- homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl- regulatory proteins, Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI).
Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI.
Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30mg/kg, i.p.) in vehicle.
TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p <0.05).
The vehicle alone administration group showed no anti-hyperalgesic effects. Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2-14 post-SCI and peaked on day 14 post-SCI (p <0.05).
Concurrently, a down-regulation of KCC2 protein was detected during day 2-14 post-SCI. The rats with TH exhibited a sustained loss of KCC2 protein during post-SCI days 21-42.
No significant changes of these proteins were detected in the rostral region of the spinal cord. Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI.
The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.
Author: Samuel W Cramer, Christopher Baggott, John Cain, Jessica Tilghman, Bradley Allcock, Gurwattan Miranpuri, Sharad Rajpal, Dandan Sun and Daniel Resnick
Credits/Source: Molecular Pain 2008, 4:36
Published on: 2008-09-17
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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