当归芍药散对牙移动导致大鼠疼痛和空间学习记忆改变的作用研究
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摘要
临床正畸过程口颌面区域痛疼引起的不适是正畸医生最常见问题之一,疼痛在正畸弓丝初次加力后随即出现,疼痛加力后持续约3-5天后逐渐缓解,正畸牙移动后疼痛发生率达91%。
既往研究表明,牙齿移动是由正畸矫治力累及牙周组织所致炎性疼痛且与SP, CGRP,EAAs等炎性因子,神经递质等密切相关,但是牙移动所致疼痛发生机制并不是很清楚。c-fos是一种重要的早期即刻表达癌基因,被称为第三信使,它能通过调节神经细胞膜上受体与核内的相应靶基因相联系来参与疼痛病理过程,动物实验表明牙齿移动后c-fos参与了中枢神经系统(CNS)神经元的可塑性变化,大量的实验证据证明胶质细胞(星形胶质细胞和小胶质细胞)也在CNS病理性疼痛产生与发过程中起重要作用。三叉神经脊束核(Sp)是口颌面部伤害性刺激向中枢传导的重要门户,而三叉神经脊束核尾侧亚核(SpVc)是口颌面部参与伤害性刺激传导的重要部位,因此,我们以实验性牙移动为模型,检测大鼠SpVc神经元可塑性变化和胶质细胞形态学改变,进一步了解神经元和胶质细胞的相互作用,有助于阐明正畸疼痛的发病机制。
另外,痛的感觉分辨成分和痛的情绪体验成分两重含义说明了痛觉的多维性和复杂性,相关文献表明,在疼痛发生进程中,伴随有厌恶、焦虑等负面情绪的产生,而且疼痛和焦虑应急反应往往具有共病性,患疼痛的病人易患焦虑症,焦虑症患者的慢性疼痛发病率也会显著增加。追述文献得知,焦虑、抑郁等情绪反应等和动物主体空间学习记忆等认知能力密切相关,我们知道海马是学习和记忆过程中的易感脑区,那么,大鼠实验性牙移动是否能够引起其相关学习记忆认知障碍?本实验拟首次通过动物实验,观察初次牙移动过程中疼痛产生是否会引起大鼠焦虑情绪应激变化,这种焦虑状态是否会引起大鼠海马区空间学习、记忆等认知功能的改变?
传统的中草药当归芍药散(DSS),最早记载于“金匮药略”药典,最新文献指出当归芍药散具有回复大脑多巴胺和增强机体免疫力以及增强认知和抵抗衰老等作用,然而当归芍药散是否有预防治疗正畸牙移动后口颌面部疼痛作用没有文献提及。本实验拟通过建立实验性牙移动模型,观察DSS对大鼠疼痛行为学变化以及在SpVc对胶质细胞,神经元,在海马区对胶质细胞形态表达变化的影响,期待为缓解临床正畸治疗牙移动后引起的疼痛,改善因疼痛可能导致的大鼠急性情绪应激行为,空间学习记忆改变提供动物实验依据。
第一部分：DSS对实验性牙移动大鼠SpVc内fos, ibal和GFAP的表达变化的影响
目的：使用实验性牙移动模型,首次采用检测大鼠牙移动后单位时间空口咀嚼和行为学指标,结合荧光免疫组化,west-blot等形态学方法观察SpVc区域c-fos和iba-1, GFAP表达的变化,进一步通过实验前,实验中胃灌服DSS,检测其对牙齿移动过程中疼痛的调节作用。
方法：使用改良Colin.K法,用镍钛丝60g力交互牵引大鼠上颌前后牙建立大鼠牙移动模型；实验分为空白对照,对照组,牙齿移动组和用药组；分别检测在牙移动后4h,12h,1d,3d,5d,7d时间点大鼠行为学改变,SpVc内fos和iba-1, GFAP形态及蛋白表达的变化,以及用药组实验前5天胃灌注DSS汤剂,150mg/Kg,2/日,和牙移动组对比,检测SpVc上述指标的变化。
结果：1.大鼠牙移动后4h空口咀嚼时间开始增加,1d达到峰值,随后缓慢下降至7d时间对照组间比较变化不明显,和传统观测直接梳理面部行为学变化趋势一致,DSS处理组和牙移动组比较,大鼠单位空口咀嚼时间和直接擦拭嘴时间改变减少,呈显著性差异。
2.和对照组比较,牙移动4hSpVc Fos-LI数量明显增加,牙移动侧较对侧间差异明显,Votm区域较对照组增加不明显,牙移动后1dFos-LI数量呈减少趋势；牙齿移动后后4h,SpVc浅层iba-1免疫阳性细胞开始表达,大鼠牙齿移动后1d, iba-1免疫阳性细胞表达明显增加,达峰值。免疫染色加深,胞体变大,形态清晰丰满,并且分布区域向SpVc较深层趋向,3d后SpVc区域iba-1免疫阳性细胞较1d表达有所减弱,7d恢复到正常；牙齿移动后4h,SpVc内GFAP免疫阳性细胞有少量表达,GFAP染色浅,分支少而短,数目较少,牙齿移动后Id,GFAP免疫阳性细胞有少量表达可见GFAP染色加深,3d GFAP染色加深明显,分支增多,数目增加,对侧有少量表达,牙齿移动后7d GFAP染色到达峰值且向SpVc深层移动,在牙移动14d染色减弱,数量减少。
3.DSS处理组牙齿移动后1d SpVc区域仅有少量Fos-LI表达,和实验组比较有显著差异,Western Blot检测在实验组SpVciba1蛋白总量表达较对照组明显增加,浅染深,胞体较大；DSS处理组牙齿移动后1d SpVc区域仅有少量iba1阳性细胞表达,小胶质细胞表达较少,浅染,胞体较小,与对照组相比无明显统计学差异。
结论：1.牙齿移动后空口咀嚼时间变化规律能够作为大鼠口颌面部疼痛行为学反应之一,应用到动物牙齿移动后疼痛基础研究中。
2.大鼠实验性后牙移动后不同时间点可以引起SpVc Fos-LI,相关性表达,和上述行为学变化密切相关。
3.大鼠实验性牙齿移动引起的局部疼痛激活SpVc小胶质细胞和星型胶质细胞的不同步增殖活化,验证了小胶质细胞的活化出现在炎性疼痛的起始阶段,星型胶质细胞在疼痛的发展和持续阶段有很强的活化反应。
