电刺激大鼠上矢状窦血管源性头痛模型的机制研究
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摘要
目的
1、通过清醒状态下电刺激大鼠上矢状窦结合免疫组织化学和免疫荧光染色的方法,系统的观察Fos阳性神经元在脑内的分布情况,筛查给予刺激时脑内参与疼痛活动的脑区,并探讨活动脑区与5-HT阳性神经元之间的关系。
2、观察苯甲酸利扎曲普坦对清醒状态下电刺激大鼠上矢状窦模型动物行为学、Fos阳性神经元表达的影响。
3、对清醒状态下电刺激大鼠上矢状窦模型动物的三叉神经核尾侧亚核做蛋白组学分析,寻找差异表达蛋白,探讨血管源性头痛发生发展可能的机制。
方法
1、雄性SD大鼠随机分为两组即实验组和对照组,手术暴露上矢状窦安放电极后,实验组电刺激硬脑膜,应用免疫组织化学染色技术观察Fos阳性神经元在脑内的分布并绘图,免疫荧光双重染色Fos与5-HT,观察双标神经元的分布情况。
2、SD大鼠手术暴露上矢状窦安放电极后,实验组自身前后对照观察腹腔给予不同浓度苯甲酸利扎曲普坦后的行为学变化。之后随机分为两组即实验组和空白对照组,观察腹腔给予生理盐水和苯甲酸利扎曲普坦后的Fos表达情况,并与实验一的结果进行对比。
3、SD大鼠随机分为两组即实验组和对照组,手术暴露上矢状窦安放电极后,实验组电刺激硬脑膜后,对两组三叉神经核尾侧亚核取材行蛋白电泳和质谱分析,寻找差异蛋白。
结果
1.电刺激后Fos阳性神经元在脑内分布广泛,主要集中在高颈段脊髓后角,三叉脊束核尾侧亚核,中缝核簇,中脑导水管周围灰质,脚间核及下丘脑等区域。荧光双重染色结果显示5-HT阳性神经元主要分布在中缝核簇及中脑导水管周围灰质,与模型Fos阳性神经元之间有重叠,仅在中缝大核等部位观察到个别双标神经元。
2、给予等及高浓度苯甲酸利扎曲普坦组的动物与低浓度组及生理盐水组相比,在同等强度电刺激时甩头、理毛的次数减少,与给予生理盐水组及空白组(实验一)相比,Fos蛋白表达的区域无明显改变,但在三叉神经核尾侧亚核的表达有所减少而在中脑导水管周围灰质的表达有所增加。
3、双向凝胶电泳后有1562对蛋白样点匹配成功,表达上调者735个,表达下调者827个。选取了9个蛋白样点进行UPLC-ESI-MS/MS肽质量指纹谱分析后为G蛋白结合核蛋白ran、溶血磷脂酶2、谷胱甘肽-S-转移酶的P-形式的酶、琥珀酸半醛脱氢酶、Haloacid脱卤类水解酶域包含蛋白2、Transgelin蛋白、ATP酶,氢离子运输,溶酶体13kDa,V1的亚基G1期、SEPT11蛋白和rCG55630, isoform CRA_a。
结论
1.脑内的多个区域参与了电刺激上矢状窦血管源性头痛模型的发生和发展过程,除了与疼痛的信息传递和调控有关外,与情感、植物神经等调控有关的核团也参与其中。电刺激大鼠上矢状窦血管源性头痛的发生和发展过程中,激活神经元的性质尚需进一步的探讨,少量5-HT阳性神经元参与其中,可能与下行镇痛系统的激活有关。
2、清醒状态下电刺激大鼠上矢状窦模型对苯甲酸利扎曲普坦有很好的行为学反应,给药后行为学指标的改变提示疼痛有所减轻,进一步验证模型的可行性。同时,给药后Fos表达的改变提示三叉神经脊束核尾侧亚核及中脑导水管周围灰质参与了药物对疼痛控制的药理过程,但具体机制尚待阐明。
3、电刺激大鼠上矢状窦后,三叉神经脊束核尾侧亚核内蛋白表达有发生上调与下调,提示核胞浆转运增加、对抗凋亡、诱导蛋白谷胱甘肽-S化的蛋白增加、GABA的降解减低等,可能与血管源性头痛的发生有关。
Objective
1、By means of electrical stimulation on superior sagittal sinus (SSS) of waking rats, combined with immunohistochemistry and immunofluorescence, the distribution of Fos-immunoreactive neurons in brain was systematically observed in order to find the active regions participating nociception during the stimulation, meaningwhile, the relationship between the Fos-immuoreactive neurons and the 5-HT-immunoreactive neurons was studied.
