经眶下神经注射蛇毒建立新型大鼠三叉神经痛模型
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摘要
[研究背景]三叉神经痛被称为人类最大的痛苦之一,临床治疗手段虽然不少,但尚无一种公认的理想手段,其主要原因是三叉神经痛发病机制尚未阐明。目前已有的中枢性病源学说、周围性病源学说、血管压迫学说等都不能完整地解释该病临床现象。三叉神经痛机制的研究障碍之一是缺乏一个理想的动物模型,以往用于研究三叉神经痛的脑闩下蛛网膜下腔注射微量青霉素G-K引起大鼠三叉神经痛样反应模型、慢性压迫性损伤大鼠眶下神经模型及猫去牙髓模型等均有操作复杂、特异性不高等缺点,为此建立一种简便、易行且可靠的动物模型实属必要。
[目的]建立一种简便、易行、可靠的三叉神经痛动物模型。
[方法]
实验1选取Wistar大鼠20只,随机分为两组,沿眉弓上缘做弧形切口,显露位于眶内侧底部的眶下神经,予大鼠眶下神经干内注射蛇毒(浓度为0.1mg·1-1)或生理盐水6ul。于术前3天以及术后3、6、9、12、15、20、25、30、40、50、60、70、80以及90天进行机械痛阈行为学测定。观察大鼠眶下神经支配区域对机械刺激的疼痛反应阈值及疼痛行为学表现。
实验2选取Wistar大鼠30只,分别为蛇毒注射组20只和对照组10只,沿眉弓上缘做弧形切口,显露位于眶内侧底部的眶下神经,予大鼠眶下神经干内注射蛇毒(浓度为0.1mg·1-1)或生理盐水6ul。于术前3天以及术后3、7、14天进行视频行为学测定。摄像机放置在笼子前面1米处观察大鼠探究行为、静止行为、抓脸行为、摇头行为、舔后肢行为和舔身体行为的次数和时间。
实验3选取Wistar大鼠4只,分为蛇毒注射组和对照组各两只。按照实验1的方法制作蛇毒三叉神经痛模型。取大鼠延髓和眶下神经组织,制作电镜切片,观察电镜下延髓和眶下神经组织。
实验4选取Wistar大鼠2只,一侧股静脉推注5%伊文氏蓝染料,待大鼠全身转蓝约几分钟后,予ION神经鞘膜内注入蛇毒毒液或生理盐水,观察ION支配区域血管通透性以伊文氏蓝漏出量。
实验5选取实验2中制作完成蛇毒模型组大鼠16只,随机分为喂药组和对照组,每组8只。普瑞巴林喂药组采取灌胃法,药物用生理盐水溶解,每只灌注量为30mg/kg,连续灌注6天,对照组不做任何处理。喂药前1天以及喂药后第1、2、3、4、5、6、14天进行行为学测定。摄像机放置在笼子前面1米处观察大鼠探究行为、静止行为、抓脸行为、摇头行为、舔后肢行为、舔身体行为的次数和时间。
[结果]
1、实验组大鼠于术后3天出现眶下神经支配区域机械痛反应阈值与术前及对照组相比明显降低(P<0.01),大鼠易激惹,具有搔抓面部或攻击行为。机械痛阈值降低持续至术后60天,此后逐渐恢复,术后90天完全恢复同术前。
2、实验组大鼠于术后3天出现探究行为、静止行为、抓脸行为、摇头行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无明显变化。大鼠术后7天、14天探究行为、静止行为、抓脸行为、摇头行为变化进一步明显,与术前及对照组相比上述行为变化均有统计学意义(P<0.01)。舔后肢、舔身体行为与术前及对照组相比上述行为变化无统计学意义。
3、实验组延髓神经细胞出现髓鞘松解、脱髓鞘改变,同时出现轴索密度分布不均匀改变。实验组眶下神经细胞出现髓鞘松解、脱髓鞘改变。
4、予大鼠眶下神经干鞘膜内注射蛇毒15分钟后,围绕鼻区的口唇部出现蓝色斑块,伊文氏蓝渗出明显,对照组则几乎无伊文氏蓝渗出。
5、普瑞巴林组大鼠于喂药后第1天出现抓脸行为、摇头行为的变化,与术前及对照组相比上述行为变化有统计学意义,探究行为、静止行为、舔后肢、舔身体行为无显著改变。普瑞巴林组大鼠于喂药后第2天出现抓脸、摇头、静止行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),探究行为、舔后肢、舔身体行为无明显变化。普瑞巴林组大鼠于喂药后第3天出现抓脸、摇头、静止行为、探究行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无显著改变。普瑞巴林组大鼠于喂药后第4、5、6、14天均出现抓脸、摇头、静止行为、探究行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无显著改变。
结论眶下神经干注射蛇毒可致眶下神经支配区域出现痛觉超敏现象,自发性疼痛以及相关行为学改变；电子显微镜研究显示,延髓及眶下神经出现神经脱髓鞘的改变；伊文氏蓝实验表明该神经支配区域血管通透性增加；此模型给予普瑞巴林喂服后,大鼠疼痛行为学改变被抑制。上述研究结果提示,这一新型大鼠模型是目前较为理想的三叉神经动物模型之一。
[background] Trigeminal neuralgia is known as one of the greatest pain in human being, although many, but no one recognized ideal means, the difficulty to treat the disease is that the pathogenesis of trigeminal neuralgia is not clear. At present, the hypotheses such as the central of the pathogenic theory, around the pathogenic theory and vascular compression theory can not explain