Chen Shu-Ling, Zang Ying, Zheng Wen-Hui, Wei Xu-Hong, Liu Xian-Guo
Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
Chin J Physiol. 2016 Feb 29;59(1):9-20. doi: 10.4077/CJP.2016.BAD332.
Diazepam binds with the same high affinity to the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor, which has been renamed translocator protein (TSPO). Both receptors could promote neurosteroid synthesis. In the present study, we investigated whether a single dose of diazepam could inhibit neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), and whether CBR and TSPO mediated this effect. We found that a single intraperitoneal injection of diazepam 9 d after L5 SNL significantly depressed the established mechanical allodynia and thermal hyperalgesia, which persisted until the end of the experiments. Furthermore, the effects were mimicked by a single intraperitoneal injection of Ro5-4864, a specific TSPO agonist and pregnenolone, a neurosteroid precursor. In addition, we found that the inhibitory effect of diazepam was also completely blocked by pretreatment with a specific CBR antagonist, flumazenil. The effects of diazepam or Ro5-4864 on neuropathic pain were completely blocked by pretreatment with a neurosteroid synthesis inhibitor, aminoglutethimide (AMG). Finally, any one of the three drugs, diazepam, Ro5-4864 and pregnenolone, could reduce the activation of astrocytes and the production of interleukin-1beta (IL-1β) in the L5 spinal dorsal horn 14 d after L5 SNL. These results suggest that in addition to exerting effects on CBR, diazepam may inhibit neuropathic pain via TSPO, which promotes neurosteroid formation, subsequently reducing the activation of astrocytes and production of cytokines.
地西泮与中枢苯二氮䓬受体（CBR）以及已重新命名为转位蛋白（TSPO）的外周苯二氮䓬受体具有相同的高亲和力。这两种受体均可促进神经甾体的合成。在本研究中，我们调查了单次剂量的地西泮是否能抑制L5脊神经结扎（L5 SNL）诱导的神经性疼痛，以及CBR和TSPO是否介导了这种作用。我们发现，在L5 SNL后9天单次腹腔注射地西泮可显著减轻已建立的机械性异常性疼痛和热痛觉过敏，这种作用一直持续到实验结束。此外，单次腹腔注射Ro5-4864（一种特异性TSPO激动剂）和孕烯醇酮（一种神经甾体前体）可模拟这些效应。此外，我们发现地西泮的抑制作用也被特异性CBR拮抗剂氟马西尼预处理完全阻断。地西泮或Ro5-4864对神经性疼痛的作用被神经甾体合成抑制剂氨鲁米特（AMG）预处理完全阻断。最后，地西泮、Ro5-4864和孕烯醇酮这三种药物中的任何一种都可在L5 SNL后14天减少L5脊髓背角星形胶质细胞的活化和白细胞介素-1β（IL-1β）的产生。这些结果表明，地西泮除了对CBR发挥作用外，还可能通过TSPO抑制神经性疼痛，TSPO促进神经甾体形成，随后减少星形胶质细胞的活化和细胞因子的产生。
