ERK与NO信号通路在神经病理性疼痛模型大鼠脊髓背角内痛觉信号传递中的交互作用

发布时间：2018-04-05 23:21

  本文选题：胞外信号调节激酶　切入点：一氧化氮　出处：《吉林大学》2011年博士论文

【摘要】：疼痛,尤其是神经病理性疼痛外周与中枢神经元可塑性变化是导致其发展为慢性持续状态的关键,脊髓背角神经元在持续刺激后所发生的可塑性变化成为近来研究的热点。细胞外信号调节激酶(extracellular signal- regulate kinase, ERK)是MAPK家族中的一员,介导多种信号的胞内转导,在不同的疼痛模型(辣椒素或完全弗氏佐剂致炎,内脏痛,电刺激等)中发现磷酸化ERK表达增加,用其上游激酶MEK的阻滞剂能减轻模型大鼠的痛敏表现,预示其活性的变化与伤害性刺激的传递及神经敏感化有关。NO是细胞内重要的信使分子和神经递质,它对炎性疼痛的发展和维持起到了重要作用。 目的:观察在CCD导致大鼠神经痛模型中应用MEK阻滞剂U0126及NOS阻滞剂对大鼠痛行为的影响和ERK活性及NOS变化,并探讨ERK与NO信号通路在CCD导致的神经病理性疼痛模型大鼠脊髓背角内痛觉信号传递中的交互作用。 材料与方法:采用吉林大学实验动物中心提供的200-250gwistar大鼠进行实验研究。鞘内置管和鞘内给药参照Yaksh和Rudy方法进行。CCD动物模型参照song方法建立。分别用热痛刺激仪和斜板实验测定大鼠的热痛阈值与运动功能的变化。pERK阳性神经元表达采用免疫组化方法进行观察,脊髓背角内pERK1与pERK2水平测定采用免疫印迹方法,脊髓背角内nNOS及iNOS免疫阳性神经元采用免疫荧光染色方法和免疫印迹方法进行观察。 实验1方法, 122只大鼠随机分成三部分,32只用于大鼠行为学检测,随机分为假手术组、CCD组、U0126组和DMSO组,每组8只,其余90只大鼠用于假手术组、CCD组、U0126组模型制作后5天、10天、15天免疫组化染色、细胞计数及免疫印迹、蛋白定量分析。在制备CCD模型前一天和CCD后连续三天鞘内注射U01265μg/10μl,DMSO组注入等容量DMSO作为对照,分别在脊髓背根神经节慢性压迫前连续测定热痛阈3天,3天的平均值为大鼠基础值,然后从压迫后第一天起隔天测定至第15天的热痛阈和运动功能的变化。分别于模型制作后5、10、15天取大鼠L4-5脊髓节段进行免疫组化染色和免疫印迹检测。 实验2方法,分假手术组、CCD组及按鞘内注射药物不同分为L-NAME组、AG组、7-NI组、8-Br-cGMP组, 180只大鼠随机分为两部分,48只用于行为学检测,另132只用于免疫荧光染色、细胞计数及免疫印迹检测。热痛阈和运动功能的检测同方法1,分别于CCD后5、10、15天取大鼠L4-5脊髓节段进行免疫荧光染色和CCD后第五天免疫印迹检测。 实验3方法,108只大鼠随机分为两部分,48只用于行为学检测,在CCD模型制备5天后按鞘内给药不同随机分为L-NAME组、AG组、8-Br-cGMP组、7-NI组、PBS组、Cremophor组6组;另外60只大鼠用于假手术组、CCD组及按鞘内注射药物不同分为L-NAME组、AG组、8-Br-cGMP组和7-NI组,在鞘内注射后2小时后取材进行免疫组化染色阳性神经元计数及免疫印迹分析。 实验4方法, 84只大鼠随机分成两部分,一部分用于行为学检测,共24只,随机分成3组,U0126组、MDSO组和模型对照组,每组8只。另一部分用于免疫荧光染色和免疫印迹分析,共60只,随机分成6个亚组,假手术组、模型对照组、U0126注射后0.5h、2h、12h、24h组,每组10只,其中6只用于免疫荧光染色,4只用于免疫印迹分析。 结果1,正常大鼠(CCD模型制作前)鞘内注射U0126与DMSO未见痛阈明显变化,CCD组大鼠于神经压迫后1天出现痛觉过敏,至5天达到高峰并在观察时间内维持稳定,预先鞘内注射U0126能明显减轻CCD所至的痛觉过敏。鞘内注射U0126和MDSO未影响大鼠运动功能。CCD引起同侧脊髓背角内pERK阳性神经元数量明显增加,预先鞘内注射U0126能明显抑制CCD引起的pERK阳性神经元表达。免疫印迹显示CCD大鼠脊髓背角内pERK1与pERK2水平明显增加,鞘内注射U0126能明显抑制CCD引起的pERK水平的增高。 