Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain.
Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain.
复制标题
DOI：
10.1016/j.celrep.2016.04.039
复制
发表时间：
2016-05-17
期刊：
影响因子：
8.8
通讯作者：
Pan HL
中科院分区：
文献类型：
--
作者：
Li L;Chen SR;Chen H;Wen L;Hittelman WN;Xie JD;Pan HL
慢性神经病理性疼痛是一种使人衰弱的疾病，仍然难以治疗。GABA和甘氨酸对突触的抑制作用减弱以及脊髓背角NMDA受体（NMDAR）活性增加是神经病理性疼痛的关键机制。然而，神经病理性疼痛中突触抑制和兴奋之间的相互关系尚不清楚。在这里，我们表明，使用慢病毒载体鞘内递送K+-Cl−协同转运蛋白-2（KCC 2）可完全和持久地逆转神经损伤诱导的疼痛超敏反应。KCC 2基因转移恢复脊髓背角和初级感觉神经元中因神经损伤而破坏的Cl−稳态。值得注意的是，恢复Cl−稳态使脊髓背角神经损伤引起的突触前和突触后NMDAR活性恢复正常。我们的研究结果表明，神经损伤通过破坏脊髓背角和初级感觉神经元中的Cl−稳态来招募NMDAR介导的信号通路。慢病毒载体介导的KCC 2基因表达是一种很有前途的神经病理性疼痛基因治疗方法。Li等人发现，脊髓KCC 2基因转移诱导持续的KCC 2表达，并恢复由背角和初级感觉神经元的神经损伤破坏的氯稳态。KCC 2基因转移完全和持久地消除神经性疼痛，并使神经损伤增加的突触前和突触后NMDA受体活性正常化。
Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR) activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain. However, the reciprocal relationship between synaptic inhibition and excitation in neuropathic pain is unclear. Here we show that intrathecal delivery of K+-Cl− cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores Cl− homeostasis disrupted by nerve injury in both spinal dorsal horn and primary sensory neurons. Remarkably, restoring Cl− homeostasis normalizes both presynaptic and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn. Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways through disrupting Cl− homeostasis in spinal dorsal horn and primary sensory neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for treating neuropathic pain. Li et al. find that spinal KCC2 gene transfer induces sustained KCC2 expression and restores chloride homeostasis disrupted by nerve injury in both dorsal horn and primary sensory neurons. KCC2 gene transfer completely and persistently eliminates neuropathic pain and normalizes pre- and postsynaptic NMDA receptor activity increased by nerve injury.