4.DSS可以通过弱化牙齿移动后大鼠SpVc神经元和胶质细胞的激活反应,起到调节大鼠牙齿移动后自发痛行为作用,为临床治疗正畸牙移动后的疼痛不适提供了动物实验依据。
第二部分：DSS对实验性牙移动导致大鼠海马空间学习记忆改变的影响
目的：观察实验性牙移动疼痛不适能否引起大鼠焦虑等急性应激行为的改变,因为情绪应激反应等和动物主体空间学习记忆等认知能力密切相关,进一步通过行为,形态学方法检测牙移动是否能够引起大鼠学习记忆认知障碍,通过和上述实验相同DSS药物干预,了解DSS对实验行后大鼠空间学习记忆的影响。
方法：使用上述相同方法建立大鼠牙移动模型；实验分为对照组,牙齿移动组和DSS用药组；使用旷场实验,高架十字迷宫分别检测在牙移动后4h,12h,1,3,5,7d时间点大鼠焦虑情绪行为学改变；使用Morris水迷宫检测大鼠牙移动后和空间学习记忆行为学改变；检测和牙移动组相比较,DSS组上述行为学变化,同时使用荧光免疫组化,westen-blot和DII方法检测牙移动后7d时间点不同实验组大鼠海马区胶质细胞形态学变化及神经元椎体细胞可塑性改变。
结果：1.牙齿移动4h后,牙移动组与对照组比较,旷场内移动平均速度、中央活动时间、中央活动路程比率减少,牙齿移动1d上述旷场实验数据值明显达到峰值,牙齿移动7天组,两组上述数值没有明显统计学差异；牙移动4h后,高架十字迷宫实验组开放臂时间百分比减少明显,和对照组相比较,有统计学差异,牙移动1d后,开放臂时间百分比、开放臂次数明显减少,和对照组比较有统计学差异,而后随牙齿移动后时间变化实验组数值逐渐增加,牙齿移动7天组,处理组间上述数值没有明显统计学差异。
2. Morris水迷宫牙齿移动1d测试结果显示：牙移动组逃避潜伏期较对照组时间变短；牙齿移动后3d对照组,DSS用药组较牙齿移动组逃避潜伏期比较时间明显变短；牙移动5d后测试上述结果组间比较差异最明显。水迷宫第五天空间学习记忆实验结果显示：牙移动实验组大鼠穿越平台次数和平台所在象限tP/tT比值时明显低于实验对照的数值,在DSS用药组和牙移动组上述数值增加明显,差异显著。
3.在对照组及DSS+牙移动7d中,海马出现少量GFAP阳性星形胶质细胞；牙齿移动7d组大鼠海马GFAP阳性细胞数目明显增加,而牙移动实验前预先灌服DSS组大鼠海马星形胶质细胞的活性明显被抑制；Western-blot检测GFAP含量(荧光强度值)结果显示,与对照组比较,牙移动组GFAP表达明显增强,而DSS用药组GFAP的表达与实验组相比明显减少,DSS用药组与对照组的GFAP比较没有显著性差异。
4.DiI染色结果提示,牙齿移动组与对照组比较在总的神经树突棘密度上明显降低,具体表现为成熟型树突棘直径变短,密度明显减低,DSS用药组树突棘密度与实验对照组无明显差异,而杆状树突棘密度明显比牙移动组高。
结论：1.牙移动后因疼痛加重大鼠情绪障碍,导致大鼠急性焦虑应激反应。
2.牙齿移动后情绪反应进一步引起大鼠学习记忆认知障碍,DSS能够明显改善大鼠因牙齿移动导致的学习记忆能力的弱化。
3.大鼠牙移动后海马神经元突触可塑性的改变与学习记忆可能存在明显的相互作用关系,而且可能与DSS作用于星形胶质细胞有关。
The pain and discomfort caused byorthodontic treatment have been considered as tough problems in orthodontic practice.Pain is almost inevitable and the most unpleasant reaction for the orthodontic patient. It begins a few hours after the application of an orthodontic force, lasts for3-5days approximately. Pain is a determinating variable of adherence to orthodontic treatment because the idea of having a painful experience discourages many patients from such treatment.
Previous research demonstrated that orthodontic pain was caused by a process of edema, ischemia, inflammation in periodontal ligament, which may lead to the release of nociceptive mediators such as SP, CGRP resulting in neuronal activation. However, the current available analgesics could not relieve all the orthodontic pain, largely because the underlying mechanisms for orthodontic pain are far from being revealed. Previous