结果2,假手术组术前和术后大鼠缩足潜伏期无明显变化,CCD术后第一天开始缩足潜伏期明显缩短,与CCD组相比较7-NI组术后第一天至第十一天缩足潜伏期明显延长, L-NAME组术后第一天至第七天缩足潜伏期明显延长,AG组术后第一天至第五天明显延长,8-Br-cGMP术后第一天缩足潜伏期明显缩短,第三天开始无明显差异。鞘内注射NOS抑制剂或激动剂对大鼠运动功能未见明显影响。 术后第五天假手术组损伤侧脊髓背角内nNOS及iNOS免疫阳性神经元很少,慢性压迫性损伤导致nNOS及iNOS免疫阳性神经元明显增加,与CCD组相比L-NAME组、AG组、7-NI组损伤侧脊髓背角内免疫反应阳性细胞数明显减少。免疫印迹结果显示与假手术相比CCD导致大鼠脊髓背角神经内nNOS及iNOS水平明显增加,鞘内注射非选择性nNOS抑制剂L-NAME和选择性nNOS抑制剂7-NI能够明显抑制CCD大鼠脊髓背角内nNOS的表达,而选择性iNOS抑制剂对nNOS表达未见明显影响。同样鞘内应用非选择性iNOS抑制剂L-NAME和选择性抑制剂AG能明显抑制iNOS的表达,而选择性nNOS抑制剂对iNOS的表达没有影响。8-Br-cGMP能增加CCD大鼠脊髓背角内nNOS和iNOS的表达。 结果3,在术后第5天所有进入实验的模型大鼠术侧后肢均产生明显痛敏。与鞘内注射前相比,PBS组和Cremophor组注射后各时间点大鼠痛行为未见明显变化;与PBS组相比,L-NAME组、AG组和7-NI组注射后12、24h大鼠术侧热缩足潜伏期无明显变化,L-NAME组、AG组和7-NI组注射后30min,2h和6h大鼠术侧热缩足潜伏期明显延长;与PBS组相比,8-Br-cGMP组注射后30min和2h大鼠术侧热缩足潜伏期明显缩短。 免疫组化结果显示CCD第5天大鼠术侧脊髓背角内pERK免疫反应阳性神经元明显增多,L-NAME组、AG组和7-NI组于鞘内注射2h时术侧脊髓背角内pERK免疫反应阳性神经元数量明显减少,8-Br-cGMP组术侧脊髓背角内pERK免疫反应阳性神经元数量增加。免疫印迹显示CCD导致大鼠脊髓背角神经元内pERK水平明显增加,与CCD组和8-Br-cGMP组相比L-NAME组、AG组、7-NI组背角神经元内pERK含量明显减少。 结果4 ,术后第五天,假手术组大鼠损伤侧脊髓背角内nNOS免疫阳性神经元很少,慢性压迫性损伤导致nNOS免疫阳性神经元明显增加。与假手术组相比,模型对照组损伤侧脊髓背角内神经型一氧化氮合酶免疫反应阳性细胞数明显增多;与模型对照组相比,U0126注射后0.5,2和12h组损伤侧脊髓背角内神经型一氧化氮合酶免疫反应阳性细胞数明显减少,U0126注射后24h组损伤侧脊髓背角内神经型一氧化氮合酶免疫反应阳性细胞数没有明显变化。免疫印迹结果显示慢性压迫性损伤导致脊髓背角内nNOS表达水平增加,与假手术组相比,模型对照组,U0126注射后12h组以及U0126注射后24h组损伤侧脊髓背角内神经型一氧化氮合酶表达水平明显增加;与模型对照组相比,U0126注射后0.5,2和12h组损伤侧脊髓背角内神经型一氧化氮合酶表达水平明显降低,而U0126注射后24h组损伤侧脊髓背角内神经型一氧化氮合酶表达水平未见明显变化。 结论 1、CCD可明显增加损伤侧脊髓背角浅层pERK、NOS阳性神经元表达。 2、鞘内注射ERK信号传导通路阻滞剂U0126及NOS抑制剂在减轻大鼠痛行为的同时,能明显抑制损伤侧脊髓背角内pERK1/2和NOS的表达。 3、大鼠痛行为及脊髓背角pERK及nNOS和iNOS的表达在时程上相一致。 4、在脊髓水平痛觉信号的调制中,脊髓背角神经元胞内ERK信号通路活性的变化能够影响脊髓背角内神经型一氧化氮合酶表达,胞外信号调节激酶参与介导了一氧化氮在神经病理性疼痛中的作用。
