电针深刺次髎抑制膀胱过度活动的特异效应及其感觉神经调控机制
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摘要
背景
膀胱排尿和储尿功能受到多个神经水平介导和控制,可分为脑干和大脑皮层高位中枢,骶髓低位中枢和外周神经三个节段。控制膀胱的外周神经主要有3条：腹下神经、阴部神经和盆神经。其中,腹下神经属于交感神经,由胸腰髓交感神经中枢发出,具有支配膀胱颈部及内尿道括约肌的功能。阴部神经属于躯体神经,支配外尿道括约肌。盆神经属于副交感神经,是参与膀胱感觉和膀胱收缩最重要的神经,来自膀胱的大多数传入纤维主要是通过盆神经进入骶髓的。
组成盆神经的膀胱感觉传入神经纤维可分为有髓鞘的Aδ纤维和无髓鞘的C纤维。Aδ纤维主要存在于逼尿肌及尿道平滑肌细胞间的胶原纤维组织内,传入信号主要来自机械感受器(膀胱牵拉作用)。C纤维主要位于膀胱和尿道黏膜及黏膜下层组织内,数量占到传入神经的60%-70%,传导疼痛、温度觉和触觉,对化学性刺激很敏感,而对机械性刺激不敏感。在正常情况下,健康个体膀胱传入神经的兴奋主要由有髓鞘传入神经(A δ纤维)传导至中脑水管周围灰质区域,给脑桥排尿中枢发出膀胱充盈的信号。当脊髓损伤或膀胱受到化学刺激时,C纤维介导的感觉神经通路开始发挥作用,表现出自发放电活性,且随膀胱压力上升而表现出活性增加,引起预防机制性排尿反射增强并使膀胱容量减低,以便排出刺激物或细菌,于此同时,患者会产生尿意,出现尿频、尿急等下尿路刺激症状。目前国际上普遍认为膀胱过度活动(overactive bladder, OAB)的神经病理机制主要在于传入性C神经纤维活动过度。这一理论可通过施加辣椒素得到证实,辣椒素对几种特定的初级感觉神经元具有选择性神经毒性,对初级C型传入神经纤维可产生长期持久的抑制作用,通过耗尽C传入神经纤维中的P物质抑制膀胱感觉传导,使逼尿肌不能正常收缩,达到抑制排尿的目的。有研究发现,膀胱灌注辣椒素可有效治疗膀胱高反应性。
膀胱过度活动症是指无明确原因导致的膀胱储尿功能障碍,以尿频、尿急和急迫性尿失禁为特征的症候群。国际尿控协会将膀胱过度活动症定义为：无任何潜在病理原因导致的尿急,伴或不伴有急迫性尿失禁,常伴有尿频和夜尿。OAB虽不危及生命,但与人们生活息息相关,不但有损患者的生理和精神健康,且影响人们的日常活动和生活质量。目前,针对膀胱活动过度的治疗方法有行为治疗、药物治疗、神经调节疗法和手术治疗等。药物的副作用和低选择性对其临床使用有一定限制,周树脂毒和辣椒素治疗过度活动膀具有一定疗效,与行为治疗类似,目前常作为临床辅助治疗使用,手术治疗通常作为患者最后的选择方式,但手术创伤和和近期远期并发症使人们饱受困扰。神经调节疗法是近年兴起的一种疗法,植入性骶神经电刺激与针灸中电针八骼穴起效作用方式类似,但该操作费用昂贵,且有效性和安全性还需进一步证据支持。总之,对于OAB患者,尤其是顽固性OAB患者来说目前能够达到满意疗效的治疗方法还很有限。膀胱过度活动症是针灸的优势病种,虽然目前还没有关于针刺治疗OAB的系统评价,但现有医学证据表明针刺抑制膀胱过度活动简便、安全、有效,已发表的临床研究和实验研究多选用次髎或中骼穴进行治疗。目前,针刺抑制膀胱活动的起效途径尚不明确,近年来,有学者从神经递质角度进行机制探讨,认为针刺可抑制膀胱传入末梢SP和CGRP的释放与合成,推测针刺可能通过降低膀胱传入神经的过度兴奋,从而起到抑制膀胱活动亢进的作用。从中枢神经系统角度解释针刺起效途径的研究覆盖了大脑皮层、丘脑、脑桥排尿中枢及中枢核团等几乎控制排尿的高级中枢的各个部位,多以这些区域的放电频率为指标评价针刺的影响。以上研究结果都比较分散,且单一的指标选取只能推测出膀胱组织中神经递质含量的改变或中枢电活动的改变可能是针刺起效环节中的一环,缺乏针对膀胱感觉过敏这一主要病理机制的特异性和完整性研究。从外周神经角度进行研究的实验目前只能证明针刺通过C纤维途径起效,但具体如何起效,针刺前后膀胱功能--递质---神经电活动整体动态变化是怎样的,目前尚缺少关于针刺起效机制的完整性研究。
目的
