Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
J Neurosci. 2013 Jan 23;33(4):1540-51. doi: 10.1523/JNEUROSCI.0324-12.2013.
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.
目前，治疗神经性疼痛的有效药物仍然缺乏。最近的研究表明，苯二氮䓬类药物外周受体转位蛋白（TSPO，18 kDa）的配体可调节炎性疼痛。在这里，我们报告 L5 脊神经结扎（L5 SNL）后，同侧脊髓背角中的星形胶质细胞和小胶质细胞中 TSPO 上调，持续到神经性疼痛的行为症状消失（约 50 d）。重要的是，L5 SNL 后 7 和 21 天单次鞘内注射特异性 TSPO 激动剂 Ro5-4864 或 FGIN-1-27 可显著抑制已建立的机械性痛觉过敏和热痛觉过敏，并且该作用可被神经甾体合成抑制剂 AMG 预处理所消除。在机制上，Ro5-4864 可显著抑制脊髓星形胶质细胞，但不抑制小胶质细胞，减少体内和体外肿瘤坏死因子-α（TNF-α）的产生。AMG 也可预防抗炎作用。有趣的是，当神经性疼痛自然愈合或被 Ro5-4864 逆转时，TSPO 的表达恢复到对照水平或显著降低，这表明 TSPO 上调的作用可能是促进神经系统疾病的恢复。最后，通过 TLR4 药理学阻断可预防 L5 SNL 引起的神经性疼痛和 TSPO 的上调。这些数据表明，TSPO 可能是治疗神经性疼痛的新的治疗靶点。
