【摘要】：頸椎根性疾病相關(guān)痛(cervical radicularpathy pain,CRP)是現(xiàn)代高壓力辦公室工作帶來的越發(fā)普遍的職業(yè)性疾病,嚴(yán)重影響人們生活質(zhì)量并且具有自發(fā)性加重的特點(diǎn)。與腰背痛相比,CRP患者并無承重障礙的癥狀,而97.5%患者是以慢性疼痛原因就診,包括長(zhǎng)期自發(fā)性疼痛、肢體放散性疼痛,以及轉(zhuǎn)動(dòng)壓迫頸椎椎骨關(guān)節(jié)引起的“閃電樣”劇痛。由于動(dòng)物頸椎椎骨關(guān)節(jié)解剖位置深,頸部神經(jīng)叢交叉和分支多,動(dòng)物頸椎部位手術(shù)難度大,一直缺乏模擬頸部病變的動(dòng)物模型,CRP動(dòng)物痛覺行為學(xué)難以觀察。目前對(duì)于頸部外周神經(jīng)病理性痛的發(fā)生發(fā)展機(jī)制尚不清楚。我們研究室前期建立腰背神經(jīng)病理性痛大鼠模型,在體研究發(fā)現(xiàn)在此模型上外周損傷背根神經(jīng)節(jié)(dorsol root ganglion,DRG)產(chǎn)生異常自發(fā)放電(spontaneous activity,SA)。在生理狀態(tài)下DRG神經(jīng)元少見,相反在慢性痛條件下DRG神經(jīng)元呈現(xiàn)出大量異位SA。研究表明在單纖維記錄實(shí)驗(yàn)中,表達(dá)與外周神經(jīng)系統(tǒng)SA的纖維的傳導(dǎo)速度多為A類有髓纖維,而極少有C類無髓纖維參與介導(dǎo)CCD模型中SA。DRG離體研究表明,損傷DRG神經(jīng)元SA起源可能依賴于神經(jīng)元的閾下膜電位振蕩(subthreshold membrane potential oscillation,SMPO),而具有SMPO神經(jīng)元往往伴隨胞膜上離子通道激活及失活的改變表現(xiàn)出細(xì)胞膜內(nèi)在性質(zhì)的變化。因此,在病理性痛模型中初級(jí)感覺DRG神經(jīng)元常常表現(xiàn)出異常細(xì)胞膜特性。興奮的外周神經(jīng)向脊髓痛覺感受區(qū)傳遞大量增加的痛覺傳入將引起脊髓第一級(jí)突觸的可塑性改變,形態(tài)學(xué)研究表明,在慢性痛條件下DRG神經(jīng)元敏化伴隨外周神經(jīng)系統(tǒng)和脊髓背角神經(jīng)終末上一系列激活基因表達(dá)的變化。但是對(duì)于CRP情況下DRG神經(jīng)元如何發(fā)生改變及其機(jī)制尚不甚明了。以往研究表明,DRG神經(jīng)元機(jī)械感覺功能參與機(jī)械痛敏。但是DRG感覺神經(jīng)元有不同亞型神經(jīng)元組成,承擔(dān)不同感覺功能。機(jī)械敏感的神經(jīng)元較不敏感神經(jīng)元更易被機(jī)械性刺激造成損傷。但是目前缺乏針對(duì)疼痛模型特異DRG神經(jīng)元的分類觀察,外周慢性痛機(jī)制中各細(xì)胞和分子靶點(diǎn)也不明確。在本課題第一部分中,我們研究結(jié)果如下:(1)建立模擬臨床CRP癥狀的大鼠模型,明確CRP模型大鼠痛行為學(xué)特征;(2)CRP大鼠模型DRG感覺神經(jīng)元進(jìn)行各亞型分類的電生理指標(biāo)研究,找出CRP相關(guān)的重要細(xì)胞和分子靶點(diǎn)。首先,我們?cè)诖笫箢i椎C7/C8椎間孔,通過插入“L型”鋼柱的手術(shù),形成DRG穩(wěn)定的慢性壓迫損傷,模擬椎間盤疝出或椎骨關(guān)節(jié)狹窄的病理學(xué)特點(diǎn)。結(jié)果表明,CRP模型組動(dòng)物較假手術(shù)組在術(shù)后1天就出現(xiàn)了雙側(cè)前足縮足痛閾明顯下降。在術(shù)后4天達(dá)到最大值,并一直持續(xù)到手術(shù)后四周。接著我們觀察了CRP模型動(dòng)物表現(xiàn)的熱痛敏,通過使用熱光源對(duì)動(dòng)物雙側(cè)前足足底皮膚造成傷害性熱刺激。結(jié)果表明CRP模型動(dòng)物在術(shù)后第3天出現(xiàn)上肢痛覺潛伏期明顯縮短,但較溫和。熱痛縮足潛伏期的縮短可以持續(xù)到術(shù)后4周。同時(shí),我們觀察CRP動(dòng)物的自發(fā)痛行為。自發(fā)痛行為測(cè)定為在一分鐘內(nèi)動(dòng)物表現(xiàn)對(duì)患側(cè)上肢體抓咬舔時(shí)間。CRP模型動(dòng)物在術(shù)后1天就表現(xiàn)出較假手術(shù)組動(dòng)物明顯增加的患側(cè)肢體的自發(fā)痛行為。在一周內(nèi)達(dá)到最大值,在術(shù)后兩周后自發(fā)痛行為時(shí)間緩慢下降。免疫組織化學(xué)結(jié)果表明,在CRP模型術(shù)后12小時(shí)C7和C8壓迫側(cè)DRG上表達(dá)c-Fos蛋白的神經(jīng)元比例明顯增加,在術(shù)后24小時(shí)達(dá)到最大值,在48小時(shí)后依然有明顯區(qū)別。而在脊髓背角淺層,在DRG損傷12小時(shí)后,表達(dá)c-Fos蛋白的脊髓神經(jīng)元也大量增加,在CRP模型術(shù)后24小時(shí)達(dá)到最大值,在48小時(shí)組仍然與假手術(shù)組有明顯差異。研究提示,脊髓痛覺感覺神經(jīng)元c-Fos蛋白表達(dá)的升高與DRG神經(jīng)元的變化趨勢(shì)一致。為了重復(fù)驗(yàn)證c-Fos蛋白的結(jié)果,我們觀察CRP模型動(dòng)物在5術(shù)后24小時(shí)后DRG和脊髓神經(jīng)元磷酸化胞外信號(hào)相關(guān)激酶(Extracellular signal-related kinase,ERK)的表達(dá)。結(jié)果表明,在術(shù)后24小時(shí),p ERK1/2在患側(cè)DRG和脊髓神經(jīng)元的表達(dá)都較假手術(shù)組明顯升高。結(jié)果表明在CRP大鼠模型上,損傷DRG神經(jīng)元早期激活,感覺神經(jīng)元異常興奮,向中樞神經(jīng)系統(tǒng)痛覺感覺區(qū)傳入增加引起脊髓背角感覺神經(jīng)元興奮,痛覺傳導(dǎo)通路激活。DRG神經(jīng)元分成Aβ大神經(jīng)元,IB4~-Aδ小神經(jīng)元、IB4~-和 IB4~+C類神經(jīng)元。IB4~-Aδ小神經(jīng)元明顯較其他DRG小神經(jīng)元更加興奮。