炎性疼痛大鼠背根神经节microRNA134对MOR1调节作用的研究
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摘要
第一部分炎性疼痛大鼠背根神经节miRNA134与MOR1的探索性研究
目的作为结合阿片类物质最重要的受体之一，阿片类受体μ1（μ opioid receptor1，MOR1）在痛觉调制和麻醉镇痛过程中参与并起着重要的作用。微小RNA(microRNA，miRNA）是一类内源性的具有调控功能的非编码RNA，特定的miRNA如miRNA134已被证实与神经生理功能及疼痛调节关系密切。生物信息学分析发现miRNA134存在与MOR1基因的3'-UTR段相匹配的区域，是MOR1基因调节的可能参与者之一。本研究的目的是探索炎性疼痛大鼠背根神经节内miRNA134与MOR1表达情况及其潜在的相互关系。
方法1）选用雄性Wistar大鼠，制备炎性疼痛模型（CFA组），即大鼠右足皮下注射完全弗氏佐剂（CFA）100μl，相同部位注射等量生理盐水作对照组（NS组）。采用压爪-缩腿法和辐射热-缩腿法来分别测定14天内的机械痛阈（Pressure stimulusthreshold）和热痛阈（Thermal stimulus latency）。2）在4小时，1天，4天，7天，14天五个时间点使用实时荧光定量PCR的方法检测注射侧L3、L4、L5三枚背根神经节内的miRNA134和MOR1mRNA的表达水平。两者表达的相互关系通过线性回归的方法进行统计学分析。3）研究还对注射CFA后4小时、4天、14天炎性疼痛大鼠致痛侧L5背根神经节内MOR1的表达水平通过免疫荧光组织化学的方法进行检测。4）CFA注射4天后大鼠同一背根神经节内miRNA134和MOR1的表达情况也通过原位杂交结合免疫组织化学的方法进行了检测。
结果1）行为学结果显示，注射CFA后大鼠右足机械痛阈和热痛阈在1天后明显降低（P＜0.05），分别于3天和4天时降至最低（P＜0.05），持续至注射后第14天（P＜0.05）。CFA注射后大鼠左足机械痛阈及热痛阈与生理盐水组无差别（P＞0.05）。2）实时荧光定量PCR的结果显示：与对照组比较， CFA大鼠背根神经节内miRNA134在1天、4天、7天时低于对照组（P＜0.01），4天后降至最低（P＜0.01）。而MOR1mRNA在4小时，1天，4天，7天，14天五个时间点均高于对照组（P＜0.01），4天后升至最高（P＜0.01）。统计学分析显示两者呈负性相关（R2=0.7363,P＜0.001）。3）免疫荧光组织化学显示： CFA大鼠致痛侧L5背根神经节内MOR1表达明显升高，特别是在注射CFA后4天达到最高。实验结果显示MOR1主要表达在背根神经节小直径神经元内。造模后4小时、4天、14天三个时间点上MOR1阳性细胞所占比例与对照组相比明显升高（P＜0.01），在4天时达到最高（P＜0.05）。荧光浓度结果也显示高于对照组（P＜0.01）。4）原位杂交显示， CFA造模后大鼠致痛侧L5背根神经节内miRNA134降低，而同一背根神经节内免疫组织化学结果显示MOR1表达升高。这种变化主要发生在小直径神经元中。
结论CFA造模引起大鼠痛行为发生变化，即痛域下降。同时，炎性疼痛大鼠背根神经节特别是小直径神经元内MOR1及其mRNA表达先升高后降低，而miRNA134则相反，表现为先降低后升高，两者呈现负相关性。背根神经节内的这些变化与痛行为存在关联。结果提示miRNA134作为一种翻译前水平的调节性小RNA，很可能在初级感受神经元水平通过调节MOR1基因表达参与慢性炎性疼痛的调制。
第二部分miRNA134在SH-SY5Y细胞系内对MOR1的调节作用研究
目的作为表观遗传学的一部分，miRNA可以通过微调基因表达参与机体生理病理功能的调节。通过使用生物信息学程序对MOR1靶基因序列中miRNA134的潜在结合位点的预测，研究发现MOR1与miRNA134具有能量上最有利的杂交位点。对炎性疼痛大鼠在体部分研究显示，炎性疼痛条件下，两者表达呈负性相关。本部分研究的目的是在体外细胞系上观察及验证miRNA134对MOR1表达的调节。
方法1）采用脂质体转染的方法，将LNA-anti-miRNA134分10nM、50nM、100nM的浓度转染人神经母细胞瘤细胞系（SH-SY5Y细胞）。2）48小时后收集细胞提取RNA，使用实时荧光定量PCR的方法检测miRNA134的抑制程度和MOR1mRNA的表达情况。3）同时在转染后72小时收集细胞并提取蛋白，使用蛋白电泳的方法观察MOR1受体蛋白的表达情况。4）实验还采用免疫荧光细胞化学的方法观察转染LNA-anti-miRNA134浓度为100nM时细胞内MOR1的表达情况。5）另外，实验还采用免疫透射电镜的方法在细胞超微水平观察MOR1受体的表达。
结果1）将LNA-anti-miRNA134按照低中高三个不同浓度（10nM、50nM、100nM）转染SH-SY5Y细胞系48小时后，实时荧光定量PCR的方法显示与对照组相比，miRNA134表达降低（P＜0.05），MOR1mRNA表达升高（P＜0.01），均具统计学意义。组间比较表明，miRNA134在转染浓度为10nM时开始降低（P＜0.05），100nM时降到最低（P＜0.01）。MOR1mRNA在转染浓度为10nM时已有升高（P＜0.01），在100nM时升至最高（P＜0.01）。两者与转染核苷酸浓度呈现出梯度变化的特点。2）蛋白电泳结果显示，SH-SY5Y转染LNA-anti-miRNA134后72小时， MOR1蛋白与对照组相比，明显升高（P＜0.01）；组间比较显示MOR1受体蛋白在转染浓度为10nM时表达已有升高（P＜0.01），在100nM时升至最高（P＜0.01），MOR1蛋白表达与基因水平表达一致。3）免疫荧光细胞化学结果显示，转染LNA-anti-miRNA134（100nM）72小时后，SH-SY5Y细胞MOR1蛋白表达升高，MOR1阳性细胞所占比例和MOR1免疫荧光浓度也明显增加（P＜0.01）。4）免疫透射电镜从细胞超微水平显示SH-SY5Y细胞转染入LNA-anti-miRNA13（4100nM）后MOR1表达升高，其主要表达部位在细胞表面。
