星形胶质细胞和前扣带回参与的痛觉下行易化通路调控脊髓中枢敏化的机制研究

Chronic non-specific low back pain (LBP) is one of the disease burdens which influence the quality of life and attract global attention. Due to its high lifetime prevalence and serious burden on society, chronic non-specific LBP has become the research hotspot. However，the chronic non-specific LBP mechanism is unclear. The effective analgesic treatment is still being explored. Lots of studies find that the central sensitization plays an important role in the transition from acute pain to chronic pain and central sensitization is related to glial activation. Our previous investigation found that the role of astrocyte activation was critical in the spinal central sensitization in the chronic non-specific LBP animal. Considering the participation of anterior cingulate cortex (ACC) pain descending facilitating pathway in the spinal central sensitization, it is speculated that the spinal central sensitization might be modulated by both spinal astrocytes and ACC pain descending facilitating pathway and their modulations differ in time. Therefore, we will inhibit the activation of spinal astrocyte and ACC function in the pain descending facilitating pathway in the chronic non-specific LBP animal. The methods of electroneurophysiology,molecule biology and animal behavior will be performed in our investigation for elucidating the different modulations of astrocyte activation and ACC pain descending facilitating pathway in the spinal central sensitization. Our study will also explore the mechanisms of sensitization modulations from different levels in chronic pain and provide theoretical basis for the new analgesics.

慢性非特异性腰痛是全球关注的影响人类生活的疾病负担之一，高发病率及由此导致的严重社会负担使其成为研究者关注的热点。目前，慢性非特异性腰痛的发病机制尚未明确，有效的镇痛方法仍在探索。研究表明，中枢敏化参与急性疼痛向慢性疼痛的转化，并与胶质细胞的活化密切相关。我们前期研究发现在慢性非特异性腰痛动物中，星形胶质细胞的活化在脊髓中枢敏化中起着重要作用，结合前扣带回（ACC）参与的痛觉下行易化通路对脊髓中枢敏化的调控作用，推测星形胶质细胞和ACC痛觉下行易化通路共同调控脊髓中枢敏化，且二者的差异性调控与时间相关。因此，我们拟在慢性非特异性腰痛动物中，抑制脊髓星形胶质细胞活化和ACC痛觉下行易化通路，使用神经电生理、分子生物学、动物行为学方法，阐明星形胶质细胞的活化和ACC参与的痛觉下行易化通路对脊髓中枢敏化的调控差异，深入了解慢性疼痛不同层次的敏化调节机制，为研究临床治疗慢性疼痛的新方法奠定基础。

慢性非特异性腰痛(LBP)是全球关注的影响人类生活的疾病负担之一，高发病率及由此导致的严重社会负担使其成为研究者关注的热点。目前，慢性非特异性LBP的发病机制尚未明确，有效的镇痛方法仍在探索。本项目拟在慢性非特异性LBP动物中，抑制脊髓星形胶质细胞活化和前扣带回的功能，使用动物行为学和分子生物学的方法探究其调控慢性非特异性LBP的生物学机制。研究结果发现：①NGF诱导的慢性非特异性LBP动物表现为持续的注射NGF侧背部机械痛觉过敏、注射NGF侧足部机械痛觉过敏、足部冷痛觉过敏（冷板）、足部热痛觉过敏（热板），并表现出持续的焦虑样行为。同时，模型动物脊髓腰2节段注射NGF侧背角浅层星形胶质细胞激活，腰2节段p-JNK、c-fos、MCP-1和CXCL1表达显著上升。②鞘内注射JNK抑制剂可以逆转慢性非特异性LBP大鼠的背部和足部痛觉过敏以及焦虑样行为，这一过程可能与抑制脊髓星形胶质细胞的活化，下调脊髓MCP-1和CXCL-1细胞因子表达有关，抑制脊髓JNK通路有望成为缓解慢性非特异性LBP的有效方法。③前扣带回定点注射NMDA受体拮抗剂可以改善慢性非特异性LBP动物足背部机械性痛觉过敏和焦虑样行为，这一过程可能与抑制脊髓水平星形胶质细胞活化、下调p-JNK和相关细胞因子MCP-1和CXCL-1的表达有关。以上发现为研究临床治疗慢性非特异性LBP的新方法奠定基础。同时，该研究项目在原有动物实验基础上拓展了其他类型慢性疼痛及麻醉镇痛药物相关的临床研究：①采用国王帕金森疼痛量表对原发性帕金森病的106例患者的疼痛症状进行评估，同时评估了患者睡眠、疲劳、认知、情绪等，发现疲劳是预测帕金森病疼痛发生和转归的因素，帕金森病患者疼痛严重程度和变化与焦虑、抑郁、睡眠、疲劳有关。②滥用麻醉镇痛剂一氧化二氮可能造成严重的神经系统损害。研究收集了一氧化二氮中毒致神经系统损害患者20例，并回顾分析了既往病例，发现一氧化二氮中毒导致的最常见的特征性神经系统损害是出现在青年人群的长节段颈段脊髓炎和/或周围神经病，且神经系统损害存在人种差异。