个别后牙移动导致大鼠初级中枢致敏的形态学研究
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摘要
口腔颌面疼痛不仅见于颞下颌关节紊乱病,牙髓牙周疾病,粘膜病,颌面创伤等疾病疼痛,而且见于一些治疗过程中,调查显示77%的病人在治疗中有不同程度的疼痛。最常见的治疗痛为正畸器具导致的疼痛,简称正畸疼痛(orthodontic pain,OP),起在正畸患者中的发生率达91%。动物实验表明,牙齿移动可以激活三叉神经脊束核表达Fos神经元增多和神经递质表达升高,三叉神经脊束核是颌面部伤害性信息重要的中继站,提示牙齿移动可能会导致初级中枢痛觉过敏。最新的研究显示,胶质细胞(星形胶质细胞和小胶质细胞)是慢性疼痛启动和维持的重要因素,胶质细胞不仅仅是神经元“谈话”(信息传递)的倾听者,还能参与神经元间的交流(疼痛调控),但是这些研究主要集中“在四肢—脊髓”。虽然脑干与脊髓结构功能相类似,但是也存在自己的特点,在少数颌面部炎症刺激的动物模型上,研究者观察到三叉神经脊束核中胶质细胞的激活。那么胶质细胞是否同样参与了如正畸疼痛等口颌面痛的调控?胶质细胞和神经元之间的信息传递在此过程中的起到什么样的作用?本课题采用大鼠为实验动物,采用正畸装置移动其一侧第一磨牙,对其初级中枢系统的形态学研究。
一、研究内容
1、建立与行为学相关的个别后牙移动的动物模型;
2、观察个别后牙移动对于颈髓和脑干中神经元与胶质细胞(星形胶质细胞和小胶质细胞)在激活情况,以探讨个别后牙移动刺激颈髓和脑干内哪些部
Pain is frequently associated with dental care. Although many dentists may be unaware of their patients' pain experiences during treatment, up to 77% of dental patients report some degree of pain during their visits to the dentist. In orthodontics, the situation does not seem to be very different. In a retrospective study of dental discomfort and pain among 203 adult Chinese patients in Singapore wearing fixed orthodontic appliances, 91% reported pain caused by their appliances. In 39% of these patients, tooth pain and discomfort were experienced during each step of the treatment, when a new archwire or elastic force was applied. Prospective investigations of both children and adults by Scheurer and Kvam revealed that 95% of the patients reported experiencing pain during orthodontic treatment. In recent Chinese investigation, the malocclusion rate is 51.84% ~ 72.92% which is much higher than 1960's. With the aesthetic request, more and more people ask for orthodontic treatment. But the orthodontic pain makes the patient fear and even give up the treatment. Animal experiment shows that tooth movement can stimulate the Fos protein expression and many neurotransimitter in spinal trigeminal subnucleus caudalis, one of the important relay nuclei for processing the nocicetptive information from the oro-facial region. It means that tooth movement may induce the sensitization in Vc. The recently researchs show that glia, including astrocyte and microglia, play an important role in the initial induction and maintenance of chronic pain in the spine. Several inflammation animal model show oro-facial stimulus can
active the trigeminal glia. Can tooth movement stimulate the trigeminal glia? If so, it will provide an surprising explanation for the orthodontic pain. The results will be useful for the future treatment research.Objective: ① To set up the tooth movement animal model related to behavior. (2) In this animal model, to observe spatial and temporal distribution of Fos protein and actived glia, including astrocyte and microglia. (3) To observe the spatial and temporal character of P2X receptors, NR2A/B receptor, EAAT1 and to investigate the mechanism of trigeminal glia activation and central sensitization induced by tooth movement.Methods: The experimental tooth movement was initiated in the rat upper molars by the method described by Waldo. Briefly, under light anesthesia with a gas mixture of ethyl ether and oxygen, a piece of the elastic band(3M Unitek, 1/8) was inserted unilaterally between the first and second upper molars (left side). ① Mechanical nociceptive threshold measurement: according to Ren's method, von Frey filaments were used to assess the muscle mechanical threshold, head withdrawal, leg raising and crying were observed as painful actions, survive for 2 h after the onset of tooth movement. (2)Immunohistochemistry: The free-floating sections were processed by the avidin-biotin complex ABC method to assess the Fos, GFAP and P2X. ③Confocal methods: FITC and Texas Red was used to obsever the Fos/OX42,NR2/EAAT1.Results:①The upper first molar moved to the maximum distance, 0.8 mm, in the 7th day. The bilateral masseter muscles and temporal muscles exhibited hyperalgesia from 3rd to 9th day, which the peak was the 5th to 7th day.②In normal animals, Fos-LI neurons were rarely observed in the SpVc and spinal cervical cord horn. The number of Fos-LI neurons increased significantly from 1 to 2h following the induction of experimental tooth movement, reaching a maximum at 2h, and then decreasing gradually. Most of the neurons were localized