1.明确电针深刺次髎穴对过度活动膀胱是否具有抑制效应；2.设置次髎穴浅刺组和次髎穴旁深刺组,探讨电针深刺次髎抑制膀胱过度活动的效应是否具有特异性,明确影响膀胱抑制效应的关键因素；3.从膀胱感觉神经调控角度探讨电针深刺次髎抑制膀胱过度活动与感觉传导通路的调控关系,初步阐明其特异机制。
方法
1.制备大鼠膀胱过度活动模型,采用膀胱内压测定方法反映膀胱的收缩活动,明确电针深刺次骼穴是否具有膀胱抑制效应,通过设置次髎浅刺和次髎旁部位针刺作为对照,研究深刺次髎穴是否对抑制膀胱过度活动具有特异效应；2.通过制定深刺标准,具体测量针刺深度,明确深刺次髎穴抑制膀胱过度活动的关键影响因素；3.通过提前皮下注射辣椒素破坏大鼠C传入纤维,与次髎穴深刺组和模型组对照,确定OAB发生和针刺起效途径4.采用神经电生理技术同步观察大鼠排尿时盆神经放电情况,分析膀胱压力发生变化时神经电活动情况的相应变化；5.使用免疫组化和RT-PCR方法检测大鼠膀胱中P物质和神经肽B的mRNA水平。
结果
1.深刺是必须是针尖最大限度接近或触及骶神经前支
对深刺组和浅刺组大鼠,针刺后使用记号笔在针身紧贴大鼠背部皮肤处进行标记,记录每只大鼠的针刺深度,计算平均值。深刺组针刺平均深度为16.33mm,针刺时针尖从后腹膜透出后使用棉签辅助将针退至后腹膜下,大鼠荐骨腹侧面水平,以此保证针尖穿过大鼠第一骶后孔后最大限度接近或触及第一骶神经前支。浅刺组刺透皮肤针尖接触荐骨即可,平均针刺深度为6.58mm。
2.电针深刺次骼穴可以抑制膀胱过度活动
使用乙酸灌注大鼠膀胱,造成膀胱过度活动模型,后给予深刺次髎穴加电针进行干预。通过对大鼠造模和电针前后进行膀胱压力测定,我们发现电针深刺次髎穴可以显著延长OAB大鼠排尿时间间隔(造模后为120.48±63.58s,电针后为156.64±58.94s)、缩短单次排尿时间(造模后为3.46±0.61s,电针后为2.34±0.83s),减小逼尿肌不稳定发生率。
3.电针次髎穴抑制膀胱过度活动具有特异效应
设置次骼穴浅刺组和次髎旁部位电针组,我们发现相同穴位浅刺加电针或次髎穴旁部位深刺加电针均不能产生膀胱抑制效应,排尿时间间隔及排尿时间均无明显改变,且逼尿肌不稳定发生率高(深刺组16.7%,浅刺组为100%,次髎旁组为83.3%)。说明这种抑制膀胱过度活动的特异效应只局限于次髎穴,电针刺激相同神经节段分布区域不能产生同等效果。且这种特异效应与次髎穴针刺深度有关,次谬穴浅剌不能发生作用,只有深刺次髎,直接对骶神经前支进行电针刺激才能产生膀胱抑制效应。
4.C纤维是电针抑制膀胱过度活动的起效途径
辣椒素组大鼠提前皮下注射辣椒素后,给予乙酸灌注膀胱时,排尿时间间隔、膀胱最大压和排尿持续时间等指标无任何变化,均与最初基线时一致,说明C纤维破坏后的大鼠不会因乙酸刺激造成膀胱过度活动模型。接着给予次髎穴电针刺激后,上述指标亦无明显变化,说明阻断C纤维后电针次髎穴的膀胱抑制效应消失。由此可证明,膀胱过度活动模型的生成及电针抑制膀胱活动的起效途径均是通过传入性C纤维。
5.电针深刺次髎穴可降低OAB大鼠盆神经放电次数和神经内递质表达
与正常组大鼠相比,乙酸灌注后,大鼠排尿前和排尿期间盆神经放电均增加,后期膀胱组织免疫组化和PCR结果提示乙酸灌注后大鼠膀胱中P物质和神经肽BmRNA表达增加,显著多于正常组。电针深刺次髎穴后,排尿前和排尿期间盆神经放电频率均显著降低。后期膀胱组织免疫组化和PCR结果提示电针后大鼠膀胱中P物质和神经肽BmRNA表达有所降低,与模型组有差别。且膀胱压力相关指标、盆神经放电与膀胱内P物质等递质表达水平的变化一致。
结论
本研究探讨了电针深刺次髎穴抑制膀胱过度活动的特异效应及其可能的起效机制。实验表明,电针深刺次髎穴可以抑制膀胱过度活动,且对膀胱活动的抑制具有特异效应。针刺通过C传入纤维起效,可能起效机制为“抑制P物质等神经递质的释放—抑制C传入纤维活动—抑制膀胱收缩”。
Background