[Abstract]:Pain, especially neuropathic pain peripheral and central neuronal plasticity is the key to the development of chronic persistent state, the plasticity of spinal dorsal horn neurons in continuous stimulation has become a research hotspot. The extracellular signal regulated kinase (extracellular signal- regulate kinase, ERK) is a member of the MAPK family the mediating a variety of signal transduction, in various pain models (capsaicin or complete Freund's adjuvant induced arthritis, visceral pain, electrical stimulation) found that phosphorylation of ERK increased expression of pain sensitive performance of its upstream kinase MEK inhibitor can reduce the rat model, and indicate that the change of activity with the transfer of nociceptive stimulation and nerve sensitization of.NO cells is an important messenger and neurotransmitter, it to the development of inflammatory pain and maintenance plays an important role.
Objective: To observe the changes and the activity of ERK and NOS in application of MEK inhibitor U0126 and NOS blockers on pain behavior in a rat model of neuropathic pain rats model in CCD, and to investigate the interaction between ERK and NO signaling pathway in CCD induced neuropathic pain model rats in the spinal dorsal horn nociceptive signal transmission.
Materials and methods: the 200-250gwistar rats were provided by experimental animal center of Jilin University were investigated. Intrathecal catheter and intrathecal administration according to the Yaksh and Rudy methods according to the song method to establish the animal model of.CCD rats. The thermal pain threshold were measured by thermal pain stimulation and tiltboard experiment values of.PERK and changes of motor function. The expression of neurons were observed by immunohistochemical method, the determination of pERK1 in the spinal dorsal horn and the level of pERK2 by Western blot method, nNOS in the spinal dorsal horn and iNOS immunoreactive neurons by immunofluorescence staining and immunoblotting method were observed.