结论对SH-SY5Y细胞系转染LNA-anti-miRNA134后，细胞内miRNA134的表达减少，但MOR1mRNA和蛋白的表达增加。这证实了在体外离体细胞模型上miRNA134与MOR1也存在负性调节的关系，这为miRNA134在体内调节MOR1基因表达参与疼痛调制提供了佐证。
Part Ⅰ Study on relationship of microRNA134and MOR1indorsal root ganglion neurons after inflammatory pain
Objective MOR1is the main transcript of μ opioid receptor (MOR） gene, whichrepresents a mandatory molecule for the analgesic effects of opioids and plays animportant role in the pathology of inflammatory pain. By using bioinformation analysis, anexact match to the seed sequence of miR-134was found in3'-untranslated region of MOR1.Given the important role of MOR1in pain modulation, the purpose of this study is toinvestigate whether miR-134can regulate the MOR1following allodynia.
Methods Using the Freund's adjuvant (CFA）-induced chronic inflammatory painmodel, we investigates the expression profiles of miR-134and MOR1in male Wistar ratdorsal root ganglia (DRG） using quantitative real-time PCR at time points of4h,1d,4d,7d and14d. The relationship of miR-134and MOR1expressions was analyzed by linearregression. The expression of MOR1was examined also by immunofluorescencedetection in ipsilateral L5DRG of inflammatory pain rats at the time of4h,4d and14d.Finally, we further examine the expression of MOR1combined with that of miRNA134inthe same DRGs by in situ hybridization and immunohistochemistry.
Results The pressure stimulus threshold and thermal stimulus latency of ipsilateralfoot were extended after CFA injection in Wistar rats. Compared with the control group,MOR1mRNA levels of experimental group significantly increased at4h following CFAinjection（p＜0.01）, with the maximum on day4after induction of inflammation （p＜0.01）, correlating with the development of thermal and pressure stimulus threshold after CFA injection. Conversely, the expression level of miRNA134was gradually decreasedfrom1d to4d(p＜0.05）and then gradually increased from7d to14d (p＜0.01）. Linearregression analysis showed that miR-134expression level was inversely related withMOR1expression level (R2=0.7363, p＜0.001）. Immunofluorescence showed that MOR1immunoreactivity was predominantly found in cytoplasm of neurons in rat DRG neurons,especially in those small diameter neurons. The percentage of MOR1-positive neuronssignificantly increased after4h of CFA injection, and reached the maximal at4d. Theimmunofluorescence intensity detection for MOR1showed the similar results that intensityincreased after CFA injection and raised to the top after4days. Down-regulation ofmiRNA134and upregulation of MOR1in the same DRG tissues after inflammatory painwere observed using the method of in situ hybridization and immunohistochemistry. Thechanges were detected mainly in small diameter neurons.