Function of the bladder is controlled by perch center (located in brain stem and cerebral cortex), sacral spinal cord and peripheral nerve. There are mainly three nerves controlling the bladder—the hypogastric nerve, the pudendal nerve and the pelvic nerve. The hypogastric nerve is the sympathetic nerve. Hypogastric nerve activation in the thoracic10-lumbar2(T10-L2) spinal cord level and could contract the internal smooth muscle sphincter and relax the bladder. The somatic pudendal nerve arises from the nucleus in S2-S4level and controls the rhabdosphincter. The pelvic nerve is parasympathetic nerve. It is the most important nerve sending impulses and regulating emptying of the bladder. The impulses travel in the pelvic nerve and goes into the sacral spinal cord.
The bladder afferent pathways are composed of two types of axons:myelinated A8fibers and unmyelinated C fibers. Located in detrusor and urethral smooth muscle, A8fibers transmit signal mainly from mechanoreceptors that detect bladder fullness or wall tension. C fibers could be found in mucosa and submucosal areas and transmit noxious signals and initiate painful sensations. They account for60%～70%in all afferent fibers and are insensitive to mechanical stimulation. Under normal conditions, A8fibers transmit signal from the bladder to the pontine micturition center. The bladder C-fiber nociceptors perform a similar function and signal the central nervous system when people have spinal cord injury or irritative condition in the bladder, which could be viewed as a defense mechanism to eliminate irritants of bacteria. At the same time, patients will have lower urinary tract symptoms like micturition and urgency. Now it is considered that the neuropathological mechanism of OAB is hyperactivity of C fibers. This could be confirmed by capsaicin. Capsaicin could suppress bladder contraction by depleting SP. Research found that capsaicin could be used for bladder hyperactivity.