2、To investigate the effect of flunarizine on ethology and Fos expression in the mode of electrical stimulation in SSS in waking rat.
3、Protemic analysing of caudal subnucleus of the trigeminal nucleus caudalis of the waking rats after electrical stimulation on SSS was performed to search for the differential protein expression and explore possible mechanims of the vascular headache.
Methods
1、The male SD rats were randomly divided into experimental group and control group. After exposure of SSS, rats in the experimental group were received electrical stimulation on the dura mater. Immunohistochemistry was then utilized to label Fos expressing neurons and immunofluorescence was to label Fos or/and 5-HT expressing neurons, at the same time, the schematic map illustrating the distribution of Fos-immunoreactive neurons was drawn.
2、After exposure of SSS of SD rats, self-control was employed to compare the behavior change after intraperitoneal injection of flunarizine with different concentration. Then the rats were randomly divided into experimental group (intraperitoneally flunarizine) and control group (intraperitoneally physiological saline) to immunochemically invesgate and compare the Fos expression between both groups and with the results from the first expriment.
3、SD rats were randomly divided into experimental group and control group. After exposure of SSS, rats in the experimental group were received electrical stimulation on the dura mater near SSS. Then protemics study (protein electrophoresis and mass chromatographic analysis) was conducted for regions of trigeminal nucleus caudal part to search for differential expressed protein.
Results
1. After the electrical stimulation the Fos-immunoreactive neurons were observed in many areas in the brain, which were upper cervical spinal dorsal horn, spinal trigeminal nucleus caudalis, raphe nuclei, periaqueductal gray, interpeduncular nucleus and hypothalamus. Double immunofluorescence staining indicated that 5-HT-immunoreactive neurons existed mainly in the raphe nuclei and periaqueductal gray. Although Fos-immunoreactive neurons and 5-HT-immuroreactive neurons overlapped in the raphe nuclei and periaqueductal gray, only few Fos/5-HT co-localized neurons were found in the raphe magnus nucleus.
2、The number of head shaking and grooming of rats with equal and high concentration of flunarizine was significantly reduced compared to low concentration and physiological saline.The distribution of Fos-immunoreactive neurons in the brain of rats in flunarizine injection group was the same with those in physiological saline injection group and normal group (experiment first), however, the Fos expression decreased in caudal subnucleus of trigeminal nuclei and increased in periadqueductal gray in rat brain of flunarizine injection group.
3、After the two-dimensional gel electrophoresis, there were 1562 pairs of protein plot matched, among which 735 plot increased and 827 decreased.9 of the protein plot were selected for UPLC-ESI-MS/MS and they were GTP-binding nuclear protein Ran, lysophospholipase 2, glutathione S-transferase P, succinate semialdehyde dehydrogenase, Haloacid dehalogenase-like hydrolase domain-containing protein 2, transgelin, ATPase, H transporting, lysosomal V1 subunit G1, Septl1 protein and rCG55630, isoform CRA_a.
Conclusions
1. Several areas in the brain are involved in the generation and development of vascular headache in the mode of electrical stimulation on superior sagittal sinus. Except for nuclei modulating and transmitting nociceptive information, those relating to both motion and autonomic nerve regulation take part in the above process. In process of generation and development of vascular headache in the mode of electrical stimulation on SSS, the chemical property of the activated neurons is still need to further investigate. Some 5-HT immunoreactive neurons are activated, which means their participating in the process and may partially relate to the activation of descending antinociceptive system.
2、The waking rat mode of electrical stimulating on SSS responed well to flunarizine for ethological parameters changed after injection of flunarizine indicating that pain was relieved, which further testified the feasibility of the mode. At the same time, the caudal subnucleus of trigeminal nuclei and periadequeductal gray were presumed to take part in the process of pain modulation from flunarizine for the Fos expression changed after injection of flunarizine, but specific mechanism was still unclear and need to explore.
3、After the electrical stimulation on SSS, protemics of trigeminal nucleus caudalis were changed, indicating increased caryoplasm-cytoplasm transportion, increased anti-apoptosis and induced S-glutathionylation and decreased GABA degradation and so on, which may participate in the generation and development of the vascular headache.
