EM2在OAB模型大鼠骶副交感核参与排尿调控的形态学和机能学研究

Morphine receptor (MOR) that can combine with morphine specifically plays the role of morphine-like effects. In vivo, morphine in combination with MOR can decrease detrusor contraction and finally lead to urinary retention. Endomorphins 2 (EM2), a novel, high-affinity, MOR specific endogenous ligands. Although there are no data of EM2 involved in urination, we can speculate that EM2 may also be involved in regulation of bladder urination according to function of morphine and other analogue endomorphins. In the lumbosacral spinal cord, the sacral parasympathetic nucleus (SPN) is the nucleus mainly dominated detrusor contraction. Our previous experiments have confirmed that all of the parasympathetic preganglionic neurons (PPNs) that constitute the SPN expressed MOR, and EM2 positive primary afferent fibers from bladder formed symmetrical synaptic connections with MOR positive PPNs. Because symmetrical synapses are mostly inhibitory synapses. Once EM2 is released from the presynaptic bouton and binding with MOR in postsynaptic membrane, it will result in inhibiting the activities of the PPNs, and finally the contractions in rat bladder will be significantly attenuated. It is already accepted that symmetric synapses are inhibitory synapses, Therefore, we assume that, from morphology and function research, EM2 and MOR will be confirmed inhibition of urination, and their mechanism in the SPN of overactive bladder (OAB) rat model will be explored. Finally, we expect to find more effective targets and replacement therapy for the clinical treatment of OAB.

吗啡和排尿相关神经元上的吗啡受体(μ-opioid receptor, MOR)特异性结合导致膀胱逼尿肌的收缩减弱。内吗啡肽(Endomorphin 2, EM2)是MOR的特异性内源性配体，它几乎具有吗啡的所有的生物学功能，而成瘾性和心肺副作用远比吗啡小。尽管目前尚无EM2参与排尿的报道，但根据它与吗啡及其他内源性吗啡肽在功能上的类似性，推测其可能参与排尿的调控。我们前期实验证实：骶副交感核区的MOR阳性的副交感节前神经元和来源于盆神经的EM2阳性初级传入纤维之间形成对称性的突触联系。对称性的突触联系通常发挥抑制性的作用，因此，我们试图通过形态和机能学的研究证实EM2结合副交感节前神经元表面的MOR发挥抑制排尿的作用，进一步探讨EM2在膀胱过度活动症大鼠模型中的作用及机理，为临床的膀胱过度活动症的治疗寻找更为有效的靶点和替代疗法。

本课题主要研究内吗啡肽2(Endomorphin 2, EM2)通过膀胱过度活动（Overactive bladder, OAB）大鼠模型骶副交感核（sacral parasympathetic nucleus, SPN）发挥抑制排尿的作用及其可能机制。主要研究内容包括：EM2 和 吗啡受体（μ-opioid receptor, MOR） 在正常 SD 大鼠SPN区的表达和联系；EM2 和 MOR 在 OAB 大鼠 SPN 区的表达变化；从排尿行为学、尿流动力学和膀胱肌电图三方面证实 EM2在 OAB 大鼠的排尿中的抑制作用。结果表明：骶副交感核区的MOR阳性的副交感节前神经元和来源于盆神经的EM2阳性初级传入纤维之间形成对称性的突触联系，是产生抑制性作用的结构基础；在OAB大鼠SPN区，MOR的表达显著性降低，而EM2的表达变化不明显(EM2在脑脊液中出现显著变化，血清中变化不明显)；在骶副交感核区定位注射给与EM2后，OAB大鼠的排尿行为学、尿流动力学及膀胱肌电图呈现抑制性表现。这些作用和表现可能和对称性突触结构以及自发性兴奋性突触后电流的抑制有关。这一结果可能为临床的OAB的治疗找到有效的作用靶点和替代疗法。