并且被認(rèn)為介導(dǎo)自發(fā)痛行為的異常SA高度表達(dá)在IB4~-Aδ小神經(jīng)元,而在CRP模型組的C-神經(jīng)元沒有出現(xiàn)任何自發(fā)電活動(dòng)。IB4~-Aδ小神經(jīng)元的SA與動(dòng)作電位幅度一致,并且在記錄中可以穩(wěn)定持續(xù)發(fā)放兩小時(shí)以上。結(jié)果提示CRP模型IB4~-Aδ小神經(jīng)元表現(xiàn)明顯SA。以往研究認(rèn)為,IB4~-AδDRG神經(jīng)元以其特殊的細(xì)胞膜柔韌機(jī)械特性介導(dǎo)外周的機(jī)械性觸覺。在本課題的第二部分中,我們研究發(fā)現(xiàn):(1)在CRP模型中IB4~-Aδ神經(jīng)元的機(jī)械敏感特性;(2)介導(dǎo)DRG神經(jīng)元機(jī)械敏感特性的離子通道機(jī)制;(3)CRP模型機(jī)械性痛覺過敏的外周鎮(zhèn)痛靶點(diǎn)。我們使用微操作器在全細(xì)胞鉗制的DRG的IB4~-AδDRG神經(jīng)元胞體表面直接給予機(jī)械壓力刺激(mechanical stimuli,MS),刺激強(qiáng)度控制在不對(duì)細(xì)胞膜造成任何傷害。結(jié)果表明,對(duì)照組觀察到MS后出現(xiàn)的神經(jīng)元放電。而在CRP組同樣的MS刺激引起超高頻的神經(jīng)元放電活動(dòng),高頻MS放電頻率較SA頻率升高10倍。IB4~-DRG神經(jīng)元在刺激后仍可以維持長(zhǎng)時(shí)間的高頻放電水平。離子通道機(jī)制研究表明,在CRP模型組IB4~-Aδ神經(jīng)元超極化激活的環(huán)核苷酸門控(hyperpolarization-activated cyclic nucleotide-gated,HCN)通道表達(dá)的Ih電流密度明顯增加,這可能是CRP模型動(dòng)物發(fā)生疼痛行為學(xué)改變和DRG、脊髓出現(xiàn)形態(tài)學(xué)改變的機(jī)制。CRP模型并未改變IB4~-的Aδ神經(jīng)元的Ih電流反轉(zhuǎn)電位。HCN通道蛋白和IB4雙標(biāo)熒光結(jié)果驗(yàn)證,HCN1和HCN3亞型在CRP模型后在IB4~-DRG神經(jīng)元中表達(dá)升高,而HCN2亞型沒有明顯改變。HCN通道的特異性阻斷劑ZD7288可以阻斷CRP模型組IB4~-Aδ神經(jīng)元包括SA、MS引起的高頻放電的超興奮性電活動(dòng),而對(duì)正常動(dòng)作電位產(chǎn)生無影響。鞘內(nèi)注射ZD7288組較生理鹽水組反轉(zhuǎn)了70%CRP模型引起的動(dòng)物反射性縮足閾值的下降。而在熱痛檢測(cè)中ZD7288未見有明顯改善熱痛縮足潛伏期的效果。在自發(fā)痛行為檢測(cè)中,ZD7288組較生理鹽水組明顯減少CRP模型動(dòng)物的自發(fā)疼痛行為,單次給藥鎮(zhèn)痛作用超過12小時(shí)。上述結(jié)果表明,IB4~-Aδ神經(jīng)元上HCN1和HCN3亞型高表達(dá)是CRP介導(dǎo)神經(jīng)元超興奮性改變的離子通道基礎(chǔ)。ZD7288抑制CRP DRG神經(jīng)元超興奮性而不影響正常感覺神經(jīng)元生理功能,為CRP治療提供新的策略。
[Abstract]:Cervical radicularpathy pain (CRP) is the more common occupational disease caused by the work of modern high pressure office, which seriously affects people's quality of life and has the characteristic of spontaneous aggravation. Compared with back pain, CRP patients have no symptoms of hindrance, and 97.5% patients are due to chronic pain. Diagnosis, including long term spontaneous pain, limb disspread pain, and "lightning like" pain caused by rotation and compression of the cervical vertebra and joints. Because of the deep anatomical position of the cervical vertebra, the cervical plexus intersecting and branching, the operation of the cervical vertebra is difficult, the animal model of the cervical vertebra is lacking, and the CRP animal is painful. It is difficult to observe. The current mechanism of the occurrence and development of neuropathic pain in the peripheral neck is not clear. We established the model of lumbar back neuropathic pain in the early stage of our laboratory. In the body study, the abnormal spontaneous discharge (spontaneous activity, SA) produced by the Dorsol root ganglion (DRG) in this model was found in this model. DRG neurons in the physiological state are rare, and on the contrary, a large number of heterotopic SA. studies in DRG neurons under chronic pain conditions show that in the single fiber recording experiment, the conduction velocity of the