the clinical manifestations of TN. One of the obstacles of trigeminal neuralgia mechanism is the lack of an ideal animal model for trigeminal neuralgia, previous research on brain bolt under subarachnoid injection of penicillin G-K induced rat model of trigeminal neuralgia, chronic constriction injury of the rat infraorbital nerve model and the cat to pulp model has complex operation, specificity is not higher shortcomings, to establish a simple, easy and reliable animal model is necessary.
[Objective] To establish a simple, easy, and reliable animal model of trigeminal neuralgia.
[Methods]
Experiment1:Forty Wistar rats were randomly divided into two groups, along the eyebrow upper margin arc incision, revealed in the medial orbital at the bottom of the infraorbital nerve, to the rat infraorbital nerve trunk injection of venom (concentration of0.1mg· L-1) or saline6u1. On the3day before surgery and after3,6,9,12,15,20,25,30,40,50,60,70,80and90days of mechanical threshold behavior determination. Observed the rat infraorbital nerve innervation area of pain threshold and pain reaction behavior of mechanical stimulation manifestations.
Experiment2:Thirty Wistar rats, respectively, venom injection group was20and10in the control group only, along the eyebrow upper margin arc incision, revealed in the medial orbital at the bottom of the infraorbital nerve, to the rat infraorbital nerve trunk injection of venom (concentration of0.1mg· L-1) or saline6u1. We use video recording behavior of rats3days before surgery and3、7、14days。 We recorded the rats exploratory behavior, static behavior, grasping the face behavior, head shaking behavior, number and time licking hind behavior and lick the behavior of the body, we will be a camera is placed in front of the cage1meters.
Experiment3:Four Wistar rats, venom injection group was2and2in the control group only. We produce venom trigeminal neuralgia model according to the method of experiment1. We cut the nerve tissue of rat medulla oblongata and infraorbital, and make electron microscopic section, to observe the medulla oblongata and infraorbital nerve tissue in the electron microscope。
Experiment4:Two Wistar rats, one side femoral vein infusion of5%Evans blue dye, when the rat body turn blue about a few minutes later, ION nerve sheath to inject venom or saline, observation of ION dominant regional vascular permeability to Evans blue leakage.