Overactive bladder (OAB) is a storage dysfunction with no obvious reasons, and it is defined by set of symptoms:urgency, with of without urge incontinence, usually with frequency and nocturia. To date, there are no satisfactory therapies for OAB patients, especially for refractory OAB patients. Acupuncture could manage this disease well. Though there is not systematic review about acupuncture for OAB, available medical evidence shows that acupuncture is easy to operate, safe and effective. BL32is an acupoint used often in treatment. Though the effectiveness, how acupuncture can treat the disease is still not known. Some scholars try to explain the mechanism with neurotransmitters. They found that acupuncture could reduce substance P (SP) in the afferent fibers, and they speculated that acupuncture could suppress the hyperactivity of afferent fibers and suppress the bladder activity correspondingly. Some studies try to explain the mechanism from the viewpoint of central nervous system (CNS) and evaluate the effect of acupuncture according to neuron activities of various areas in CNS. Adoption of single indicator in those studies could only make sure that neurotransmitter or neuron activity is a point in the mechanism link, and the whole mechanism is still not clear. In recent years, studies focusing on peripheral nerve concluded that acupuncture suppress bladder hyperactivity through C fibers. But how it works through C fibers and the systematic change of bladder function, neurotransmitter and nerve activity are still not clear.
Objective
1. To detect whether deep needling at BL32is effective for OAB;2. Set shallow needling group and non point needling group (point
besides BL32) as controls to detect whether the effect of electroacupuncture at BL32is specific and the key influence factors;
3. Try to discuss the relation between acupuncture's effect and afferent pathway and elucidate the possible mechanism.
Methods
1. To detect acupuncture's effect on bladder hyperactivity using cystometry in anesthetized rats. With shallow needling group and non point needling group as controls, to study whether the effect is specific;2. Make principle of deep needling at B132on rat and measure the needling depth to examine the key influence factor;3. Block the C-fiber activity by capsaicin injection to examine the pathways that acupuncture works through;4. Observe the pelvic nerve activity using technique of neurological electrophysiology and analyze the change of nerve activity corresponding to the change of bladder pressure;5. To measure the mRNA expression level of SP and neruokinin B by RT-PCR.
Results
1. For deep needling at BL32, the needle should get near to or touch the anterior branch of the sacral nerve.
The mean depth of deep needling is16.33mm and that of the shallow needle group is6.58mm. Push the needle back to the sacrum with a cotton swab to ensure the tip of the needle is near to or touch the sacral nerve. For shallow needling, stop puncture when the tip of the needle touch the sacrum.
2. Eletroacupuncture at BL32could suppress bladder hyperactivity.
Deep needling at BL32must be get near to or touch the anterior branch of the sacral nerve.
0.25%acetic acid was infused to the rat's bladder to cause irritation and after that electroacupuncture was given. Using cystometry, we found that electroacupuncture could increase the ICI, decrease the micturition time and the incidence of detrusor instability.
3. The effect of electroacupuncture for OAB is specific.
Setting shallow needling group and non point needling group (point besides BL32) as controls, we found that both the control groups were not effective for suppressing bladder hyperactivity. Data suggested that the effect of electroacupuncture at BL32was specific and needling at other points in the same nerve innervated area didn't have the same effect. The key influence factor is needling depth. Only deep needling at B132to stimulate the sacral nerve the bladder hyperactivity could be suppressed.
4. Eletroacupuncture works by suppressing C fibers.
Capsaicin pretreated rats didn't show any change in ICI, bladder pressure and micturition time after acetic acid infusion, which meant the bladder of the rat would not be irritated after C fibers were blocked. The indicators above still didn't change after electroacupuncture suggested that needling didn't have influence on C-fiber blocked rats. Those results suggested that bladder hyperactivity was caused and suppressed both through C fibers.
5. Eletroacupuncture decreased afferent nerve activity and expression of neurotransmitters.
Activity of the pelvic nerve before and during each micturition increased after acetic acid infusion, and so was the expression of SP and neruokinin B. After eletroacupuncture at BL32, both nerve activity and expression of neurotransmitters decreased, much lower than those of the model group.
Conclusion
The study detected the specific effect of eletroacupuncture and deep needling at BL32for suppressing bladder hyperactivity and the possible mechanism. The results suggested that eletroacupuncture and deep needling at BL32had specific effect for suppressing bladder hyperactivity. The possible mechanism was suppression of neurotransmitters—suppression of C-fiber activity—suppression of bladder contraction.
