Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn
Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn
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DOI：
10.1016/j.pain.2007.10.016
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发表时间：
2008-07-31
期刊：
影响因子：
7.4
通讯作者：
Miletic, Vjekoslav
中科院分区：
文献类型：
--
作者：
Miletic, Gordana;Miletic, Vjekoslav
坐骨神经松解结扎后4h，同侧脊髓背角KCC2蛋白水平显著降低。这些减少与后肢重量分布的改变有关，提示疼痛行为。相比之下。GABA-A受体亚单位α-1水平无明显变化。KCC2的减少与同侧BDNF蛋白水平的显著上升相一致。鞘内注射隔离BDNF的TrkB/Fc嵌合体蛋白或酪氨酸激酶阻滞剂K252a可预防KCC2水平的下降和早期疼痛行为。与结扎相关的KCC2水平下降是暂时的。在结扎后7天出现负重疼痛行为的动物同侧脊髓背角，KCC2水平与对照组或假手术组相同。这些数据表明，脊髓背角中TrkB依赖的KCC2蛋白水平的降低是周围神经损伤的早期结果。KCC2的这种减少可能引起了整个背角神经元兴奋性的早期增加，可能是通过失去对GABA的抑制，而GABA的抑制是严重依赖KCC2活性的。神经元兴奋性的增加可能反过来导致初级传入神经元和背角神经元之间的沟通增强和夸大，从而导致疼痛的早期行为迹象。(C)2007年国际疼痛研究协会。爱思唯尔出版，版权所有。
Significant decreases in the protein levels of potassium-chloride co-transporter 2 (KCC2) were detected in the ipsilateral spinal dorsal horn 4 h following loose ligation of the sciatic nerve. These decreases were associated with a change in hindlimb weight distribution suggestive of pain behavior. In contrast. no changes in GABA-A receptor subunit alpha-1 levels were detected. The decreases in KCC2 coincided with a significant ipsilateral increase in BDNF protein levels. Both the decreases in KCC2 levels and the early pain behavior were prevented by intrathecal pre-treatment with the BDNF-sequestering TrkB/Fc chimera protein or the tyrosine kinase blocker K252a. The ligation-associated decreases in KCC2 levels were transient. In the ipsilateral spinal dorsal horn of ligated animals exhibiting weight-bearing pain behavior 7 days after the ligation the KCC2 levels were identical to those in control or sham-operated animals. These data suggested that TrkB-dependent reduction in KCC2 protein levels in the spinal dorsal horn was an early consequence of peripheral nerve injury. This decrease in KCC2 may have elicited an early increase in overall dorsal horn neuronal excitability perhaps through a loss of GABA inhibition which is critically dependent on KCC2 activity. The increased neuronal excitability may in turn have caused enhanced and exaggerated Communication between primary afferents and dorsal horn neurons to contribute to the early behavioral signs of pain. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.