脊髓TSPO在术后疼痛发生发展中的痛觉调制作用研究

Postoperative pain is difficult to prevent and therapy. The neurobiological mechanism of its initiation and maintenance is unclear. An increasing number of evidences have shown that spinal translocator protein (18 kDa) (TSPO) was involved in the modulation of chronic pain. Our previous data demonstrated that the expression of TSPO in the spinal cord is increased in rats with postoperative pain; however, the effect of TSPO on the modulation of postoperative pain is unknown. In this study, we investigate the modulation of spinal TSPO in the initiation and maintenance of postoperative pain by electrophysiological and behavioral methods in rat foot incision induced chronic postoperative pain model. Furthermore, we analyze whether the effect of spinal TSPO is mediated by up-regulation of neuroactive steroids to inhibit the initiation and maintenance of postoperative pain. In the end, we evaluate whether the pain modulation of TSPO is mediated by positive modulating GABAA receptor followed by TSPO up-regulating neuroactive steroids. Accordingly, we aim to clarify the pain modulation of spinal TSPO in the initiation and maintenance of postoperative pain and its underlying possible neurobiological molecular pathway (TSPO - Neuroactive steroids - GABAA receptor). The study is helpful to understand the molecular neurobiological mechanism of the initiation and maintenance of postoperative pain, and to provide the new target for investigating and developing new drugs in the prevention and therapy of postoperative pain.

术后疼痛防治困难，其发生发展的神经生物学机制不清楚。脊髓胶质细胞内TSPO[translocator protein (18 kDa)]在慢性疼痛发生发展中的调控作用日益受到重视。我们前期工作显示，TSPO在术后痛大鼠脊髓表达增强，但其痛觉调制作用有待探索。本项目拟在大鼠足底切口术后疼痛模型上，从电生理、行为学角度，首先观察脊髓TSPO在术后疼痛发生发展过程中的痛觉调制作用；进而分析脊髓TSPO是否通过上调靶神经活性甾体水平而抑制术后痛痛敏的发生发展；最后探讨脊髓TSPO上调靶神经活性甾体后是否通过正性调控GABAA受体调制术后痛，以期较为深入系统地阐释脊髓TSPO对术后疼痛的痛觉调制作用，明确介导该作用可能的分子通路（TSPO-神经活性甾体-GABAA受体）。本研究将有助于深化理解术后疼痛发生发展的分子神经生物学机制，为防治术后疼痛新药研发提供新的药物作用靶标与作用途径。

术后疼痛防治困难，其发生发展的神经生物学机制不清楚。脊髓胶质细胞内TSPO[translocator protein (18 kDa)]在慢性疼痛发生发展中的调控作用日益受到重视。本项目拟在大鼠足底切口术后疼痛模型上，首先观察脊髓TSPO在术后疼痛发生发展过程中的痛觉调制作用，荧光免疫组化结果显示术后痛大鼠术侧脊髓背角出现TSPO上调的现象，小胶质细胞和星形胶质细胞呈现持续活化状态，激光共聚焦结果显示TSPO的变化与小胶质细胞的变化可能存在相关性，定量PCR结果显示术后痛大鼠脊髓TSPO mRNA上调，提示脊髓TSPO参与术后痛的发生发展过程；进而采用鞘内注射TSPO拮抗剂PK11195观察其对大鼠术后疼痛发生发展过程的影响，结果显示PK11195翻转术后痛大鼠的疼痛状态，作用与剂量相关，提示脊髓TSPO上调参与术后痛的镇痛过程；最后采用鞘内注射GABAA受体拮抗剂Bicuculline观察脊髓TSPO上调靶神经活性甾体后是否通过正性调控GABAA受体调制术后痛，结果显示Bicuculline翻转术后痛大鼠的疼痛状态，作用呈剂量相关，提示脊髓TSPO对术后疼痛的痛觉调制作用可能是通过TSPO-神经活性甾体-GABAA受体的分子通路介导的。本研究将有助于深化理解术后疼痛发生发展的分子神经生物学机制，为防治术后疼痛新药研发提供新的药物作用靶标与作用途径。