Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat
Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat
复制标题
脊髓损伤引起的脊髓背角回路中 GABA 能抑制的减弱与大鼠氯离子转运蛋白 KCC2 的下调相关
DOI：
10.1113/jphysiol.2008.152348
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发表时间：
2008-12-01
影响因子：
5.5
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Lu, Yan;Zheng, Jihong;Yang, Jing
大多数脊髓损伤（SCI）患者患有慢性疼痛。这种疼痛缺乏有效的治疗方法，并且对潜在的机制知之甚少。脊髓浅层背角（SDH）包含能够调节参与疼痛处理的初级传入信息的神经元回路。KCC 2是K+-Cl-协同转运蛋白的一种亚型，有助于调节跨膜阴离子梯度，在CNS中形成GABA（A）受体介导的信号传导中起关键作用。我们检验了SCI导致损伤远端KCC 2下调并导致神经元高反应性和疼痛相关行为的假设。脊髓损伤是成年SD大鼠T-13水平的半横断损伤。在L4 ~ L 6水平制备带背根的矢状面切片。采用短杆菌肽穿孔膜片钳技术，比较了假手术和脊髓损伤大鼠L4-6 SDH神经元的GABA反应反转电位（E-GABA）和DR诱发的IPSP和EPSP。在这里，我们报告说，胸部SCI诱导的下调KCC 2在腰椎SDH平行异常性疼痛的发展。SDH神经元中E-GABA的随后变化减弱GABA（A）受体介导的抑制性突触传递。这些变化导致某些正常阈下初级A和C纤维输入引起SDH神经元的动作电位输出。我们的结论是，SCI诱导KCC 2下调和随后的变化E-GABA在SDH低于损伤部位。由此产生的去抑制揭示了通常无效的SDH神经元回路，并可能有助于不完全SCI后的中枢疼痛相关行为。
Most spinal cord injury (SCI) patients suffer from chronic pain. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. The spinal superficial dorsal horn (SDH) contains neuronal circuits capable of modulating primary afferent information involved in pain processing. KCC2 is an isoform of the K+-Cl- cotransporter that contributes to the regulation of transmembrane anion gradient which plays a key role in shaping GABA(A) receptor-mediated signalling in the CNS. We tested the hypothesis that SCI causes down-regulation of KCC2 distal to the injury and contributes to the neuronal hyperresponsiveness and pain-related behaviours. SCI was a hemisection at T-13 level of adult Sprague-Dawley rats. Spinal sagittal slices with attached dorsal roots (DR) were prepared from L-4 to L-6 level. The reversal potentials of GABA responses (E-GABA) and DR-evoked IPSPs and EPSPs of L4-6 SDH neurones in sham-operated and SCI rats were compared using gramicidin-perforated patch-clamp recordings. Here we report that thoracic SCI-induced down-regulation of KCC2 in the lumbar SDH parallels the development of allodynia. The subsequent changes of E-GABA in SDH neurones attenuate the GABA(A) receptor-mediated inhibitory synaptic transmission. These changes cause certain normally subthreshold primary A and C fibre inputs to evoke action potential output in SDH neurones. We conclude that SCI induces KCC2 down-regulation and subsequent changes of E-GABA in the SDH below the injury site. The resulting disinhibition unmasks normally ineffective SDH neuronal circuits and may contribute to the below-level central pain-related behaviours after incomplete SCI.