in the superficial layers of the ipsilateral spinal cervical cord horn and the ipsilateral SpVc near the obex, but a few were observed at the ventral portion of the SpVc, NTS and VLM. The neurons at the superficial layers and ventral portion of the contralateral SpVc also showed Fos-like immunoreactivity, but their numbers were significantly smaller than those on the ipsilateral side.(3)Glial fibrillary acidic protein (GFAP) was labeled by immunohistochemistry and served as a marker for Astrocytes. Increased GFAP immunoreactivity was found in the bilateral spinal cervical horn and trigeminal nucleus nucleus within 1-7 days after tooth movement. No side differences were observed in the Vi after tooth movement.④Complement receptor 3, which is recognized by the antibody OX42, served as a marker for Microglias. Activated microglia was found in the SpVc and AP from 1st to 3 rd day, and light 0X42 immoreactivity was found in the Vi, VLM and ION. The peak expression was the 1st day.(5)In normal animals, P2X4 receptor was rarely expressed. Increased P2X4 immunoreactivity was found in the ipsilateral spinal cervical horn and SpVc and MVZ; While the P2X7 is only expressed on the contralateral spinal horn and ipsilateral SpV.?The central glutamatergic system has been implicated in the pathogenesis of europathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after tooth movement and contributed to neuropathic pain behaviors in rats. Tooth movement induced an initial GT upregulation up to at least postoperative day 3 primarily within the ipsilateral spinal cord dorsal horn and SpV, which was followed by a GT downregulation when examined on postoperative days 7 by immunohistochemistry. Increased EAAT1 immunoreactivity was observed within the ipsilateral SpV, and the contralateral SpV showed no difference in the experiment time. Tooth movement induced an initial GT upregulation up to at least postoperative day
一、研究内容
1、建立与行为学相关的个别后牙移动的动物模型;
2、观察个别后牙移动对于颈髓和脑干中神经元与胶质细胞(星形胶质细胞和小胶质细胞)在激活情况,以探讨个别后牙移动刺激颈髓和脑干内哪些部
Pain is frequently associated with dental care. Although many dentists may be unaware of their patients' pain experiences during treatment, up to 77% of dental patients report some degree of pain during their visits to the dentist. In orthodontics, the situation does not seem to be very different. In a retrospective study of dental discomfort and pain among 203 adult Chinese patients in Singapore wearing fixed orthodontic appliances, 91% reported pain caused by their appliances. In 39% of these patients, tooth pain and discomfort were experienced during each step of the treatment, when a new archwire or elastic force was applied. Prospective investigations of both children and adults by Scheurer and Kvam revealed that 95% of the patients reported experiencing pain during orthodontic treatment. In recent Chinese investigation, the malocclusion rate is 51.84% ~ 72.92% which is much higher than 1960's. With the aesthetic request, more and more people ask for orthodontic treatment. But the orthodontic pain makes the patient fear and even give up the treatment. Animal experiment shows that tooth movement can stimulate the Fos protein expression and many neurotransimitter in spinal trigeminal subnucleus caudalis, one of the important relay nuclei for processing the nocicetptive information from the oro-facial region. It means that tooth movement may induce the sensitization in Vc. The recently researchs show that glia, including astrocyte and microglia, play an important role in the initial induction and maintenance of chronic pain in the spine. Several inflammation animal model show oro-facial stimulus can
