从“膀胱交感-副交感调控机制”研究电针通过5-HT信号系统治疗脊髓损伤后逼尿肌-括约肌协同失调型膀胱的效应机制

Neurogenic bladder is a severe complication of spinal cord injury (SCI), which is the main cause of death for paraplegia patients. Among them, more than 80% are injuried above sacral. It leads to detrusor-sphincter dysfunction, which reduces urination efficiency and cause urinary incontinence. The regulation of sympathetic-parasympathetic nerve and detrusor-sphincter will improve function of urine storage and micturition control, in which 5-HT and "presynaptic inhibition" of autonomic nerve mediated by its receptors play key roles. The project takes rats with urinary incontinence caused by SCI as subjects, electroacupuncture as treatment, urodynamic test, neuroelectrophysiological test, protein chip, and Western-blot as means of detection. By testing the expression of 5-HT receptors in presynaptic membrane of autonomic nerve, phosphorylation of cAMP, PKA and BK, as well as the expression of Ach and NE in smooth muscle, we try to explore the “sympathetic-parasympathetic coregulation” mechanism of electroacupuncture in regulating detrusor-sphincter dysfunction of neurogenic bladder based on 5-HT signal system.

神经源性膀胱是脊髓损伤(SCI)后严重的合并症，是截瘫患者晚期的主要病死原因。SCI患者80%以上为骶上脊髓损伤，其所导致的膀胱功能障碍主要表现为逼尿肌-括约肌协同失调，导致排尿效率低下，出现尿潴留。抑制下尿路交感-副交感神经兴奋性、促进膀胱逼尿肌、尿道内括约肌舒张可有效改善膀胱储尿和排尿功能，5-HT及其受体所介导自主神经“突触前抑制”对此具有有重要作用。本项目以此为切入点，以骶上脊髓损伤所致的尿潴留大鼠模型为受试对象，利用电针治疗，采用尿流动力学、神经电生理学、蛋白芯片、Western-blot等多种检测手段，通过观察膀胱尿流动力学等效应指标的变化，自主神经突触前膜5-HT受体表达的变化，突触前膜cAMP、PKA、BK磷酸化状态，及平滑肌组织Ach、NE含量变化，从“膀胱交感-副交感外周调控”的角度，揭示电针通过5-HT信号系统改善骶上脊髓损伤后逼尿肌-括约肌协同失调型膀胱的效应机制。

本项目紧扣骶上脊髓损伤后膀胱逼尿肌-括约肌协同失调（Bladder neck dyscoordination，BND）的基本病理，从“膀胱交感-副交感外周调控机制”的角度，以5-HT及其受体所介导自主神经末梢“突触前抑制”为切入点，采用电针，以骶上脊髓损伤所致的BND模型大鼠为受试对象，运用尿流动力学、组织形态学、神经电生理学、蛋白组学和分子生物学等多种技术手段，基于5-HT信号系统对膀胱储尿能力和排尿效率的调节作用，进一步明确了电针治疗脊髓损伤后BND的效应机制。本研究结果显示：①骶上脊髓损伤会导致大鼠膀胱最大容量和漏尿点压力显著增高，电针治疗可明显降低膀胱最大容量，恢复漏尿点压力，从而改善膀胱功能。②电针治疗可逆转骶上脊髓损伤BND模型大鼠多种差异蛋白表达，并激活多条蛋白信号通路，其中5-HT能信号系统是促进BND大鼠下尿路功能恢复的重要通路。③电针可有效调控逼尿肌、括约肌、交感和副交感中枢5-HT受体的表达，协调逼尿肌和括约肌的舒缩，恢复脊髓对排尿自主反射的调控，改善下尿路功能。以上实验明确电针通过调控5-HT信号系统发挥对膀胱储尿能力和排尿效率的调节作用，从“膀胱交感-副交感外周调控机制”的角度，揭示了治疗骶上脊髓损伤后BND神经源性膀胱的作用机制，为针灸的临床应用提供一定的科学理论依据。