Conclusions Our present data suggested a model that miR-134participated inCFA-induced inflammatory pain by balancing the expression of MOR1in DRGs. Theseresults implied that miR-134might be a potential target for the treatment of neuropathicpain.
Part Ⅱ Study on relationship of microRNA134and MOR1inSH-SY5Y cell line after transfection
Objective MicroRNAs are non-coding molecules that primarily regulate geneexpression at the post-transcriptional level by predominantly hybridizing tocomplementary sequences in the3'-UTR of their corresponding mRNAs. Considering theimportant roles of MOR1in pain modulation and the relationship of miRNA134andMOR1, we study in vivo in part1. The purpose of this study is to detect whethermiRNA134can regulate the MOR1in vitro.
Methods In this study, we transfected LNA-anti-miRNA134(10nM、50nM、100nM）into SH-SY5Y cell line using lipofectamine2000. We investigated the expression ofmiRNA134and MOR1mRNA after transfection by the way of real-time PCR.MOR1 (protein）expression in cell culture after transfection was detected by Western Blot,immunohistochemistry and electron microscopy.
Results After transfection with LNA-anti-miRNA134(10nM,50nM,100nM） usinglipofectamine2000for48h, compared with NC group, the expression of miRNA134wassignificantly reduced（p＜0.01）, while the level of MOR1mRNA increased（p＜0.01）.They changed gradually according to the density of LNA-anti-miRNA134. After treatedfor72h, the expression of MOR1increased accordingly by western blot, as same as theresult of real-time PCR（p＜0.01）. We found the expression of MOR1increased afterLNA-anti-miRNA134(100nM） transfection by the methods of immunohistochemistry.The percentage of MOR1-positive neurons significantly increased after transfection. Theimmunofluorescence detection for MOR1showed the similar results that the intensityincreased after transfection of LNA-anti-miRNA134. We also found the increased MOR1after transfection at the level of ultra microstructure by using electron microscopy analysis.
Conclusions miRNA134can inversely regulate MOR1in vitro. Inhibition ofmiRNA134activity leads to an increase of the expression of MOR1and MOR1mRNA,which can also testify the relationship of miRNA134and MOR1partly in vivo.MiRNA134is an important potential target in pain modulation.
目的作为结合阿片类物质最重要的受体之一，阿片类受体μ1（μ opioid receptor1，MOR1）在痛觉调制和麻醉镇痛过程中参与并起着重要的作用。微小RNA(microRNA，miRNA）是一类内源性的具有调控功能的非编码RNA，特定的miRNA如miRNA134已被证实与神经生理功能及疼痛调节关系密切。生物信息学分析发现miRNA134存在与MOR1基因的3'-UTR段相匹配的区域，是MOR1基因调节的可能参与者之一。本研究的目的是探索炎性疼痛大鼠背根神经节内miRNA134与MOR1表达情况及其潜在的相互关系。
方法1）选用雄性Wistar大鼠，制备炎性疼痛模型（CFA组），即大鼠右足皮下注射完全弗氏佐剂（CFA）100μl，相同部位注射等量生理盐水作对照组（NS组）。采用压爪-缩腿法和辐射热-缩腿法来分别测定14天内的机械痛阈（Pressure stimulusthreshold）和热痛阈（Thermal stimulus latency）。2）在4小时，1天，4天，7天，14天五个时间点使用实时荧光定量PCR的方法检测注射侧L3、L4、L5三枚背根神经节内的miRNA134和MOR1mRNA的表达水平。两者表达的相互关系通过线性回归的方法进行统计学分析。3）研究还对注射CFA后4小时、4天、14天炎性疼痛大鼠致痛侧L5背根神经节内MOR1的表达水平通过免疫荧光组织化学的方法进行检测。4）CFA注射4天后大鼠同一背根神经节内miRNA134和MOR1的表达情况也通过原位杂交结合免疫组织化学的方法进行了检测。