1、通过清醒状态下电刺激大鼠上矢状窦结合免疫组织化学和免疫荧光染色的方法,系统的观察Fos阳性神经元在脑内的分布情况,筛查给予刺激时脑内参与疼痛活动的脑区,并探讨活动脑区与5-HT阳性神经元之间的关系。
2、观察苯甲酸利扎曲普坦对清醒状态下电刺激大鼠上矢状窦模型动物行为学、Fos阳性神经元表达的影响。
3、对清醒状态下电刺激大鼠上矢状窦模型动物的三叉神经核尾侧亚核做蛋白组学分析,寻找差异表达蛋白,探讨血管源性头痛发生发展可能的机制。
方法
1、雄性SD大鼠随机分为两组即实验组和对照组,手术暴露上矢状窦安放电极后,实验组电刺激硬脑膜,应用免疫组织化学染色技术观察Fos阳性神经元在脑内的分布并绘图,免疫荧光双重染色Fos与5-HT,观察双标神经元的分布情况。
2、SD大鼠手术暴露上矢状窦安放电极后,实验组自身前后对照观察腹腔给予不同浓度苯甲酸利扎曲普坦后的行为学变化。之后随机分为两组即实验组和空白对照组,观察腹腔给予生理盐水和苯甲酸利扎曲普坦后的Fos表达情况,并与实验一的结果进行对比。
3、SD大鼠随机分为两组即实验组和对照组,手术暴露上矢状窦安放电极后,实验组电刺激硬脑膜后,对两组三叉神经核尾侧亚核取材行蛋白电泳和质谱分析,寻找差异蛋白。
结果
1.电刺激后Fos阳性神经元在脑内分布广泛,主要集中在高颈段脊髓后角,三叉脊束核尾侧亚核,中缝核簇,中脑导水管周围灰质,脚间核及下丘脑等区域。荧光双重染色结果显示5-HT阳性神经元主要分布在中缝核簇及中脑导水管周围灰质,与模型Fos阳性神经元之间有重叠,仅在中缝大核等部位观察到个别双标神经元。
2、给予等及高浓度苯甲酸利扎曲普坦组的动物与低浓度组及生理盐水组相比,在同等强度电刺激时甩头、理毛的次数减少,与给予生理盐水组及空白组(实验一)相比,Fos蛋白表达的区域无明显改变,但在三叉神经核尾侧亚核的表达有所减少而在中脑导水管周围灰质的表达有所增加。
3、双向凝胶电泳后有1562对蛋白样点匹配成功,表达上调者735个,表达下调者827个。选取了9个蛋白样点进行UPLC-ESI-MS/MS肽质量指纹谱分析后为G蛋白结合核蛋白ran、溶血磷脂酶2、谷胱甘肽-S-转移酶的P-形式的酶、琥珀酸半醛脱氢酶、Haloacid脱卤类水解酶域包含蛋白2、Transgelin蛋白、ATP酶,氢离子运输,溶酶体13kDa,V1的亚基G1期、SEPT11蛋白和rCG55630, isoform CRA_a。
结论
1.脑内的多个区域参与了电刺激上矢状窦血管源性头痛模型的发生和发展过程,除了与疼痛的信息传递和调控有关外,与情感、植物神经等调控有关的核团也参与其中。电刺激大鼠上矢状窦血管源性头痛的发生和发展过程中,激活神经元的性质尚需进一步的探讨,少量5-HT阳性神经元参与其中,可能与下行镇痛系统的激活有关。
2、清醒状态下电刺激大鼠上矢状窦模型对苯甲酸利扎曲普坦有很好的行为学反应,给药后行为学指标的改变提示疼痛有所减轻,进一步验证模型的可行性。同时,给药后Fos表达的改变提示三叉神经脊束核尾侧亚核及中脑导水管周围灰质参与了药物对疼痛控制的药理过程,但具体机制尚待阐明。
3、电刺激大鼠上矢状窦后,三叉神经脊束核尾侧亚核内蛋白表达有发生上调与下调,提示核胞浆转运增加、对抗凋亡、诱导蛋白谷胱甘肽-S化的蛋白增加、GABA的降解减低等,可能与血管源性头痛的发生有关。
Objective
1、By means of electrical stimulation on superior sagittal sinus (SSS) of waking rats, combined with immunohistochemistry and immunofluorescence, the distribution of Fos-immunoreactive neurons in brain was systematically observed in order to find the active regions participating nociception during the stimulation, meaningwhile, the relationship between the Fos-immuoreactive neurons and the 5-HT-immunoreactive neurons was studied.
