5-羟色胺能递质改善脊髓损伤逼尿肌括约肌失协调的作用机制研究

The detrusor sphincter dyssyneria is the main voiding dysfunction caused by spinal cord injury. Serotonin (5-HT) is one of the central neurotransmitter involved in micturition control. We recently demonstrated that the intravenous administration of 5-HT1A, 5-HT2A/2C, or 5-HT7 receptor agonist can treat the detrusor sphincter dyssyneria, improve voiding dysfunction in spinal cord injury rat. However, the mechanism is still not clear. The source of most spinal cord serotonin-containing terminals are neuronal somata located in brainstem raphe nuclei. The spinal cord transection interrupts axons of the brainstem serotonin-producing neurons. However, 5-HT receptors remain within the lumbosacral spinal cord following destruction of descending serotonin-containing pathways. We presume that the exogenous serotonin can act on these receptors in the lumbosacral spinal cord, enhance the external urethral sphincter function, and improve the detrusor sphincter dyssyneria. We will use the urodynamics , neural tracer technique, immunohistochemistry, Western blot, real time PCR and other molecular biological techniques, reveal the mechanism of improving the detrusor sphincter dyssyneria by serotonin in spinal cord injury rat.

脊髓损伤导致以逼尿肌括约肌失协调为主的排尿障碍。5-羟色胺(5-HT)是参与排尿控制的中枢神经递质之一。我们前期利用脊髓损伤大鼠模型，证实静脉给予5-HT1A，5-HT2A/2C,及5-HT7受体激动剂可以治疗逼尿肌括约肌失协调，改善排尿障碍，但作用机制尚不清楚。 5-HT神经细胞体位于高位脑干中缝核部位，脊髓损伤切断了神经轴突，5-HT能递质不能向腰骶髓控尿神经核团的5-HT受体传送影响排尿。推测静脉给予5-HT能递质作用于这些受体促进尿道外括约肌功能，改善逼尿肌括约肌失协调。计划利用脊髓损伤大鼠模型，综合尿动力学和神经示踪技术、免疫组化、以及蛋白质免疫印迹法（Western Blot）和实时荧光定量PCR（Real-time PCR）等分子生物学技术，分别从功能改善、组织形态学、受体蛋白表达、受体基因表达等不同层面展开研究，阐明5-羟色胺能递质改善脊髓损伤逼尿肌括约肌失协调的作用机制。

脊髓损伤导致以逼尿肌括约肌失协调为主的排尿障碍，我们前期证实静脉给予5-羟色胺( 5-HT)受体激动剂可以治疗逼尿肌括约肌失协调，改善脊髓损伤大鼠的排尿障碍，推测静脉给予5-羟色胺（5-HT2A/2C, 5-HT7) 能递质作用于这些受体促进尿道外括约肌功能，从而改善逼尿肌括约肌失协调，但药物具体的作用部位及作用机制还不清楚。本研究分别在大鼠腰骶髓（L6-S1）髓腔内给予不同浓度的5-羟色胺受体激动剂后行尿动力学检测，记录与脊髓损伤大鼠排尿相关的功能学改变；同时利用伪狂犬病毒逆行神经示踪联合免疫组化，蛋白免疫印迹技术，检测脊髓损伤大鼠腰骶髓5-羟色胺受体数量的改变。证实腰骶髓给予5-羟色胺受体激动剂可以改善脊髓损伤后排尿障碍，同时发现脊髓损伤大鼠腰骶髓前角运动神经元核团中5-HT2A、2C受体，控制大鼠尿道外括约肌活动的Onuf’s核团中5-HT7受体数量较正常大鼠都发生明显上调。推测5-羟色胺受体激动剂可能是通过与腰骶髓上调的5-羟色胺受体结合，从而加强尿道外括约肌的活动，改善逼尿肌和括约肌的失协调状态，最终改善脊髓损伤导致的排尿功能障碍，这为以后临床开发新药来治疗脊髓损伤后排尿障碍提供理论和实验依据。