experiments shown that tooth movement can stimulated the Fos protein expression in spinal trigeminal subnucleus caudalis (SpVc), one of the important relay nuclei for processing the nocicetptive information from the orofacial region.recently researches shown that glia, including astrocyte and microglia, play an important role in the initial induction and maintenance of chronic pain in the central neural system (CNS).Several inflammation animal model show oro-facial stimulus can Current pain theory has been shifted from a pure neuronal to contribution to neuronal-glia interaction.Can tooth movement stimulate neuronal-glia interaction involving neuron, microglia and astrocytein SpVc? If so, it will provide an new explanation for the orthodontic pain.
Chronic pain and anxiety are prevalent and frequently co-occur,several studies have assessed the impact of pain on anxiety outcomes, there is substantial literatures on the effects of anxiety and learning and memoryfrom behavioral and pharmacologic perspectives. Our purpose was to examine the association between experimental tooth movement (ETM) and anxiety.if so, can anxiety evoked by ETM functional impair the spacial learning and memory inhippocampusof rat?
Danggui-Shaoyao-San (DSS) is a traditional herbal medicine. It is first recorded in "JinKuiYaoLue".Recentexperiment evidence showed that DSS possesses antioxidative, cognitive enhancing and antidepressant effects. Further study suggested that the effect of DSS is related with the reversion of brain noradrenaline concentrations under depressive conditions. However, the potential analgesic effect of DSS and its underlying mechanism have not been investigated. One shared effect for first line antidepressant is analgesia for different pain modalities, eg duloxetine is efficacious for both severe depression and pain. Thus we hypothesized that DSS also possesses analgesic effect for orthodontic pain. Since glia system is involved in both depressionand pain, the potential analgesic mechanismsforantidepressant is inhibiting the interaction between neuron and glia. Thus we raised the hypothesis that DSS also possesses analgesic effect for orthodontic pain, and the possible analgesic mechanism for DSS is inhibiting the interaction between neuron and glia in SpVc.
