吗啡依赖自然戒断后抑郁样症状大鼠的血清蛋白质组学研究
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摘要
阿片依赖患者戒断后常导致一系列躯体戒断症状,也包括情绪和情感症状如抑郁样症状,烦躁不安,焦虑,高度激惹,这些负性情绪导致冲动性药物使用增加、维持和戒断后复吸。本研究筛选出吗啡依赖自然戒断后抑郁样大鼠,从血清蛋白质组学方面着手研究,采用双向电泳技术和生物质谱鉴定技术,寻找吗啡依赖自然戒断后血清中的差异表达蛋白,并对这些差异表达蛋白分子进行深入研究和筛选,为进一步明确吗啡依赖戒断后抑郁样症状病理生理变化的分子机制和更好地指导吗啡戒断后抑郁样症状的临床治疗打下基础。
本研究首先选出敞箱基线测试活动水平相当的Wistar大鼠30只,再随机分为吗啡给药组和生理盐水对照组,吗啡给药组采用腹腔注射吗啡连续7d的方法建立吗啡依赖大鼠模型,进而在自然戒断的情况下筛选出吗啡依赖戒断后抑郁样症状大鼠,即通过观察基线、戒断第3天(d3)、戒断第9天(d9)时大鼠行为学改变(敞箱、蔗糖水偏爱测试、强迫游泳测试)来筛选出有抑郁样症状的大鼠。在戒断d3,吗啡戒断组活动路程和垂直运动得分下降,蔗糖水饮用减少,和正常对照组比较有统计学差异,但强迫游泳测试不动时间未延长；在戒断d9,吗啡戒断组活动路程和垂直运动得分均下降,强迫游泳测试不动时间延长,蔗糖水饮用较少,但和正常对照组比较都无显著性差异。吗啡戒断d9组中连续活动低下的大鼠被认为是恢复阶段抑郁样大鼠。因此分别筛选出戒断d3和d9吗啡戒断后抑郁样症状大鼠,再分别收集正常大鼠(3只)血液,戒断d3和戒断后d9仍有抑郁样症状大鼠(各3只)的血液并制备血清蛋白样品,随后分别做双向电泳。在血清双向电泳试验中未祛除高峰度蛋白,血清蛋白的2-DE胶考染平均每张胶有420多个点。图像分析结果得到了25个差异表达蛋白点,其中正常对照组和戒断d3组相比有14个差异蛋白点,戒断d3组和戒断d9组相比有11个差异蛋白点,25个差异蛋白送检经过酶切和基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS),有22个蛋白点得到鉴定,它们可基本分为以下5类：第一类为受体蛋白类,如：crystal structure of rat alpha 1-macroglobulin receptor binding domain;第二类为快速时相蛋白类,如：preprohaptoglobin;第三类为脂蛋白类,如：apolipoproteinA-I；第四类为各种血清蛋白酶的变化,如：泛素羧基末端脂酶L3；第五类为未鉴定出的蛋白质。这些差异蛋白的出现为下一步鉴定及寻找吗啡戒断后抑郁样症状的特异性的蛋白标志物打下基础。
Opiate withdrawal in human addicts can result in not only a number of well-characterized autonomic and somatic symptoms, but also emotional or affective symptoms such as depressed mood/dysphoria, restlessness, hyperirritability, and anxiety. These negative emotional states resulting from withdrawal may contribute to escalation, compulsive use, maintenance of use, and relapse after periods of abstinence. In this study, we successfully screened depressive-like model of rats after morphine withdrawal, and then utilized serum comparative proteomic analysis and MADLA-TOF to find differentially expressed proteins and their information, and this may be helpful to discover the pathophysiologic molecular mechanisms involved in depressive-like symptom after withdrawal and to guide better treatment of depressive-like symptom after withdrawal.
At first,30 rats with basic open-filed test result alike were chosen and randomly divided into morphine treatment group and saline treatment group. Morphine group was administrated by intraperitoneally administrated (IP) for 7 days to establish morphine dependence rat model, then screened rats of depressive-like symptom after spontaneous withdrawal. We observed their behavior on the third and ninth day after withdrawal in following tests:the open field test, the sucrose preference test, the forced swimming test (FST), and found that rats withdrawal from morphine dependence had somatic withdrawal symptom and depressive-like behavior:on withdrawal d3, the travel distances and the scores of rearing decreased (P<0.05), there was significant differences between the normal group and the withdrawal group, percentage of sucrose consumption decreased (P<0.05), but the immobility time of two groups had little differences; On withdrawal d9, not only the travel distances and scores of rearing decreased, but also the time prolonged in the FST, but no differences in the open field test or in the sucrose preference test or in FST was observed. Rats still less active on withdrawal d9 were thought as depressive-like rats, and then we extracted serum from the control rats and the depressive rats respectively and separated and identified differentially expressed proteins spots in serum at different time at different group with the techniques of two-dimensional electrophoresis (2-DE) and mass spectrometer (MS). Through image analysis of serum proteins, we could obtain about 420 spots by coomassie staining. Twenty-five protein spots of interest were excised from the gels and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Twenty-two protein spots were identified in the database. These protein spots could be divided into five kinds:the first was about receptor proteins; the second was about acute phase proteins; the third was about lipoproteins; the fourth was about serum protease; the fifth was associated with proteins that were not identified. These differentially expressed proteins can offer us a clue about the biomarkers of the depressive-like symptom of morphine withdrawal.
