本文選題：胞外信號(hào)調(diào)節(jié)激酶　切入點(diǎn)：一氧化氮　出處：《吉林大學(xué)》2011年博士論文

【摘要】：疼痛,尤其是神經(jīng)病理性疼痛外周與中樞神經(jīng)元可塑性變化是導(dǎo)致其發(fā)展為慢性持續(xù)狀態(tài)的關(guān)鍵,脊髓背角神經(jīng)元在持續(xù)刺激后所發(fā)生的可塑性變化成為近來(lái)研究的熱點(diǎn)。細(xì)胞外信號(hào)調(diào)節(jié)激酶(extracellular signal- regulate kinase, ERK)是MAPK家族中的一員,介導(dǎo)多種信號(hào)的胞內(nèi)轉(zhuǎn)導(dǎo),在不同的疼痛模型(辣椒素或完全弗氏佐劑致炎,內(nèi)臟痛,電刺激等)中發(fā)現(xiàn)磷酸化ERK表達(dá)增加,用其上游激酶MEK的阻滯劑能減輕模型大鼠的痛敏表現(xiàn),預(yù)示其活性的變化與傷害性刺激的傳遞及神經(jīng)敏感化有關(guān)。NO是細(xì)胞內(nèi)重要的信使分子和神經(jīng)遞質(zhì),它對(duì)炎性疼痛的發(fā)展和維持起到了重要作用。 目的:觀察在CCD導(dǎo)致大鼠神經(jīng)痛模型中應(yīng)用MEK阻滯劑U0126及NOS阻滯劑對(duì)大鼠痛行為的影響和ERK活性及NOS變化,并探討ERK與NO信號(hào)通路在CCD導(dǎo)致的神經(jīng)病理性疼痛模型大鼠脊髓背角內(nèi)痛覺(jué)信號(hào)傳遞中的交互作用。 材料與方法:采用吉林大學(xué)實(shí)驗(yàn)動(dòng)物中心提供的200-250gwistar大鼠進(jìn)行實(shí)驗(yàn)研究。鞘內(nèi)置管和鞘內(nèi)給藥參照Yaksh和Rudy方法進(jìn)行。CCD動(dòng)物模型參照song方法建立。分別用熱痛刺激儀和斜板實(shí)驗(yàn)測(cè)定大鼠的熱痛閾值與運(yùn)動(dòng)功能的變化。pERK陽(yáng)性神經(jīng)元表達(dá)采用免疫組化方法進(jìn)行觀察,脊髓背角內(nèi)pERK1與pERK2水平測(cè)定采用免疫印跡方法,脊髓背角內(nèi)nNOS及iNOS免疫陽(yáng)性神經(jīng)元采用免疫熒光染色方法和免疫印跡方法進(jìn)行觀察。 實(shí)驗(yàn)1方法, 122只大鼠隨機(jī)分成三部分,32只用于大鼠行為學(xué)檢測(cè),隨機(jī)分為假手術(shù)組、CCD組、U0126組和DMSO組,每組8只,其余90只大鼠用于假手術(shù)組、CCD組、U0126組模型制作后5天、10天、15天免疫組化染色、細(xì)胞計(jì)數(shù)及免疫印跡、蛋白定量分析。在制備CCD模型前一天和CCD后連續(xù)三天鞘內(nèi)注射U01265μg/10μl,DMSO組注入等容量DMSO作為對(duì)照,分別在脊髓背根神經(jīng)節(jié)慢性壓迫前連續(xù)測(cè)定熱痛閾3天,3天的平均值為大鼠基礎(chǔ)值,然后從壓迫后第一天起隔天測(cè)定至第15天的熱痛閾和運(yùn)動(dòng)功能的變化。分別于模型制作后5、10、15天取大鼠L4-5脊髓節(jié)段進(jìn)行免疫組化染色和免疫印跡檢測(cè)。 實(shí)驗(yàn)2方法,分假手術(shù)組、CCD組及按鞘內(nèi)注射藥物不同分為L(zhǎng)-NAME組、AG組、7-NI組、8-Br-cGMP組, 180只大鼠隨機(jī)分為兩部分,48只用于行為學(xué)檢測(cè),另132只用于免疫熒光染色、細(xì)胞計(jì)數(shù)及免疫印跡檢測(cè)。熱痛閾和運(yùn)動(dòng)功能的檢測(cè)同方法1,分別于CCD后5、10、15天取大鼠L4-5脊髓節(jié)段進(jìn)行免疫熒光染色和CCD后第五天免疫印跡檢測(cè)。 