膀胱排尿和储尿功能受到多个神经水平介导和控制,可分为脑干和大脑皮层高位中枢,骶髓低位中枢和外周神经三个节段。控制膀胱的外周神经主要有3条：腹下神经、阴部神经和盆神经。其中,腹下神经属于交感神经,由胸腰髓交感神经中枢发出,具有支配膀胱颈部及内尿道括约肌的功能。阴部神经属于躯体神经,支配外尿道括约肌。盆神经属于副交感神经,是参与膀胱感觉和膀胱收缩最重要的神经,来自膀胱的大多数传入纤维主要是通过盆神经进入骶髓的。
组成盆神经的膀胱感觉传入神经纤维可分为有髓鞘的Aδ纤维和无髓鞘的C纤维。Aδ纤维主要存在于逼尿肌及尿道平滑肌细胞间的胶原纤维组织内,传入信号主要来自机械感受器(膀胱牵拉作用)。C纤维主要位于膀胱和尿道黏膜及黏膜下层组织内,数量占到传入神经的60%-70%,传导疼痛、温度觉和触觉,对化学性刺激很敏感,而对机械性刺激不敏感。在正常情况下,健康个体膀胱传入神经的兴奋主要由有髓鞘传入神经(A δ纤维)传导至中脑水管周围灰质区域,给脑桥排尿中枢发出膀胱充盈的信号。当脊髓损伤或膀胱受到化学刺激时,C纤维介导的感觉神经通路开始发挥作用,表现出自发放电活性,且随膀胱压力上升而表现出活性增加,引起预防机制性排尿反射增强并使膀胱容量减低,以便排出刺激物或细菌,于此同时,患者会产生尿意,出现尿频、尿急等下尿路刺激症状。目前国际上普遍认为膀胱过度活动(overactive bladder, OAB)的神经病理机制主要在于传入性C神经纤维活动过度。这一理论可通过施加辣椒素得到证实,辣椒素对几种特定的初级感觉神经元具有选择性神经毒性,对初级C型传入神经纤维可产生长期持久的抑制作用,通过耗尽C传入神经纤维中的P物质抑制膀胱感觉传导,使逼尿肌不能正常收缩,达到抑制排尿的目的。有研究发现,膀胱灌注辣椒素可有效治疗膀胱高反应性。
膀胱过度活动症是指无明确原因导致的膀胱储尿功能障碍,以尿频、尿急和急迫性尿失禁为特征的症候群。国际尿控协会将膀胱过度活动症定义为：无任何潜在病理原因导致的尿急,伴或不伴有急迫性尿失禁,常伴有尿频和夜尿。OAB虽不危及生命,但与人们生活息息相关,不但有损患者的生理和精神健康,且影响人们的日常活动和生活质量。目前,针对膀胱活动过度的治疗方法有行为治疗、药物治疗、神经调节疗法和手术治疗等。药物的副作用和低选择性对其临床使用有一定限制,周树脂毒和辣椒素治疗过度活动膀具有一定疗效,与行为治疗类似,目前常作为临床辅助治疗使用,手术治疗通常作为患者最后的选择方式,但手术创伤和和近期远期并发症使人们饱受困扰。神经调节疗法是近年兴起的一种疗法,植入性骶神经电刺激与针灸中电针八骼穴起效作用方式类似,但该操作费用昂贵,且有效性和安全性还需进一步证据支持。总之,对于OAB患者,尤其是顽固性OAB患者来说目前能够达到满意疗效的治疗方法还很有限。膀胱过度活动症是针灸的优势病种,虽然目前还没有关于针刺治疗OAB的系统评价,但现有医学证据表明针刺抑制膀胱过度活动简便、安全、有效,已发表的临床研究和实验研究多选用次髎或中骼穴进行治疗。目前,针刺抑制膀胱活动的起效途径尚不明确,近年来,有学者从神经递质角度进行机制探讨,认为针刺可抑制膀胱传入末梢SP和CGRP的释放与合成,推测针刺可能通过降低膀胱传入神经的过度兴奋,从而起到抑制膀胱活动亢进的作用。从中枢神经系统角度解释针刺起效途径的研究覆盖了大脑皮层、丘脑、脑桥排尿中枢及中枢核团等几乎控制排尿的高级中枢的各个部位,多以这些区域的放电频率为指标评价针刺的影响。以上研究结果都比较分散,且单一的指标选取只能推测出膀胱组织中神经递质含量的改变或中枢电活动的改变可能是针刺起效环节中的一环,缺乏针对膀胱感觉过敏这一主要病理机制的特异性和完整性研究。从外周神经角度进行研究的实验目前只能证明针刺通过C纤维途径起效,但具体如何起效,针刺前后膀胱功能--递质---神经电活动整体动态变化是怎样的,目前尚缺少关于针刺起效机制的完整性研究。
目的
1.明确电针深刺次髎穴对过度活动膀胱是否具有抑制效应；2.设置次髎穴浅刺组和次髎穴旁深刺组,探讨电针深刺次髎抑制膀胱过度活动的效应是否具有特异性,明确影响膀胱抑制效应的关键因素；3.从膀胱感觉神经调控角度探讨电针深刺次髎抑制膀胱过度活动与感觉传导通路的调控关系,初步阐明其特异机制。