In Experiment 1, 122 rats were randomly divided into three parts, 32 for the behavior of rats, were randomly divided into sham operation group, CCD group, U0126 group and DMSO group, 8 rats in each group, the remaining 90 rats in sham operation group, CCD group, U0126 group of 5 days after modeling 10 day 15 days, immunohistochemical staining, cell counting and immunoblotting, protein quantitative analysis. In the day of preparation of CCD model and CCD for three consecutive days after the intrathecal injection of U01265 g/10 L, DMSO DMSO as the control group were injected with equal volume, before 3 days of continuous determination of thermal pain threshold in chronic compression of the dorsal root ganglion the spinal cord respectively. The average of 3 days for the rat value, and then change the thermal pain threshold and motor function of the determination to fifteenth days from the first day after the pressure. Immunohistochemical staining and Western blotting in 5,10,15 days after making model from segments of rat spinal cord L4-5 respectively.
2 experimental methods, divided into sham operation group, CCD group and by intrathecal injection of different drugs were divided into L-NAME group, AG group, 7-NI group, 8-Br-cGMP group, 180 rats were randomly divided into two parts, 48 were used for behavioral testing, the other 132 were used for immunofluorescence staining, cell counting and Western blot detection detection of thermal pain threshold and motor function with the method of 1 CCD respectively in 5,10,15 days after the spinal cord segments of rat L4-5 by immunofluorescence staining and CCD after fifth days of Western blotting.
In Experiment 3, 108 rats were randomly divided into two parts, 48 were used for behavioral testing, CCD model in preparation for 5 days by intrathecal injection were randomly divided into L-NAME group, AG group, 8-Br-cGMP group, 7-NI group, PBS group, Cremophor group 6; the other 60 rats were used for false operation group, CCD group and by intrathecal injection of different drugs were divided into L-NAME group, AG group, 8-Br-cGMP group and 7-NI group, in 2 hours after intrathecal injection were examined after immunohistochemical analysis and Western blot positive neurons count.
In Experiment 4, 84 rats were randomly divided into two parts, one part is used for behavioral testing, a total of 24 rats were randomly divided into 3 groups, U0126 group, MDSO group and model group, 8 rats in each group. The other part is used for the analysis of immunofluorescence staining and Western blot, 60 rats were randomly divided into 6 subgroups group, sham operation group, model control group, U0126 after injection of 0.5h, 2h, 12h, 24h group, 10 rats in each group, of which 6 for immunofluorescence staining, 4 were used for Western blot analysis.
The results of 1 normal rats (CCD model preparation) of intrathecal injection of U0126 and DMSO showed no obvious change of pain threshold, the rats in the CCD group of nerve compression occurred 1 days after hyperalgesia, to 5 days to reach the peak and remained stable during the observation time, intrathecal injection of U0126 can significantly reduce CCD and hyperalgesia. Intrathecal injection of U0126 and MDSO did not affect the motor function of rats caused by.CCD number of ipsilateral pERK in the spinal dorsal horn neurons increased significantly, the expression of pERK by intrathecal injection of U0126 significantly inhibited CCD induced. Western blot showed that the CCD positive neurons in the spinal dorsal horn of rat pERK1 and pERK2 levels increased significantly, increased intrathecal injection of U0126 can significantly inhibit CCD induced pERK levels.
Results 2 sham operation group rats before and after surgery withdrawal latency had no obvious change after CCD first day withdrawal latency shortened obviously, compared with the CCD group, 7-NI group after the first day of the eleventh day withdrawal latency was significantly prolonged, L-NAME group after the first day of the seventh day withdrawal latency was prolonged AG, the first day of the fifth day after the operation of group 8-Br-cGMP was significantly prolonged, the first postoperative day withdrawal latency was shortened third days. No significant difference of intrathecal injection of NOS inhibitors or agonists on motor function of rats had no obvious effect.