2、To investigate the effect of flunarizine on ethology and Fos expression in the mode of electrical stimulation in SSS in waking rat.
3、Protemic analysing of caudal subnucleus of the trigeminal nucleus caudalis of the waking rats after electrical stimulation on SSS was performed to search for the differential protein expression and explore possible mechanims of the vascular headache.
Methods
1、The male SD rats were randomly divided into experimental group and control group. After exposure of SSS, rats in the experimental group were received electrical stimulation on the dura mater. Immunohistochemistry was then utilized to label Fos expressing neurons and immunofluorescence was to label Fos or/and 5-HT expressing neurons, at the same time, the schematic map illustrating the distribution of Fos-immunoreactive neurons was drawn.
2、After exposure of SSS of SD rats, self-control was employed to compare the behavior change after intraperitoneal injection of flunarizine with different concentration. Then the rats were randomly divided into experimental group (intraperitoneally flunarizine) and control group (intraperitoneally physiological saline) to immunochemically invesgate and compare the Fos expression between both groups and with the results from the first expriment.
3、SD rats were randomly divided into experimental group and control group. After exposure of SSS, rats in the experimental group were received electrical stimulation on the dura mater near SSS. Then protemics study (protein electrophoresis and mass chromatographic analysis) was conducted for regions of trigeminal nucleus caudal part to search for differential expressed protein.
Results
1. After the electrical stimulation the Fos-immunoreactive neurons were observed in many areas in the brain, which were upper cervical spinal dorsal horn, spinal trigeminal nucleus caudalis, raphe nuclei, periaqueductal gray, interpeduncular nucleus and hypothalamus. Double immunofluorescence staining indicated that 5-HT-immunoreactive neurons existed mainly in the raphe nuclei and periaqueductal gray. Although Fos-immunoreactive neurons and 5-HT-immuroreactive neurons overlapped in the raphe nuclei and periaqueductal gray, only few Fos/5-HT co-localized neurons were found in the raphe magnus nucleus.
2、The number of head shaking and grooming of rats with equal and high concentration of flunarizine was significantly reduced compared to low concentration and physiological saline.The distribution of Fos-immunoreactive neurons in the brain of rats in flunarizine injection group was the same with those in physiological saline injection group and normal group (experiment first), however, the Fos expression decreased in caudal subnucleus of trigeminal nuclei and increased in periadqueductal gray in rat brain of flunarizine injection group.
3、After the two-dimensional gel electrophoresis, there were 1562 pairs of protein plot matched, among which 735 plot increased and 827 decreased.9 of the protein plot were selected for UPLC-ESI-MS/MS and they were GTP-binding nuclear protein Ran, lysophospholipase 2, glutathione S-transferase P, succinate semialdehyde dehydrogenase, Haloacid dehalogenase-like hydrolase domain-containing protein 2, transgelin, ATPase, H transporting, lysosomal V1 subunit G1, Septl1 protein and rCG55630, isoform CRA_a.
Conclusions
1. Several areas in the brain are involved in the generation and development of vascular headache in the mode of electrical stimulation on superior sagittal sinus. Except for nuclei modulating and transmitting nociceptive information, those relating to both motion and autonomic nerve regulation take part in the above process. In process of generation and development of vascular headache in the mode of electrical stimulation on SSS, the chemical property of the activated neurons is still need to further investigate. Some 5-HT immunoreactive neurons are activated, which means their participating in the process and may partially relate to the activation of descending antinociceptive system.
2、The waking rat mode of electrical stimulating on SSS responed well to flunarizine for ethological parameters changed after injection of flunarizine indicating that pain was relieved, which further testified the feasibility of the mode. At the same time, the caudal subnucleus of trigeminal nuclei and periadequeductal gray were presumed to take part in the process of pain modulation from flunarizine for the Fos expression changed after injection of flunarizine, but specific mechanism was still unclear and need to explore.
3、After the electrical stimulation on SSS, protemics of trigeminal nucleus caudalis were changed, indicating increased caryoplasm-cytoplasm transportion, increased anti-apoptosis and induced S-glutathionylation and decreased GABA degradation and so on, which may participate in the generation and development of the vascular headache.
引文
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