TY - JOUR
T1 - The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury
AU - Cramer, Samuel W.
AU - Baggott, Christopher
AU - Cain, John
AU - Tilghman, Jessica
AU - Allcock, Bradley
AU - Miranpuri, Gurwattan
AU - Rajpal, Sharad
AU - Sun, Dandan
AU - Resnick, Daniel
PY - 2008/9/17
Y1 - 2008/9/17
N2 - Background: 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). Results: 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, 30 mg/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 group administered with the vehicle alone 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. Conclusion: 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.
AB - Background: 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). Results: 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, 30 mg/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 group administered with the vehicle alone 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. Conclusion: 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.
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U2 - 10.1186/1744-8069-4-36
DO - 10.1186/1744-8069-4-36
M3 - Article
C2 - 18799000
AN - SCOPUS:53549122751
SN - 1744-8069
VL - 4
JO - Molecular Pain
JF - Molecular Pain
M1 - 36
ER -