fibers expressed in the peripheral nervous system SA is more than that of the a-kind of myelinated fibers, but few C like unmyelinated fibers participate in the CCD model in the CCD model, which indicates that the injured DRG is damaged. The origin of neuron SA may depend on the subthreshold membrane potential oscillation (subthreshold membrane potential oscillation, SMPO) of neurons, while the changes in the activation and inactivation of the ionic channels on the membrane of the cell often accompany the changes in the intrinsic properties of the membrane of the cell membrane. Therefore, the primary sensory DRG neurons in the pathological pain model are often expressed in the pathological pain model. The excitability of the peripheral nerve transmitted to the sensory region of the spinal cord caused by a large number of increased pain afferents will cause the plasticity of the first stage synapses in the spinal cord. Morphological studies suggest that DRG neurons sensitized to the peripheral nervous system and the dorsal horn nerve terminals of the spinal cord are associated with a series of activation genes under chronic pain conditions. But it is not clear how the DRG neuron changes and its mechanism in the case of CRP. Previous studies have shown that the mechanical sensory function of DRG neurons is involved in mechanical pain sensitivity. But the DRG sensory neurons have different subtypes of neurons and bear different sensory functions. The neurons of mechanical sensitization are more likely to be machine than the insensitive neurons. There is a lack of classified observation on the specific DRG neurons in the pain model, and the various cell and molecular targets in the peripheral chronic pain mechanism are not clear. In the first part of this subject, our results are as follows: (1) to establish the rat model of the simulated clinical CRP symptoms and to identify the behavioral characteristics of the CRP model rats; (2) C RP rat model DRG sensory neurons are used to study the electrophysiological indexes of the subtypes of the subtypes to identify the important cells and molecular targets related to CRP. First, we set up a "L" type of steel column by inserting a "L" steel column in the rat's cervical vertebra C7/C8, to form a stable chronic compression injury of DRG, and to simulate the pathological characteristics of the herniation of intervertebral disc or the stenosis of the vertebral joint. The results showed that the CRP model group had a significant decrease in the pain threshold of bilateral forefoot contraction at 1 days after the operation than the sham operation group. It reached the maximum at the 4 day after the operation and continued to the four weeks after the operation. Then we observed the thermal pain sensitivity of the CRP model animal, and caused the injury by using the hot light source to the bilateral plantar skin of the