1. Effects of Danggui-Shaoyao-san on the expression of Fos, iba1and GFAPin SpVc after ETM in rat
Objective:To observe spatial and temporal distribution of Fos protein and actived glia, including microglia and astrocytein SpVc duing ETM and its underlying neuron-glia interaction mechanisms for DSS's analgesia on orthodontic pain.
Methods:Rats were randomly divided into naive,sham,ETM, DSS plus ETM (DETM) groups, rats were pregavaged with DSS in the DETM groups. The right upper-first-molar was moved mesially described by Colin K.for rats in ETM and DETM groups, vacuous chewing movements (VCM) were evaluated at4h,12h,1,3,5and7d after operation. Immunofluorescent histochemistry analysis were used to quantify the Iba-1,GFAP and Fos expression levels in SpVc.Based on the behavioral feature and Fos or Iba-1expression data, the Iba-1and Fos expression of west-blot were only investigated at1d after operation in DETM group.
Results:1.The duration of VCM per unit-time was found significantly increased at4h in ETM group, peaked1d, and then decreased continuously until7d as compared with the sham group. The duration of VCM per unit-time in DETM group was expectedly lower than ETM group. However, a drastic peak increase of Vc Fos expression was observed at4h and gradually decreased after7d; while the increased Iba-1level reached the peak at1d after operation and gradually decreased after7days and GFAP reached the peak at7d after operation and gradually decreased. Furthermore, treatment with DSS significantly attenuated the ETM induced spontaneous pain. In parallel with the behavioral observations, pretreatment with DSS (for5days) significantly attenuated the Fos and Iba-1levels at1d after ETM operation.
Conclusions:1.change of VCM can be a reliable measure for tooth-movement pain in rats, which could be widely used in investigating the orthodontic pain mechanism.2.0ur data suggested that treatment with DSS has significant analgesic effects for ETM induced pain, which is accompanied with inhibition on both neuronal and microglial activation. The present study offered evidence that the traditional Chinese medicine DSS has analgesic effects via inhibiting microglia and neuronal activation at the primary integration site of orofacial nociceptive information, SpVc.
2. Effects of Danggui-Shaoyao-san on the influence of spacial learning and memory evocked by experimental tooth movement
Objective:To investigate methods the relationship betweenpainand anxietyduring ETM in ratscombined methods including behavioral testing, molecular neurobiology and morphology, we investigated the underlying mechanisms of astrocytes invloved in the impairment of learning and memory evoked by ETM, and the effects of DSS on synaptic plasticity in hippocampus and its possible therapeutic mechanisms.
Methods:The level of anxiety behavior were measured by the open field test and elevated plus maze test;Morris water maze testwas performed to test the change of learn and memory in the ETM rats with or without DSS administration; Iimmunofluorescent histochemistry was used to detect the expressions of astrocytic GFAP in hippocampus; immunofiuorescent Western blot was performed to observe the change of astrocytic GFAP in hippocampus; Dil staining method was performed to test the density of spines with3D analyzing method and detailed changes in hippocampus in the ETM rats with or without DSS administration.
Results:Parameters related to anxiety were higher in the ETM group compared to the shanm group,Statistically significant differences in anxiety-related behavior between sham and ETM group were found4h after ETM and pain-related behavior was significantly greater in the ETM group than in the shaml group at1d;Parameters related to learning and memory were lower in the ETM group compared to the shamgroup7d after ETM, the DSS significantly increased parameters related to learning and memory in EDTM rats compared to the ETM group; Astrocytic GFAP is significantly upregulated1d after ETM in the hippocampus, the DSS was significantly decreased express of GFAP in EDTM rats compared to the ETM group; The spine density, mean spines area and volume were decreased in ETM group, but the DSS administration could increase the spine density compared to the ETM group.
Conclusions:The ETMcould increase anxietyin rat that maybeprecede the appearance of periodontal pain in rat;DSS could block ETM-induced decrease of learning and memory behavior. Thedecreased spines density in hippocampus in the ETM rats may be related with the decline of the ability of learn and memory. The ability to change the synaptic plasticity after DSS administration may be correlated with the alleviation of impairment of learn and memory after ETM.