Experiment5:We select the production has been completed venom model group16rats in experiment2. were randomly divided into treatment group and control group, with8rats in each group. Pregabalin treatment group take gastric lavage, drug dissolved in physiological saline solution, each perfusion30mg/kg, continuous infusion for6days,1daysbefore taking medicine and after taking medicine1,2,3,4,5,6,14days of ethology determination. We recorded the rats exploratory behavior, static behavior, grasping the face behavior, head shaking behavior, number and time licking hind behavior and lick the behavior of the body, we will be a camera is placed in front of the cage1meters.
[results]
1, Group of the experimental rats with mechanical pain threshold was significantly lower compared with the preoperative and group of the control。in infraorbital innervation area after three days(P<0.01)。 compared to rats with irritable, scratching the face or aggressive behavior. The pain threshold decreased mechanical continued to60days after operation, then gradually recovered, after90days to fully recover the preoperative.
2, The experimental group rats with exploratory behavior, static behavior, grasping the face behavior, shook his head behavior,compared with the preoperative and the control group had significant changes in the behavior after three days(P<0.01), behavior of Licking hind legs and licking body had no obvious change3day after surgery。 exploratory behavior, static behavior, grasping the face behavior, behavior change greatly shook his head, compared with the preoperative and the control group had significant changes in behavior. behavior of Licking hind legs and licking body had no obvious change and before operation and compared with the control group had no significant changes in the behavior of,7and14days after surgery。
3,Group of venom modle, bulbar neurons appeared loose, myelin demyelination and axonal density, uneven distribution of change. Snake venom model group infraorbital nerve cells, demyelination changes of myelin loose solution.
4, We inject venom in the rat infraorbital nerve sheath, after15minutes, the blue plaque around the nose lips. leakage of Evans blue significantly, while the control group almost no leakage of Evans blue.
5, The experimental group rats with exploratory grasping the face behavior, shook his head behavior,compared with the preoperative and the control group had significant changes in the behavior, exploratory behavior, static behaviors, licking hind, licking behavior without significant change in body. Changes in the pregabalin group rats in second days feeding after grasping the face, head, static behavior, compared with the preoperative and the control group had significant changes in the behavior of exploratory behavior, licking hind, no significant change in body, licking behavior. Pregabalin group rats in third days feeding after grasping the face, head, change static behavior, exploratory behavior, compared with the preoperative and the control group had significant changes in the behavior, and no significant change of licking hind, licking behavior of the body. Pregabalin group rats in medicine,5,6, fourth and14days were grasping the face, head, static behavior, exploratory behavior, compared with the preoperative and the control group had significant changes in the behavior, and no significant change of licking hind legs, licking behavior of the body.
[Conclusion] We injected the venom in the infraorbital nerve can cause allodynia in area supplied by the infraorbital nerve, spontaneous pain and related behavioral changes, medulla oblongata and infraorbital nerve demyelination changes, increased vascular permeability. This model gives the pregabalin Hello clothing, behavior changes of rats is inhibited, the above research results proved that the model can be used as animal model of trigeminal neuralgia.