方法
1.制备大鼠膀胱过度活动模型,采用膀胱内压测定方法反映膀胱的收缩活动,明确电针深刺次骼穴是否具有膀胱抑制效应,通过设置次髎浅刺和次髎旁部位针刺作为对照,研究深刺次髎穴是否对抑制膀胱过度活动具有特异效应；2.通过制定深刺标准,具体测量针刺深度,明确深刺次髎穴抑制膀胱过度活动的关键影响因素；3.通过提前皮下注射辣椒素破坏大鼠C传入纤维,与次髎穴深刺组和模型组对照,确定OAB发生和针刺起效途径4.采用神经电生理技术同步观察大鼠排尿时盆神经放电情况,分析膀胱压力发生变化时神经电活动情况的相应变化；5.使用免疫组化和RT-PCR方法检测大鼠膀胱中P物质和神经肽B的mRNA水平。
结果
1.深刺是必须是针尖最大限度接近或触及骶神经前支
对深刺组和浅刺组大鼠,针刺后使用记号笔在针身紧贴大鼠背部皮肤处进行标记,记录每只大鼠的针刺深度,计算平均值。深刺组针刺平均深度为16.33mm,针刺时针尖从后腹膜透出后使用棉签辅助将针退至后腹膜下,大鼠荐骨腹侧面水平,以此保证针尖穿过大鼠第一骶后孔后最大限度接近或触及第一骶神经前支。浅刺组刺透皮肤针尖接触荐骨即可,平均针刺深度为6.58mm。
2.电针深刺次骼穴可以抑制膀胱过度活动
使用乙酸灌注大鼠膀胱,造成膀胱过度活动模型,后给予深刺次髎穴加电针进行干预。通过对大鼠造模和电针前后进行膀胱压力测定,我们发现电针深刺次髎穴可以显著延长OAB大鼠排尿时间间隔(造模后为120.48±63.58s,电针后为156.64±58.94s)、缩短单次排尿时间(造模后为3.46±0.61s,电针后为2.34±0.83s),减小逼尿肌不稳定发生率。
3.电针次髎穴抑制膀胱过度活动具有特异效应
设置次骼穴浅刺组和次髎旁部位电针组,我们发现相同穴位浅刺加电针或次髎穴旁部位深刺加电针均不能产生膀胱抑制效应,排尿时间间隔及排尿时间均无明显改变,且逼尿肌不稳定发生率高(深刺组16.7%,浅刺组为100%,次髎旁组为83.3%)。说明这种抑制膀胱过度活动的特异效应只局限于次髎穴,电针刺激相同神经节段分布区域不能产生同等效果。且这种特异效应与次髎穴针刺深度有关,次谬穴浅剌不能发生作用,只有深刺次髎,直接对骶神经前支进行电针刺激才能产生膀胱抑制效应。
4.C纤维是电针抑制膀胱过度活动的起效途径
辣椒素组大鼠提前皮下注射辣椒素后,给予乙酸灌注膀胱时,排尿时间间隔、膀胱最大压和排尿持续时间等指标无任何变化,均与最初基线时一致,说明C纤维破坏后的大鼠不会因乙酸刺激造成膀胱过度活动模型。接着给予次髎穴电针刺激后,上述指标亦无明显变化,说明阻断C纤维后电针次髎穴的膀胱抑制效应消失。由此可证明,膀胱过度活动模型的生成及电针抑制膀胱活动的起效途径均是通过传入性C纤维。
5.电针深刺次髎穴可降低OAB大鼠盆神经放电次数和神经内递质表达
与正常组大鼠相比,乙酸灌注后,大鼠排尿前和排尿期间盆神经放电均增加,后期膀胱组织免疫组化和PCR结果提示乙酸灌注后大鼠膀胱中P物质和神经肽BmRNA表达增加,显著多于正常组。电针深刺次髎穴后,排尿前和排尿期间盆神经放电频率均显著降低。后期膀胱组织免疫组化和PCR结果提示电针后大鼠膀胱中P物质和神经肽BmRNA表达有所降低,与模型组有差别。且膀胱压力相关指标、盆神经放电与膀胱内P物质等递质表达水平的变化一致。
结论
本研究探讨了电针深刺次髎穴抑制膀胱过度活动的特异效应及其可能的起效机制。实验表明,电针深刺次髎穴可以抑制膀胱过度活动,且对膀胱活动的抑制具有特异效应。针刺通过C传入纤维起效,可能起效机制为“抑制P物质等神经递质的释放—抑制C传入纤维活动—抑制膀胱收缩”。
Background