實(shí)驗(yàn)3方法,108只大鼠隨機(jī)分為兩部分,48只用于行為學(xué)檢測(cè),在CCD模型制備5天后按鞘內(nèi)給藥不同隨機(jī)分為L(zhǎng)-NAME組、AG組、8-Br-cGMP組、7-NI組、PBS組、Cremophor組6組;另外60只大鼠用于假手術(shù)組、CCD組及按鞘內(nèi)注射藥物不同分為L(zhǎng)-NAME組、AG組、8-Br-cGMP組和7-NI組,在鞘內(nèi)注射后2小時(shí)后取材進(jìn)行免疫組化染色陽(yáng)性神經(jīng)元計(jì)數(shù)及免疫印跡分析。 實(shí)驗(yàn)4方法, 84只大鼠隨機(jī)分成兩部分,一部分用于行為學(xué)檢測(cè),共24只,隨機(jī)分成3組,U0126組、MDSO組和模型對(duì)照組,每組8只。另一部分用于免疫熒光染色和免疫印跡分析,共60只,隨機(jī)分成6個(gè)亞組,假手術(shù)組、模型對(duì)照組、U0126注射后0.5h、2h、12h、24h組,每組10只,其中6只用于免疫熒光染色,4只用于免疫印跡分析。 結(jié)果1,正常大鼠(CCD模型制作前)鞘內(nèi)注射U0126與DMSO未見(jiàn)痛閾明顯變化,CCD組大鼠于神經(jīng)壓迫后1天出現(xiàn)痛覺(jué)過(guò)敏,至5天達(dá)到高峰并在觀察時(shí)間內(nèi)維持穩(wěn)定,預(yù)先鞘內(nèi)注射U0126能明顯減輕CCD所至的痛覺(jué)過(guò)敏。鞘內(nèi)注射U0126和MDSO未影響大鼠運(yùn)動(dòng)功能。CCD引起同側(cè)脊髓背角內(nèi)pERK陽(yáng)性神經(jīng)元數(shù)量明顯增加,預(yù)先鞘內(nèi)注射U0126能明顯抑制CCD引起的pERK陽(yáng)性神經(jīng)元表達(dá)。免疫印跡顯示CCD大鼠脊髓背角內(nèi)pERK1與pERK2水平明顯增加,鞘內(nèi)注射U0126能明顯抑制CCD引起的pERK水平的增高。 結(jié)果2,假手術(shù)組術(shù)前和術(shù)后大鼠縮足潛伏期無(wú)明顯變化,CCD術(shù)后第一天開(kāi)始縮足潛伏期明顯縮短,與CCD組相比較7-NI組術(shù)后第一天至第十一天縮足潛伏期明顯延長(zhǎng), L-NAME組術(shù)后第一天至第七天縮足潛伏期明顯延長(zhǎng),AG組術(shù)后第一天至第五天明顯延長(zhǎng),8-Br-cGMP術(shù)后第一天縮足潛伏期明顯縮短,第三天開(kāi)始無(wú)明顯差異。鞘內(nèi)注射NOS抑制劑或激動(dòng)劑對(duì)大鼠運(yùn)動(dòng)功能未見(jiàn)明顯影響。 術(shù)后第五天假手術(shù)組損傷側(cè)脊髓背角內(nèi)nNOS及iNOS免疫陽(yáng)性神經(jīng)元很少,慢性壓迫性損傷導(dǎo)致nNOS及iNOS免疫陽(yáng)性神經(jīng)元明顯增加,與CCD組相比L-NAME組、AG組、7-NI組損傷側(cè)脊髓背角內(nèi)免疫反應(yīng)陽(yáng)性細(xì)胞數(shù)明顯減少。免疫印跡結(jié)果顯示與假手術(shù)相比CCD導(dǎo)致大鼠脊髓背角神經(jīng)內(nèi)nNOS及iNOS水平明顯增加,鞘內(nèi)注射非選擇性nNOS抑制劑L-NAME和選擇性nNOS抑制劑7-NI能夠明顯抑制CCD大鼠脊髓背角內(nèi)nNOS的表達(dá),而選擇性iNOS抑制劑對(duì)nNOS表達(dá)未見(jiàn)明顯影響。同樣鞘內(nèi)應(yīng)用非選擇性iNOS抑制劑L-NAME和選擇性抑制劑AG能明顯抑制iNOS的表達(dá),而選擇性nNOS抑制劑對(duì)iNOS的表達(dá)沒(méi)有影響。8-Br-cGMP能增加CCD大鼠脊髓背角內(nèi)nNOS和iNOS的表達(dá)。 結(jié)果3,在術(shù)后第5天所有進(jìn)入實(shí)驗(yàn)的模型大鼠術(shù)側(cè)后肢均產(chǎn)生明顯痛敏。