结果1）行为学结果显示，注射CFA后大鼠右足机械痛阈和热痛阈在1天后明显降低（P＜0.05），分别于3天和4天时降至最低（P＜0.05），持续至注射后第14天（P＜0.05）。CFA注射后大鼠左足机械痛阈及热痛阈与生理盐水组无差别（P＞0.05）。2）实时荧光定量PCR的结果显示：与对照组比较， CFA大鼠背根神经节内miRNA134在1天、4天、7天时低于对照组（P＜0.01），4天后降至最低（P＜0.01）。而MOR1mRNA在4小时，1天，4天，7天，14天五个时间点均高于对照组（P＜0.01），4天后升至最高（P＜0.01）。统计学分析显示两者呈负性相关（R2=0.7363,P＜0.001）。3）免疫荧光组织化学显示： CFA大鼠致痛侧L5背根神经节内MOR1表达明显升高，特别是在注射CFA后4天达到最高。实验结果显示MOR1主要表达在背根神经节小直径神经元内。造模后4小时、4天、14天三个时间点上MOR1阳性细胞所占比例与对照组相比明显升高（P＜0.01），在4天时达到最高（P＜0.05）。荧光浓度结果也显示高于对照组（P＜0.01）。4）原位杂交显示， CFA造模后大鼠致痛侧L5背根神经节内miRNA134降低，而同一背根神经节内免疫组织化学结果显示MOR1表达升高。这种变化主要发生在小直径神经元中。
结论CFA造模引起大鼠痛行为发生变化，即痛域下降。同时，炎性疼痛大鼠背根神经节特别是小直径神经元内MOR1及其mRNA表达先升高后降低，而miRNA134则相反，表现为先降低后升高，两者呈现负相关性。背根神经节内的这些变化与痛行为存在关联。结果提示miRNA134作为一种翻译前水平的调节性小RNA，很可能在初级感受神经元水平通过调节MOR1基因表达参与慢性炎性疼痛的调制。
第二部分miRNA134在SH-SY5Y细胞系内对MOR1的调节作用研究
目的作为表观遗传学的一部分，miRNA可以通过微调基因表达参与机体生理病理功能的调节。通过使用生物信息学程序对MOR1靶基因序列中miRNA134的潜在结合位点的预测，研究发现MOR1与miRNA134具有能量上最有利的杂交位点。对炎性疼痛大鼠在体部分研究显示，炎性疼痛条件下，两者表达呈负性相关。本部分研究的目的是在体外细胞系上观察及验证miRNA134对MOR1表达的调节。
方法1）采用脂质体转染的方法，将LNA-anti-miRNA134分10nM、50nM、100nM的浓度转染人神经母细胞瘤细胞系（SH-SY5Y细胞）。2）48小时后收集细胞提取RNA，使用实时荧光定量PCR的方法检测miRNA134的抑制程度和MOR1mRNA的表达情况。3）同时在转染后72小时收集细胞并提取蛋白，使用蛋白电泳的方法观察MOR1受体蛋白的表达情况。4）实验还采用免疫荧光细胞化学的方法观察转染LNA-anti-miRNA134浓度为100nM时细胞内MOR1的表达情况。5）另外，实验还采用免疫透射电镜的方法在细胞超微水平观察MOR1受体的表达。
结果1）将LNA-anti-miRNA134按照低中高三个不同浓度（10nM、50nM、100nM）转染SH-SY5Y细胞系48小时后，实时荧光定量PCR的方法显示与对照组相比，miRNA134表达降低（P＜0.05），MOR1mRNA表达升高（P＜0.01），均具统计学意义。组间比较表明，miRNA134在转染浓度为10nM时开始降低（P＜0.05），100nM时降到最低（P＜0.01）。MOR1mRNA在转染浓度为10nM时已有升高（P＜0.01），在100nM时升至最高（P＜0.01）。两者与转染核苷酸浓度呈现出梯度变化的特点。2）蛋白电泳结果显示，SH-SY5Y转染LNA-anti-miRNA134后72小时， MOR1蛋白与对照组相比，明显升高（P＜0.01）；组间比较显示MOR1受体蛋白在转染浓度为10nM时表达已有升高（P＜0.01），在100nM时升至最高（P＜0.01），MOR1蛋白表达与基因水平表达一致。3）免疫荧光细胞化学结果显示，转染LNA-anti-miRNA134（100nM）72小时后，SH-SY5Y细胞MOR1蛋白表达升高，MOR1阳性细胞所占比例和MOR1免疫荧光浓度也明显增加（P＜0.01）。4）免疫透射电镜从细胞超微水平显示SH-SY5Y细胞转染入LNA-anti-miRNA13（4100nM）后MOR1表达升高，其主要表达部位在细胞表面。
结论对SH-SY5Y细胞系转染LNA-anti-miRNA134后，细胞内miRNA134的表达减少，但MOR1mRNA和蛋白的表达增加。这证实了在体外离体细胞模型上miRNA134与MOR1也存在负性调节的关系，这为miRNA134在体内调节MOR1基因表达参与疼痛调制提供了佐证。
Part Ⅰ Study on relationship of microRNA134and MOR1indorsal root ganglion neurons after inflammatory pain
Objective MOR1is the main transcript of μ opioid receptor (MOR） gene, whichrepresents a mandatory molecule for the analgesic effects of opioids and plays animportant role in the pathology of inflammatory pain. By using bioinformation analysis, anexact match to the seed sequence of miR-134was found in3'-untranslated region of MOR1.Given the important role of MOR1in pain modulation, the purpose of this study is toinvestigate whether miR-134can regulate the MOR1following allodynia.