After fifth days of sham injury group in nNOS and iNOS positive cells in spinal cord dorsal rarely lead to immune, nNOS and iNOS immunoreactive neurons increased chronic constriction injury compared with CCD group, L-NAME group, AG group, 7-NI group of spinal cord dorsal horn immunoreactive positive cells decreased. Western blot the results showed that compared with sham CCD in rat spinal cord dorsal horn in the nNOS and iNOS levels were significantly increased, intrathecal injection of non selective nNOS inhibitor L-NAME and selective nNOS inhibitor 7-NI can inhibit the growth of CCD in the spinal dorsal horn of rat and the expression of nNOS, a selective inhibitor of iNOS has no obvious effect on the expression of nNOS. The expression of the same sheath in the application of non selective iNOS inhibitor L-NAME and the selective inhibitor AG significantly inhibited iNOS, but no expression of selective nNOS inhibitor on iNOS effect of.8-Br-cGMP can increase the spinal dorsal CCD rats Expression of nNOS and iNOS in the corner.
The 3, on the fifth day after operation all entered the experimental rat model of right hindlimbs were significant hyperalgesia. Compared with before intrathecal injection, PBS group and Cremophor group after injection pain behavior of rats at each time point had no obvious change; compared with group PBS, group L-NAME, no significant changes in 12,24h rats the operation side thermal withdrawal latency in AG group and 7-NI group after injection of L-NAME group, AG group and 7-NI group after injection of 30min, 2h and 6h in rats of lateral thermal withdrawal latency was prolonged; compared with PBS group, 8-Br-cGMP group after injection of 30min and 2h in rats with lateral thermal withdrawal latency was significantly shortened.
Immunohistochemistry results showed that CCD rats fifth days postoperatively in the spinal dorsal horn of pERK immunoreactive positive neurons increased significantly, L-NAME group, AG group and 7-NI group in the intrathecal injection of 2H when the operation side of pERK in the spinal dorsal horn neurons was significantly reduced in number, number of group 8-Br-cGMP side of pERK in the spinal dorsal horn immune neurons increased. Western blot showed that the CCD level of pERK in spinal dorsal horn neurons in rats increased significantly, and CCD group and 8-Br-cGMP group compared with L-NAME group, AG group, 7-NI group of dorsal horn neurons in pERK were significantly reduced.
Results 4, fifth days after operation, the rats in the sham operation group nNOS immune positive neurons injury in spinal cord dorsal horn rarely, lead to nNOS immunoreactive neurons increased chronic constriction injury. Compared with sham operation group, model control group, spinal cord dorsal horn neuronal nitric oxide synthase immunoreactive cells increased significantly; compared with the model group, U0126 after injection of 0.5,2 and 12h group of spinal cord dorsal horn neuronal nitric oxide synthase immunoreactive cells were decreased after U0126 injection 24h group of spinal cord dorsal horn neuronal nitric oxide synthase immunoreactive cell number did not change significantly. The results of Western blot the nNOS expression in spinal dorsal horn increased levels of chronic constriction injury, compared with sham operation group, model control group, U0126 after injection of 12h group and U0126 injection group 24h after injury in spinal cord dorsal horn In the expression of neuronal nitric oxide synthase levels were significantly increased; compared with the model group, U0126 after injection of 0.5,2 and 12h group of spinal cord dorsal horn neuronal nitric oxide synthase expression level significantly decreased, and U0126 after injection of 24h group of spinal cord dorsal horn neuronal nitric oxide synthase expression level showed no obvious change.
conclusion
1, CCD could significantly increase the expression of pERK and NOS positive neurons in the superficial layer of the dorsal horn of the spinal cord of the injured side.
2, intrathecal injection of ERK signal transduction inhibitor U0126 and NOS inhibitor can alleviate the pain behavior of rats, meanwhile, it can significantly inhibit the expression of pERK1/2 and NOS in the injured spinal cord dorsal horn.
3, the expression of pERK, nNOS and iNOS in the pain behavior of the rat and the dorsal horn of the spinal cord was consistent with the time history.
4, in the modulation of pain signal at spinal cord level, the activity of ERK signaling pathway in spinal dorsal horn neurons can influence the expression of nNOS in spinal dorsal horn, and extracellular signal regulated kinase is involved in the role of nitric oxide in neuropathic pain.

【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363

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4 黄，

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