既往研究表明,牙齿移动是由正畸矫治力累及牙周组织所致炎性疼痛且与SP, CGRP,EAAs等炎性因子,神经递质等密切相关,但是牙移动所致疼痛发生机制并不是很清楚。c-fos是一种重要的早期即刻表达癌基因,被称为第三信使,它能通过调节神经细胞膜上受体与核内的相应靶基因相联系来参与疼痛病理过程,动物实验表明牙齿移动后c-fos参与了中枢神经系统(CNS)神经元的可塑性变化,大量的实验证据证明胶质细胞(星形胶质细胞和小胶质细胞)也在CNS病理性疼痛产生与发过程中起重要作用。三叉神经脊束核(Sp)是口颌面部伤害性刺激向中枢传导的重要门户,而三叉神经脊束核尾侧亚核(SpVc)是口颌面部参与伤害性刺激传导的重要部位,因此,我们以实验性牙移动为模型,检测大鼠SpVc神经元可塑性变化和胶质细胞形态学改变,进一步了解神经元和胶质细胞的相互作用,有助于阐明正畸疼痛的发病机制。
另外,痛的感觉分辨成分和痛的情绪体验成分两重含义说明了痛觉的多维性和复杂性,相关文献表明,在疼痛发生进程中,伴随有厌恶、焦虑等负面情绪的产生,而且疼痛和焦虑应急反应往往具有共病性,患疼痛的病人易患焦虑症,焦虑症患者的慢性疼痛发病率也会显著增加。追述文献得知,焦虑、抑郁等情绪反应等和动物主体空间学习记忆等认知能力密切相关,我们知道海马是学习和记忆过程中的易感脑区,那么,大鼠实验性牙移动是否能够引起其相关学习记忆认知障碍?本实验拟首次通过动物实验,观察初次牙移动过程中疼痛产生是否会引起大鼠焦虑情绪应激变化,这种焦虑状态是否会引起大鼠海马区空间学习、记忆等认知功能的改变?
传统的中草药当归芍药散(DSS),最早记载于“金匮药略”药典,最新文献指出当归芍药散具有回复大脑多巴胺和增强机体免疫力以及增强认知和抵抗衰老等作用,然而当归芍药散是否有预防治疗正畸牙移动后口颌面部疼痛作用没有文献提及。本实验拟通过建立实验性牙移动模型,观察DSS对大鼠疼痛行为学变化以及在SpVc对胶质细胞,神经元,在海马区对胶质细胞形态表达变化的影响,期待为缓解临床正畸治疗牙移动后引起的疼痛,改善因疼痛可能导致的大鼠急性情绪应激行为,空间学习记忆改变提供动物实验依据。
第一部分：DSS对实验性牙移动大鼠SpVc内fos, ibal和GFAP的表达变化的影响
目的：使用实验性牙移动模型,首次采用检测大鼠牙移动后单位时间空口咀嚼和行为学指标,结合荧光免疫组化,west-blot等形态学方法观察SpVc区域c-fos和iba-1, GFAP表达的变化,进一步通过实验前,实验中胃灌服DSS,检测其对牙齿移动过程中疼痛的调节作用。
方法：使用改良Colin.K法,用镍钛丝60g力交互牵引大鼠上颌前后牙建立大鼠牙移动模型；实验分为空白对照,对照组,牙齿移动组和用药组；分别检测在牙移动后4h,12h,1d,3d,5d,7d时间点大鼠行为学改变,SpVc内fos和iba-1, GFAP形态及蛋白表达的变化,以及用药组实验前5天胃灌注DSS汤剂,150mg/Kg,2/日,和牙移动组对比,检测SpVc上述指标的变化。
结果：1.大鼠牙移动后4h空口咀嚼时间开始增加,1d达到峰值,随后缓慢下降至7d时间对照组间比较变化不明显,和传统观测直接梳理面部行为学变化趋势一致,DSS处理组和牙移动组比较,大鼠单位空口咀嚼时间和直接擦拭嘴时间改变减少,呈显著性差异。
2.和对照组比较,牙移动4hSpVc Fos-LI数量明显增加,牙移动侧较对侧间差异明显,Votm区域较对照组增加不明显,牙移动后1dFos-LI数量呈减少趋势；牙齿移动后后4h,SpVc浅层iba-1免疫阳性细胞开始表达,大鼠牙齿移动后1d, iba-1免疫阳性细胞表达明显增加,达峰值。免疫染色加深,胞体变大,形态清晰丰满,并且分布区域向SpVc较深层趋向,3d后SpVc区域iba-1免疫阳性细胞较1d表达有所减弱,7d恢复到正常；牙齿移动后4h,SpVc内GFAP免疫阳性细胞有少量表达,GFAP染色浅,分支少而短,数目较少,牙齿移动后Id,GFAP免疫阳性细胞有少量表达可见GFAP染色加深,3d GFAP染色加深明显,分支增多,数目增加,对侧有少量表达,牙齿移动后7d GFAP染色到达峰值且向SpVc深层移动,在牙移动14d染色减弱,数量减少。
3.DSS处理组牙齿移动后1d SpVc区域仅有少量Fos-LI表达,和实验组比较有显著差异,Western Blot检测在实验组SpVciba1蛋白总量表达较对照组明显增加,浅染深,胞体较大；DSS处理组牙齿移动后1d SpVc区域仅有少量iba1阳性细胞表达,小胶质细胞表达较少,浅染,胞体较小,与对照组相比无明显统计学差异。
结论：1.牙齿移动后空口咀嚼时间变化规律能够作为大鼠口颌面部疼痛行为学反应之一,应用到动物牙齿移动后疼痛基础研究中。
2.大鼠实验性后牙移动后不同时间点可以引起SpVc Fos-LI,相关性表达,和上述行为学变化密切相关。
3.大鼠实验性牙齿移动引起的局部疼痛激活SpVc小胶质细胞和星型胶质细胞的不同步增殖活化,验证了小胶质细胞的活化出现在炎性疼痛的起始阶段,星型胶质细胞在疼痛的发展和持续阶段有很强的活化反应。
4.DSS可以通过弱化牙齿移动后大鼠SpVc神经元和胶质细胞的激活反应,起到调节大鼠牙齿移动后自发痛行为作用,为临床治疗正畸牙移动后的疼痛不适提供了动物实验依据。