bilateral forefoot. Heat stimulation. The results showed that the latent period of the upper limb pain in the CRP model animals shortened obviously on the third day after the operation, but it was mild. The shortening of the latent period of the heat pain contraction could last to 4 weeks after the operation. At the same time, we observed the spontaneous pain behavior of the CRP animals. The spontaneous pain behavior was measured in one minute to the affected side of the extremities,.CRP The model animals showed a significant increase in the spontaneous pain of the affected side limbs in the 1 day after the operation. The maximum value was reached within one week, and the time of self pain decreased slowly after two weeks after the operation. The immunohistochemical results showed that the proportion of neurons of the c-Fos protein was expressed on the C7 and C8 pressure side DRG 12 hours after the CRP model operation. A significant increase was achieved at 24 hours after the operation, and there was a significant difference after 48 hours. In the shallow layer of the dorsal horn of the spinal cord, the spinal neurons expressing c-Fos protein increased significantly after 12 hours of DRG injury and reached the maximum at 24 hours after the CRP model, and there was still a significant difference between the 48 hour group and the sham operation group. The expression of c-Fos protein in sensory neurons was in accordance with the change trend of DRG neurons. In order to repeat the results of c-Fos protein, we observed the expression of phosphorylated extracellular signal related kinase (Extracellular signal-related kinase, ERK) in DRG and spinal neurons in CRP model animals after 24 hours after 5. The results showed that 24 after the operation. The expression of P ERK1/2 in the affected DRG and spinal cord neurons in the affected side was significantly higher than that in the sham operation group. The results showed that on the CRP rat model, the early activation of the DRG neurons, the abnormal excitement of the sensory neurons, the increase of the afferent area of the central nervous system to the pain sensation area of the central nervous system caused the excitation of the sensory neurons of the dorsal horn of the spinal cord and the activation of the.DRG God in the pain conduction pathway. It was divided into A beta neurons, IB4~-A delta neurons, IB4~- and IB4~+C neuron.IB4~-A delta neurons more excited than other DRG neurons, and the abnormal SA was highly expressed in IB4~-A Delta small neurons, while the C- God Jing Yuan in the CRP model group did not appear any self generating activity.IB4~-A Delta in the CRP model group. The SA of the small neurons is consistent with the action potential amplitude and can be steadily continued for more than two hours in the record. The results suggest that the CRP model IB4~-A delta neurons exhibit a significant