The Upregulation of Translocator Protein (18 kDa) Promotes Recovery from Neuropathic Pain in Rats
The Upregulation of Translocator Protein (18 kDa) Promotes Recovery from Neuropathic Pain in Rats
复制标题
易位蛋白 (18 kDa) 的上调促进大鼠神经性疼痛的恢复
DOI：
10.1523/jneurosci.0324-12.2013
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发表时间：
2013-01-23
影响因子：
5.3
通讯作者：
Liu, Xian-Guo
中科院分区：
文献类型：
--
作者：
Wei, Xu-Hong;Wei, Xiao;Liu, Xian-Guo
目前，治疗神经病理性疼痛的有效药物尚缺乏。最近的研究表明，转运蛋白（TSPO，18 kDa），苯二氮卓类的外周受体的配体，调节炎症性疼痛。在这里，我们报告，TSPO上调星形胶质细胞和小胶质细胞在同侧脊髓背角的大鼠L5脊神经结扎（L5 SNL），持续到消失的神经病理性疼痛的行为体征（150天）。重要的是，在L5 SNL后7和21 d单次鞘内注射特异性TSPO激动剂Ro 5 -4864或FGIN-1-27显著抑制了已建立的机械异常性疼痛和热痛觉过敏，并且通过用神经类固醇合成抑制剂AMG预处理消除了该作用。机械上，Ro 5 -4864实质上抑制脊髓星形胶质细胞，但不抑制小胶质细胞，并减少体内和体外肿瘤坏死因子-α（TNF-α）的产生。AMG也阻止了抗神经炎症作用。有趣的是，当神经性疼痛自然愈合或被Ro 5 -4864逆转时，TSPO表达恢复到对照水平或显著降低，表明TSPO上调的作用可能是促进从神经障碍中恢复。最后，通过Toll样受体4（TLR 4）的药理学阻断来防止神经病理性疼痛和L5 SNL对TSPO的上调。这些数据表明，TSPO可能是治疗神经病理性疼痛的一个新的治疗靶点。
At present, effective drug for treatment of neuropathic pain is still lacking. Recent studies have shown that the ligands of translocator protein (TSPO, 18 kDa), a peripheral receptor for benzodiazepine, modulate inflammatory pain. Here, we report that TSPO was upregulated in astrocytes and microglia in the ipsilateral spinal dorsal horn of rats following L5 spinal nerve ligation (L5 SNL), lasting until the vanishing of the behavioral signs of neuropathic pain (∼50 d). Importantly, a single intrathecal injection of specific TSPO agonists Ro5-4864 or FGIN-1-27 at 7 and 21 d after L5 SNL depressed the established mechanical allodynia and thermal hyperalgesia dramatically, and the effect was abolished by pretreatment with AMG, a neurosteroid synthesis inhibitor. Mechanically, Ro5-4864 substantially inhibited spinal astrocytes but not microglia, and reduced the production of tumor necrosis factor-α (TNF-α) in vivo and in vitro. The anti-neuroinflammatory effect was also prevented by AMG. Interestingly, TSPO expression returned to control levels or decreased substantially, when neuropathic pain healed naturally or was reversed by Ro5-4864, suggesting that the role of TSPO upregulation might be to promote recovery from the neurological disorder. Finally, the neuropathic pain and the upregulation of TSPO by L5 SNL were prevented by pharmacological blockage of Toll-like receptor 4 (TLR4). These data suggested that TSPO might be a novel therapeutic target for the treatment of neuropathic pain.