本研究首先选出敞箱基线测试活动水平相当的Wistar大鼠30只,再随机分为吗啡给药组和生理盐水对照组,吗啡给药组采用腹腔注射吗啡连续7d的方法建立吗啡依赖大鼠模型,进而在自然戒断的情况下筛选出吗啡依赖戒断后抑郁样症状大鼠,即通过观察基线、戒断第3天(d3)、戒断第9天(d9)时大鼠行为学改变(敞箱、蔗糖水偏爱测试、强迫游泳测试)来筛选出有抑郁样症状的大鼠。在戒断d3,吗啡戒断组活动路程和垂直运动得分下降,蔗糖水饮用减少,和正常对照组比较有统计学差异,但强迫游泳测试不动时间未延长；在戒断d9,吗啡戒断组活动路程和垂直运动得分均下降,强迫游泳测试不动时间延长,蔗糖水饮用较少,但和正常对照组比较都无显著性差异。吗啡戒断d9组中连续活动低下的大鼠被认为是恢复阶段抑郁样大鼠。因此分别筛选出戒断d3和d9吗啡戒断后抑郁样症状大鼠,再分别收集正常大鼠(3只)血液,戒断d3和戒断后d9仍有抑郁样症状大鼠(各3只)的血液并制备血清蛋白样品,随后分别做双向电泳。在血清双向电泳试验中未祛除高峰度蛋白,血清蛋白的2-DE胶考染平均每张胶有420多个点。图像分析结果得到了25个差异表达蛋白点,其中正常对照组和戒断d3组相比有14个差异蛋白点,戒断d3组和戒断d9组相比有11个差异蛋白点,25个差异蛋白送检经过酶切和基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS),有22个蛋白点得到鉴定,它们可基本分为以下5类：第一类为受体蛋白类,如：crystal structure of rat alpha 1-macroglobulin receptor binding domain;第二类为快速时相蛋白类,如：preprohaptoglobin;第三类为脂蛋白类,如：apolipoproteinA-I；第四类为各种血清蛋白酶的变化,如：泛素羧基末端脂酶L3；第五类为未鉴定出的蛋白质。这些差异蛋白的出现为下一步鉴定及寻找吗啡戒断后抑郁样症状的特异性的蛋白标志物打下基础。
Opiate withdrawal in human addicts can result in not only a number of well-characterized autonomic and somatic symptoms, but also emotional or affective symptoms such as depressed mood/dysphoria, restlessness, hyperirritability, and anxiety. These negative emotional states resulting from withdrawal may contribute to escalation, compulsive use, maintenance of use, and relapse after periods of abstinence. In this study, we successfully screened depressive-like model of rats after morphine withdrawal, and then utilized serum comparative proteomic analysis and MADLA-TOF to find differentially expressed proteins and their information, and this may be helpful to discover the pathophysiologic molecular mechanisms involved in depressive-like symptom after withdrawal and to guide better treatment of depressive-like symptom after withdrawal.
At first,30 rats with basic open-filed test result alike were chosen and randomly divided into morphine treatment group and saline treatment group. Morphine group was administrated by intraperitoneally administrated (IP) for 7 days to establish morphine dependence rat model, then screened rats of depressive-like symptom after spontaneous withdrawal. We observed their behavior on the third and ninth day after withdrawal in following tests:the open field test, the sucrose preference test, the forced swimming test (FST), and found that rats withdrawal from morphine dependence had somatic withdrawal symptom and depressive-like behavior:on withdrawal d3, the travel distances and the scores of rearing decreased (P<0.05), there was significant differences between the normal group and the withdrawal group, percentage of sucrose consumption decreased (P<0.05), but the immobility time of two groups had little differences; On withdrawal d9, not only the travel distances and scores of rearing decreased, but also the time prolonged in the FST, but no differences in the open field test or in the sucrose preference test or in FST was observed. Rats still less active on withdrawal d9 were thought as depressive-like rats, and then we extracted serum from the control rats and the depressive rats respectively and separated and identified differentially expressed proteins spots in serum at different time at different group with the techniques of two-dimensional electrophoresis (2-DE) and mass spectrometer (MS). Through image analysis of serum proteins, we could obtain about 420 spots by coomassie staining. Twenty-five protein spots of interest were excised from the gels and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Twenty-two protein spots were identified in the database. These protein spots could be divided into five kinds:the first was about receptor proteins; the second was about acute phase proteins; the third was about lipoproteins; the fourth was about serum protease; the fifth was associated with proteins that were not identified. These differentially expressed proteins can offer us a clue about the biomarkers of the depressive-like symptom of morphine withdrawal.
引文
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