active the trigeminal glia. Can tooth movement stimulate the trigeminal glia? If so, it will provide an surprising explanation for the orthodontic pain. The results will be useful for the future treatment research.Objective: ① To set up the tooth movement animal model related to behavior. (2) In this animal model, to observe spatial and temporal distribution of Fos protein and actived glia, including astrocyte and microglia. (3) To observe the spatial and temporal character of P2X receptors, NR2A/B receptor, EAAT1 and to investigate the mechanism of trigeminal glia activation and central sensitization induced by tooth movement.Methods: The experimental tooth movement was initiated in the rat upper molars by the method described by Waldo. Briefly, under light anesthesia with a gas mixture of ethyl ether and oxygen, a piece of the elastic band(3M Unitek, 1/8) was inserted unilaterally between the first and second upper molars (left side). ① Mechanical nociceptive threshold measurement: according to Ren's method, von Frey filaments were used to assess the muscle mechanical threshold, head withdrawal, leg raising and crying were observed as painful actions, survive for 2 h after the onset of tooth movement. (2)Immunohistochemistry: The free-floating sections were processed by the avidin-biotin complex ABC method to assess the Fos, GFAP and P2X. ③Confocal methods: FITC and Texas Red was used to obsever the Fos/OX42,NR2/EAAT1.Results:①The upper first molar moved to the maximum distance, 0.8 mm, in the 7th day. The bilateral masseter muscles and temporal muscles exhibited hyperalgesia from 3rd to 9th day, which the peak was the 5th to 7th day.②In normal animals, Fos-LI neurons were rarely observed in the SpVc and spinal cervical cord horn. The number of Fos-LI neurons increased significantly from 1 to 2h following the induction of experimental tooth movement, reaching a maximum at 2h, and then decreasing gradually. Most of the neurons were localized
in the superficial layers of the ipsilateral spinal cervical cord horn and the ipsilateral SpVc near the obex, but a few were observed at the ventral portion of the SpVc, NTS and VLM. The neurons at the superficial layers and ventral portion of the contralateral SpVc also showed Fos-like immunoreactivity, but their numbers were significantly smaller than those on the ipsilateral side.(3)Glial fibrillary acidic protein (GFAP) was labeled by immunohistochemistry and served as a marker for Astrocytes. Increased GFAP immunoreactivity was found in the bilateral spinal cervical horn and trigeminal nucleus nucleus within 1-7 days after tooth movement. No side differences were observed in the Vi after tooth movement.④Complement receptor 3, which is recognized by the antibody OX42, served as a marker for Microglias. Activated microglia was found in the SpVc and AP from 1st to 3 rd day, and light 0X42 immoreactivity was found in the Vi, VLM and ION. The peak expression was the 1st day.(5)In normal animals, P2X4 receptor was rarely expressed. Increased P2X4 immunoreactivity was found in the ipsilateral spinal cervical horn and SpVc and MVZ; While the P2X7 is only expressed on the contralateral spinal horn and ipsilateral SpV.?The central glutamatergic system has been implicated in the pathogenesis of europathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after tooth movement and contributed to neuropathic pain behaviors in rats. Tooth movement induced an initial GT upregulation up to at least postoperative day 3 primarily within the ipsilateral spinal cord dorsal horn and SpV, which was followed by a GT downregulation when examined on postoperative days 7 by immunohistochemistry. Increased EAAT1 immunoreactivity was observed within the ipsilateral SpV, and the contralateral SpV showed no difference in the experiment time. Tooth movement induced an initial GT upregulation up to at least postoperative day
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