與鞘內(nèi)注射前相比,PBS組和Cremophor組注射后各時(shí)間點(diǎn)大鼠痛行為未見(jiàn)明顯變化;與PBS組相比,L-NAME組、AG組和7-NI組注射后12、24h大鼠術(shù)側(cè)熱縮足潛伏期無(wú)明顯變化,L-NAME組、AG組和7-NI組注射后30min,2h和6h大鼠術(shù)側(cè)熱縮足潛伏期明顯延長(zhǎng);與PBS組相比,8-Br-cGMP組注射后30min和2h大鼠術(shù)側(cè)熱縮足潛伏期明顯縮短。 免疫組化結(jié)果顯示CCD第5天大鼠術(shù)側(cè)脊髓背角內(nèi)pERK免疫反應(yīng)陽(yáng)性神經(jīng)元明顯增多,L-NAME組、AG組和7-NI組于鞘內(nèi)注射2h時(shí)術(shù)側(cè)脊髓背角內(nèi)pERK免疫反應(yīng)陽(yáng)性神經(jīng)元數(shù)量明顯減少,8-Br-cGMP組術(shù)側(cè)脊髓背角內(nèi)pERK免疫反應(yīng)陽(yáng)性神經(jīng)元數(shù)量增加。免疫印跡顯示CCD導(dǎo)致大鼠脊髓背角神經(jīng)元內(nèi)pERK水平明顯增加,與CCD組和8-Br-cGMP組相比L-NAME組、AG組、7-NI組背角神經(jīng)元內(nèi)pERK含量明顯減少。 結(jié)果4 ,術(shù)后第五天,假手術(shù)組大鼠損傷側(cè)脊髓背角內(nèi)nNOS免疫陽(yáng)性神經(jīng)元很少,慢性壓迫性損傷導(dǎo)致nNOS免疫陽(yáng)性神經(jīng)元明顯增加。與假手術(shù)組相比,模型對(duì)照組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶免疫反應(yīng)陽(yáng)性細(xì)胞數(shù)明顯增多;與模型對(duì)照組相比,U0126注射后0.5,2和12h組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶免疫反應(yīng)陽(yáng)性細(xì)胞數(shù)明顯減少,U0126注射后24h組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶免疫反應(yīng)陽(yáng)性細(xì)胞數(shù)沒(méi)有明顯變化。免疫印跡結(jié)果顯示慢性壓迫性損傷導(dǎo)致脊髓背角內(nèi)nNOS表達(dá)水平增加,與假手術(shù)組相比,模型對(duì)照組,U0126注射后12h組以及U0126注射后24h組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶表達(dá)水平明顯增加;與模型對(duì)照組相比,U0126注射后0.5,2和12h組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶表達(dá)水平明顯降低,而U0126注射后24h組損傷側(cè)脊髓背角內(nèi)神經(jīng)型一氧化氮合酶表達(dá)水平未見(jiàn)明顯變化。 結(jié)論 1、CCD可明顯增加損傷側(cè)脊髓背角淺層pERK、NOS陽(yáng)性神經(jīng)元表達(dá)。 2、鞘內(nèi)注射ERK信號(hào)傳導(dǎo)通路阻滯劑U0126及NOS抑制劑在減輕大鼠痛行為的同時(shí),能明顯抑制損傷側(cè)脊髓背角內(nèi)pERK1/2和NOS的表達(dá)。 3、大鼠痛行為及脊髓背角pERK及nNOS和iNOS的表達(dá)在時(shí)程上相一致。 4、在脊髓水平痛覺(jué)信號(hào)的調(diào)制中,脊髓背角神經(jīng)元胞內(nèi)ERK信號(hào)通路活性的變化能夠影響脊髓背角內(nèi)神經(jīng)型一氧化氮合酶表達(dá),胞外信號(hào)調(diào)節(jié)激酶參與介導(dǎo)了一氧化氮在神經(jīng)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.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類號(hào)】：R363

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