Function of the bladder is controlled by perch center (located in brain stem and cerebral cortex), sacral spinal cord and peripheral nerve. There are mainly three nerves controlling the bladder—the hypogastric nerve, the pudendal nerve and the pelvic nerve. The hypogastric nerve is the sympathetic nerve. Hypogastric nerve activation in the thoracic10-lumbar2(T10-L2) spinal cord level and could contract the internal smooth muscle sphincter and relax the bladder. The somatic pudendal nerve arises from the nucleus in S2-S4level and controls the rhabdosphincter. The pelvic nerve is parasympathetic nerve. It is the most important nerve sending impulses and regulating emptying of the bladder. The impulses travel in the pelvic nerve and goes into the sacral spinal cord.
The bladder afferent pathways are composed of two types of axons:myelinated A8fibers and unmyelinated C fibers. Located in detrusor and urethral smooth muscle, A8fibers transmit signal mainly from mechanoreceptors that detect bladder fullness or wall tension. C fibers could be found in mucosa and submucosal areas and transmit noxious signals and initiate painful sensations. They account for60%～70%in all afferent fibers and are insensitive to mechanical stimulation. Under normal conditions, A8fibers transmit signal from the bladder to the pontine micturition center. The bladder C-fiber nociceptors perform a similar function and signal the central nervous system when people have spinal cord injury or irritative condition in the bladder, which could be viewed as a defense mechanism to eliminate irritants of bacteria. At the same time, patients will have lower urinary tract symptoms like micturition and urgency. Now it is considered that the neuropathological mechanism of OAB is hyperactivity of C fibers. This could be confirmed by capsaicin. Capsaicin could suppress bladder contraction by depleting SP. Research found that capsaicin could be used for bladder hyperactivity.