第二部分：DSS对实验性牙移动导致大鼠海马空间学习记忆改变的影响
目的：观察实验性牙移动疼痛不适能否引起大鼠焦虑等急性应激行为的改变,因为情绪应激反应等和动物主体空间学习记忆等认知能力密切相关,进一步通过行为,形态学方法检测牙移动是否能够引起大鼠学习记忆认知障碍,通过和上述实验相同DSS药物干预,了解DSS对实验行后大鼠空间学习记忆的影响。
方法：使用上述相同方法建立大鼠牙移动模型；实验分为对照组,牙齿移动组和DSS用药组；使用旷场实验,高架十字迷宫分别检测在牙移动后4h,12h,1,3,5,7d时间点大鼠焦虑情绪行为学改变；使用Morris水迷宫检测大鼠牙移动后和空间学习记忆行为学改变；检测和牙移动组相比较,DSS组上述行为学变化,同时使用荧光免疫组化,westen-blot和DII方法检测牙移动后7d时间点不同实验组大鼠海马区胶质细胞形态学变化及神经元椎体细胞可塑性改变。
结果：1.牙齿移动4h后,牙移动组与对照组比较,旷场内移动平均速度、中央活动时间、中央活动路程比率减少,牙齿移动1d上述旷场实验数据值明显达到峰值,牙齿移动7天组,两组上述数值没有明显统计学差异；牙移动4h后,高架十字迷宫实验组开放臂时间百分比减少明显,和对照组相比较,有统计学差异,牙移动1d后,开放臂时间百分比、开放臂次数明显减少,和对照组比较有统计学差异,而后随牙齿移动后时间变化实验组数值逐渐增加,牙齿移动7天组,处理组间上述数值没有明显统计学差异。
2. Morris水迷宫牙齿移动1d测试结果显示：牙移动组逃避潜伏期较对照组时间变短；牙齿移动后3d对照组,DSS用药组较牙齿移动组逃避潜伏期比较时间明显变短；牙移动5d后测试上述结果组间比较差异最明显。水迷宫第五天空间学习记忆实验结果显示：牙移动实验组大鼠穿越平台次数和平台所在象限tP/tT比值时明显低于实验对照的数值,在DSS用药组和牙移动组上述数值增加明显,差异显著。
3.在对照组及DSS+牙移动7d中,海马出现少量GFAP阳性星形胶质细胞；牙齿移动7d组大鼠海马GFAP阳性细胞数目明显增加,而牙移动实验前预先灌服DSS组大鼠海马星形胶质细胞的活性明显被抑制；Western-blot检测GFAP含量(荧光强度值)结果显示,与对照组比较,牙移动组GFAP表达明显增强,而DSS用药组GFAP的表达与实验组相比明显减少,DSS用药组与对照组的GFAP比较没有显著性差异。
4.DiI染色结果提示,牙齿移动组与对照组比较在总的神经树突棘密度上明显降低,具体表现为成熟型树突棘直径变短,密度明显减低,DSS用药组树突棘密度与实验对照组无明显差异,而杆状树突棘密度明显比牙移动组高。
结论：1.牙移动后因疼痛加重大鼠情绪障碍,导致大鼠急性焦虑应激反应。
2.牙齿移动后情绪反应进一步引起大鼠学习记忆认知障碍,DSS能够明显改善大鼠因牙齿移动导致的学习记忆能力的弱化。
3.大鼠牙移动后海马神经元突触可塑性的改变与学习记忆可能存在明显的相互作用关系,而且可能与DSS作用于星形胶质细胞有关。
The pain and discomfort caused byorthodontic treatment have been considered as tough problems in orthodontic practice.Pain is almost inevitable and the most unpleasant reaction for the orthodontic patient. It begins a few hours after the application of an orthodontic force, lasts for3-5days approximately. Pain is a determinating variable of adherence to orthodontic treatment because the idea of having a painful experience discourages many patients from such treatment.
Previous research demonstrated that orthodontic pain was caused by a process of edema, ischemia, inflammation in periodontal ligament, which may lead to the release of nociceptive mediators such as SP, CGRP resulting in neuronal activation. However, the current available analgesics could not relieve all the orthodontic pain, largely because the underlying mechanisms for orthodontic pain are far from being revealed. Previous experiments shown that tooth movement can stimulated the Fos