SA. previous study that the IB4~-A Delta DRG neuron mediated the peripheral mechanical touch with its special cellular membrane flexibility mechanical properties. We have found that: (1) the mechanical sensitivity of IB4~-A delta neurons in the CRP model; (2) the mechanism of ion channel that mediates the mechanical sensitivity of DRG neurons; (3) the peripheral pain target of the CRP model of mechanical hyperalgesia. We use the micromanipulator to direct the machine directly to the surface of the cell body surface of the DRG IB4~-A Delta DRG neuron of the whole cell forceps. Stress stimulation (mechanical stimuli, MS), the stimulation intensity control does not cause any damage to the cell membrane. The result shows that the control group observed the neuronal discharge after MS. In the CRP group, the same MS stimulation causes the ultrahigh frequency neuron discharge, and the high-frequency MS discharge frequency is 10 times higher than the SA frequency, and the neuron can still be stimulated after the stimulation. In order to maintain a long time high frequency discharge level, the ion channel mechanism studies showed that the Ih current density in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel expressed in the CRP model group of IB4~-A delta neurons was significantly increased, which could be a painful behavioral change and DRG in CRP model animals. The mechanism.CRP model of the morphological changes in the spinal cord did not change the Ih current reversal potential.HCN channel protein and the IB4 double standard fluorescence results of the IB4~- A delta neurons. The HCN1 and HCN3 subtypes increased in IB4~-DRG neurons after the CRP model, while the HCN2 subtype did not significantly alter the specific blocker of the.HCN channel. The model group IB4~-A delta neurons include the hyperexcitability electrical activity of high frequency discharge caused by SA and MS, but no effect on the normal action potential. The intrathecal injection of ZD7288 group and the saline group reverses the decrease of the reflex threshold of the animals caused by the 70%CRP model. In the heat pain detection, there is no obvious improvement in the incubation period of the heat pain. In the test of self pain, the ZD7288 group significantly reduced the spontaneous pain behavior of the CRP model animal compared with the saline group, and the analgesic effect of the single dose was more than 12 hours. The results showed that the high expression of HCN1 and HCN3 subtypes on the IB4~-A delta neurons was the ionic channel basis of CRP mediated neuronal hyper excitability and the inhibition of CRP DRG by.ZD7288. Neurons are excitable without affecting the physiological functions of normal sensory neurons, and provide a new strategy for the treatment of CRP.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R681.5;R-332

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