Overactive bladder (OAB) is a storage dysfunction with no obvious reasons, and it is defined by set of symptoms:urgency, with of without urge incontinence, usually with frequency and nocturia. To date, there are no satisfactory therapies for OAB patients, especially for refractory OAB patients. Acupuncture could manage this disease well. Though there is not systematic review about acupuncture for OAB, available medical evidence shows that acupuncture is easy to operate, safe and effective. BL32is an acupoint used often in treatment. Though the effectiveness, how acupuncture can treat the disease is still not known. Some scholars try to explain the mechanism with neurotransmitters. They found that acupuncture could reduce substance P (SP) in the afferent fibers, and they speculated that acupuncture could suppress the hyperactivity of afferent fibers and suppress the bladder activity correspondingly. Some studies try to explain the mechanism from the viewpoint of central nervous system (CNS) and evaluate the effect of acupuncture according to neuron activities of various areas in CNS. Adoption of single indicator in those studies could only make sure that neurotransmitter or neuron activity is a point in the mechanism link, and the whole mechanism is still not clear. In recent years, studies focusing on peripheral nerve concluded that acupuncture suppress bladder hyperactivity through C fibers. But how it works through C fibers and the systematic change of bladder function, neurotransmitter and nerve activity are still not clear.
Objective
1. To detect whether deep needling at BL32is effective for OAB;2. Set shallow needling group and non point needling group (point
besides BL32) as controls to detect whether the effect of electroacupuncture at BL32is specific and the key influence factors;
3. Try to discuss the relation between acupuncture's effect and afferent pathway and elucidate the possible mechanism.
Methods
1. To detect acupuncture's effect on bladder hyperactivity using cystometry in anesthetized rats. With shallow needling group and non point needling group as controls, to study whether the effect is specific;2. Make principle of deep needling at B132on rat and measure the needling depth to examine the key influence factor;3. Block the C-fiber activity by capsaicin injection to examine the pathways that acupuncture works through;4. Observe the pelvic nerve activity using technique of neurological electrophysiology and analyze the change of nerve activity corresponding to the change of bladder pressure;5. To measure the mRNA expression level of SP and neruokinin B by RT-PCR.
Results
1. For deep needling at BL32, the needle should get near to or touch the anterior branch of the sacral nerve.
The mean depth of deep needling is16.33mm and that of the shallow needle group is6.58mm. Push the needle back to the sacrum with a cotton swab to ensure the tip of the needle is near to or touch the sacral nerve. For shallow needling, stop puncture when the tip of the needle touch the sacrum.
2. Eletroacupuncture at BL32could suppress bladder hyperactivity.
Deep needling at BL32must be get near to or touch the anterior branch of the sacral nerve.
0.25%acetic acid was infused to the rat's bladder to cause irritation and after that electroacupuncture was given. Using cystometry, we found that electroacupuncture could increase the ICI, decrease the micturition time and the incidence of detrusor instability.
3. The effect of electroacupuncture for OAB is specific.
Setting shallow needling group and non point needling group (point besides BL32) as controls, we found that both the control groups were not effective for suppressing bladder hyperactivity. Data suggested that the effect of electroacupuncture at BL32was specific and needling at other points in the same nerve innervated area didn't have the same effect. The key influence factor is needling depth. Only deep needling at B132to stimulate the sacral nerve the bladder hyperactivity could be suppressed.
4. Eletroacupuncture works by suppressing C fibers.
Capsaicin pretreated rats didn't show any change in ICI, bladder pressure and micturition time after acetic acid infusion, which meant the bladder of the rat would not be irritated after C fibers were blocked. The indicators above still didn't change after electroacupuncture suggested that needling didn't have influence on C-fiber blocked rats. Those results suggested that bladder hyperactivity was caused and suppressed both through C fibers.
5. Eletroacupuncture decreased afferent nerve activity and expression of neurotransmitters.
Activity of the pelvic nerve before and during each micturition increased after acetic acid infusion, and so was the expression of SP and neruokinin B. After eletroacupuncture at BL32, both nerve activity and expression of neurotransmitters decreased, much lower than those of the model group.
Conclusion
The study detected the specific effect of eletroacupuncture and deep needling at BL32for suppressing bladder hyperactivity and the possible mechanism. The results suggested that eletroacupuncture and deep needling at BL32had specific effect for suppressing bladder hyperactivity. The possible mechanism was suppression of neurotransmitters—suppression of C-fiber activity—suppression of bladder contraction.
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