protein expression in spinal trigeminal subnucleus caudalis (SpVc), one of the important relay nuclei for processing the nocicetptive information from the orofacial region.recently researches shown that glia, including astrocyte and microglia, play an important role in the initial induction and maintenance of chronic pain in the central neural system (CNS).Several inflammation animal model show oro-facial stimulus can Current pain theory has been shifted from a pure neuronal to contribution to neuronal-glia interaction.Can tooth movement stimulate neuronal-glia interaction involving neuron, microglia and astrocytein SpVc? If so, it will provide an new explanation for the orthodontic pain.
Chronic pain and anxiety are prevalent and frequently co-occur,several studies have assessed the impact of pain on anxiety outcomes, there is substantial literatures on the effects of anxiety and learning and memoryfrom behavioral and pharmacologic perspectives. Our purpose was to examine the association between experimental tooth movement (ETM) and anxiety.if so, can anxiety evoked by ETM functional impair the spacial learning and memory inhippocampusof rat?
Danggui-Shaoyao-San (DSS) is a traditional herbal medicine. It is first recorded in "JinKuiYaoLue".Recentexperiment evidence showed that DSS possesses antioxidative, cognitive enhancing and antidepressant effects. Further study suggested that the effect of DSS is related with the reversion of brain noradrenaline concentrations under depressive conditions. However, the potential analgesic effect of DSS and its underlying mechanism have not been investigated. One shared effect for first line antidepressant is analgesia for different pain modalities, eg duloxetine is efficacious for both severe depression and pain. Thus we hypothesized that DSS also possesses analgesic effect for orthodontic pain. Since glia system is involved in both depressionand pain, the potential analgesic mechanismsforantidepressant is inhibiting the interaction between neuron and glia. Thus we raised the hypothesis that DSS also possesses analgesic effect for orthodontic pain, and the possible analgesic mechanism for DSS is inhibiting the interaction between neuron and glia in SpVc.