Methods Using the Freund's adjuvant (CFA）-induced chronic inflammatory painmodel, we investigates the expression profiles of miR-134and MOR1in male Wistar ratdorsal root ganglia (DRG） using quantitative real-time PCR at time points of4h,1d,4d,7d and14d. The relationship of miR-134and MOR1expressions was analyzed by linearregression. The expression of MOR1was examined also by immunofluorescencedetection in ipsilateral L5DRG of inflammatory pain rats at the time of4h,4d and14d.Finally, we further examine the expression of MOR1combined with that of miRNA134inthe same DRGs by in situ hybridization and immunohistochemistry.
Results The pressure stimulus threshold and thermal stimulus latency of ipsilateralfoot were extended after CFA injection in Wistar rats. Compared with the control group,MOR1mRNA levels of experimental group significantly increased at4h following CFAinjection（p＜0.01）, with the maximum on day4after induction of inflammation （p＜0.01）, correlating with the development of thermal and pressure stimulus threshold after CFA injection. Conversely, the expression level of miRNA134was gradually decreasedfrom1d to4d(p＜0.05）and then gradually increased from7d to14d (p＜0.01）. Linearregression analysis showed that miR-134expression level was inversely related withMOR1expression level (R2=0.7363, p＜0.001）. Immunofluorescence showed that MOR1immunoreactivity was predominantly found in cytoplasm of neurons in rat DRG neurons,especially in those small diameter neurons. The percentage of MOR1-positive neuronssignificantly increased after4h of CFA injection, and reached the maximal at4d. Theimmunofluorescence intensity detection for MOR1showed the similar results that intensityincreased after CFA injection and raised to the top after4days. Down-regulation ofmiRNA134and upregulation of MOR1in the same DRG tissues after inflammatory painwere observed using the method of in situ hybridization and immunohistochemistry. Thechanges were detected mainly in small diameter neurons.
Conclusions Our present data suggested a model that miR-134participated inCFA-induced inflammatory pain by balancing the expression of MOR1in DRGs. Theseresults implied that miR-134might be a potential target for the treatment of neuropathicpain.
Part Ⅱ Study on relationship of microRNA134and MOR1inSH-SY5Y cell line after transfection
Objective MicroRNAs are non-coding molecules that primarily regulate geneexpression at the post-transcriptional level by predominantly hybridizing tocomplementary sequences in the3'-UTR of their corresponding mRNAs. Considering theimportant roles of MOR1in pain modulation and the relationship of miRNA134andMOR1, we study in vivo in part1. The purpose of this study is to detect whethermiRNA134can regulate the MOR1in vitro.
Methods In this study, we transfected LNA-anti-miRNA134(10nM、50nM、100nM）into SH-SY5Y cell line using lipofectamine2000. We investigated the expression ofmiRNA134and MOR1mRNA after transfection by the way of real-time PCR.MOR1 (protein）expression in cell culture after transfection was detected by Western Blot,immunohistochemistry and electron microscopy.
Results After transfection with LNA-anti-miRNA134(10nM,50nM,100nM） usinglipofectamine2000for48h, compared with NC group, the expression of miRNA134wassignificantly reduced（p＜0.01）, while the level of MOR1mRNA increased（p＜0.01）.They changed gradually according to the density of LNA-anti-miRNA134. After treatedfor72h, the expression of MOR1increased accordingly by western blot, as same as theresult of real-time PCR（p＜0.01）. We found the expression of MOR1increased afterLNA-anti-miRNA134(100nM） transfection by the methods of immunohistochemistry.The percentage of MOR1-positive neurons significantly increased after transfection. Theimmunofluorescence detection for MOR1showed the similar results that the intensityincreased after transfection of LNA-anti-miRNA134. We also found the increased MOR1after transfection at the level of ultra microstructure by using electron microscopy analysis.
Conclusions miRNA134can inversely regulate MOR1in vitro. Inhibition ofmiRNA134activity leads to an increase of the expression of MOR1and MOR1mRNA,which can also testify the relationship of miRNA134and MOR1partly in vivo.MiRNA134is an important potential target in pain modulation.
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