1. Effects of Danggui-Shaoyao-san on the expression of Fos, iba1and GFAPin SpVc after ETM in rat
Objective:To observe spatial and temporal distribution of Fos protein and actived glia, including microglia and astrocytein SpVc duing ETM and its underlying neuron-glia interaction mechanisms for DSS's analgesia on orthodontic pain.
Methods:Rats were randomly divided into naive,sham,ETM, DSS plus ETM (DETM) groups, rats were pregavaged with DSS in the DETM groups. The right upper-first-molar was moved mesially described by Colin K.for rats in ETM and DETM groups, vacuous chewing movements (VCM) were evaluated at4h,12h,1,3,5and7d after operation. Immunofluorescent histochemistry analysis were used to quantify the Iba-1,GFAP and Fos expression levels in SpVc.Based on the behavioral feature and Fos or Iba-1expression data, the Iba-1and Fos expression of west-blot were only investigated at1d after operation in DETM group.
Results:1.The duration of VCM per unit-time was found significantly increased at4h in ETM group, peaked1d, and then decreased continuously until7d as compared with the sham group. The duration of VCM per unit-time in DETM group was expectedly lower than ETM group. However, a drastic peak increase of Vc Fos expression was observed at4h and gradually decreased after7d; while the increased Iba-1level reached the peak at1d after operation and gradually decreased after7days and GFAP reached the peak at7d after operation and gradually decreased. Furthermore, treatment with DSS significantly attenuated the ETM induced spontaneous pain. In parallel with the behavioral observations, pretreatment with DSS (for5days) significantly attenuated the Fos and Iba-1levels at1d after ETM operation.
Conclusions:1.change of VCM can be a reliable measure for tooth-movement pain in rats, which could be widely used in investigating the orthodontic pain mechanism.2.0ur data suggested that treatment with DSS has significant analgesic effects for ETM induced pain, which is accompanied with inhibition on both neuronal and microglial activation. The present study offered evidence that the traditional Chinese medicine DSS has analgesic effects via inhibiting microglia and neuronal activation at the primary integration site of orofacial nociceptive information, SpVc.
2. Effects of Danggui-Shaoyao-san on the influence of spacial learning and memory evocked by experimental tooth movement
Objective:To investigate methods the relationship betweenpainand anxietyduring ETM in ratscombined methods including behavioral testing, molecular neurobiology and morphology, we investigated the underlying mechanisms of astrocytes invloved in the impairment of learning and memory evoked by ETM, and the effects of DSS on synaptic plasticity in hippocampus and its possible therapeutic mechanisms.
Methods:The level of anxiety behavior were measured by the open field test and elevated plus maze test;Morris water maze testwas performed to test the change of learn and memory in the ETM rats with or without DSS administration; Iimmunofluorescent histochemistry was used to detect the expressions of astrocytic GFAP in hippocampus; immunofiuorescent Western blot was performed to observe the change of astrocytic GFAP in hippocampus; Dil staining method was performed to test the density of spines with3D analyzing method and detailed changes in hippocampus in the ETM rats with or without DSS administration.
Results:Parameters related to anxiety were higher in the ETM group compared to the shanm group,Statistically significant differences in anxiety-related behavior between sham and ETM group were found4h after ETM and pain-related behavior was significantly greater in the ETM group than in the shaml group at1d;Parameters related to learning and memory were lower in the ETM group compared to the shamgroup7d after ETM, the DSS significantly increased parameters related to learning and memory in EDTM rats compared to the ETM group; Astrocytic GFAP is significantly upregulated1d after ETM in the hippocampus, the DSS was significantly decreased express of GFAP in EDTM rats compared to the ETM group; The spine density, mean spines area and volume were decreased in ETM group, but the DSS administration could increase the spine density compared to the ETM group.
Conclusions:The ETMcould increase anxietyin rat that maybeprecede the appearance of periodontal pain in rat;DSS could block ETM-induced decrease of learning and memory behavior. Thedecreased spines density in hippocampus in the ETM rats may be related with the decline of the ability of learn and memory. The ability to change the synaptic plasticity after DSS administration may be correlated with the alleviation of impairment of learn and memory after ETM.
引文
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