[目的]建立一种简便、易行、可靠的三叉神经痛动物模型。
[方法]
实验1选取Wistar大鼠20只,随机分为两组,沿眉弓上缘做弧形切口,显露位于眶内侧底部的眶下神经,予大鼠眶下神经干内注射蛇毒(浓度为0.1mg·1-1)或生理盐水6ul。于术前3天以及术后3、6、9、12、15、20、25、30、40、50、60、70、80以及90天进行机械痛阈行为学测定。观察大鼠眶下神经支配区域对机械刺激的疼痛反应阈值及疼痛行为学表现。
实验2选取Wistar大鼠30只,分别为蛇毒注射组20只和对照组10只,沿眉弓上缘做弧形切口,显露位于眶内侧底部的眶下神经,予大鼠眶下神经干内注射蛇毒(浓度为0.1mg·1-1)或生理盐水6ul。于术前3天以及术后3、7、14天进行视频行为学测定。摄像机放置在笼子前面1米处观察大鼠探究行为、静止行为、抓脸行为、摇头行为、舔后肢行为和舔身体行为的次数和时间。
实验3选取Wistar大鼠4只,分为蛇毒注射组和对照组各两只。按照实验1的方法制作蛇毒三叉神经痛模型。取大鼠延髓和眶下神经组织,制作电镜切片,观察电镜下延髓和眶下神经组织。
实验4选取Wistar大鼠2只,一侧股静脉推注5%伊文氏蓝染料,待大鼠全身转蓝约几分钟后,予ION神经鞘膜内注入蛇毒毒液或生理盐水,观察ION支配区域血管通透性以伊文氏蓝漏出量。
实验5选取实验2中制作完成蛇毒模型组大鼠16只,随机分为喂药组和对照组,每组8只。普瑞巴林喂药组采取灌胃法,药物用生理盐水溶解,每只灌注量为30mg/kg,连续灌注6天,对照组不做任何处理。喂药前1天以及喂药后第1、2、3、4、5、6、14天进行行为学测定。摄像机放置在笼子前面1米处观察大鼠探究行为、静止行为、抓脸行为、摇头行为、舔后肢行为、舔身体行为的次数和时间。
[结果]
1、实验组大鼠于术后3天出现眶下神经支配区域机械痛反应阈值与术前及对照组相比明显降低(P<0.01),大鼠易激惹,具有搔抓面部或攻击行为。机械痛阈值降低持续至术后60天,此后逐渐恢复,术后90天完全恢复同术前。
2、实验组大鼠于术后3天出现探究行为、静止行为、抓脸行为、摇头行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无明显变化。大鼠术后7天、14天探究行为、静止行为、抓脸行为、摇头行为变化进一步明显,与术前及对照组相比上述行为变化均有统计学意义(P<0.01)。舔后肢、舔身体行为与术前及对照组相比上述行为变化无统计学意义。
3、实验组延髓神经细胞出现髓鞘松解、脱髓鞘改变,同时出现轴索密度分布不均匀改变。实验组眶下神经细胞出现髓鞘松解、脱髓鞘改变。
4、予大鼠眶下神经干鞘膜内注射蛇毒15分钟后,围绕鼻区的口唇部出现蓝色斑块,伊文氏蓝渗出明显,对照组则几乎无伊文氏蓝渗出。
5、普瑞巴林组大鼠于喂药后第1天出现抓脸行为、摇头行为的变化,与术前及对照组相比上述行为变化有统计学意义,探究行为、静止行为、舔后肢、舔身体行为无显著改变。普瑞巴林组大鼠于喂药后第2天出现抓脸、摇头、静止行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),探究行为、舔后肢、舔身体行为无明显变化。普瑞巴林组大鼠于喂药后第3天出现抓脸、摇头、静止行为、探究行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无显著改变。普瑞巴林组大鼠于喂药后第4、5、6、14天均出现抓脸、摇头、静止行为、探究行为的变化,与术前及对照组相比上述行为变化有统计学意义(P<0.01),舔后肢、舔身体行为无显著改变。
结论眶下神经干注射蛇毒可致眶下神经支配区域出现痛觉超敏现象,自发性疼痛以及相关行为学改变；电子显微镜研究显示,延髓及眶下神经出现神经脱髓鞘的改变；伊文氏蓝实验表明该神经支配区域血管通透性增加；此模型给予普瑞巴林喂服后,大鼠疼痛行为学改变被抑制。上述研究结果提示,这一新型大鼠模型是目前较为理想的三叉神经动物模型之一。
[background] Trigeminal neuralgia is known as one of the greatest pain in human being, although many, but no one recognized ideal means, the difficulty to treat the disease is that the pathogenesis of trigeminal neuralgia is not clear. At present, the hypotheses such as the central of the pathogenic theory, around the pathogenic theory and vascular compression theory can not explain the clinical manifestations of TN. One of the obstacles of trigeminal neuralgia mechanism is the lack of an ideal animal model for trigeminal neuralgia, previous research on brain bolt under subarachnoid injection of penicillin G-K induced rat model of trigeminal neuralgia, chronic constriction injury of the rat infraorbital nerve model and the cat to pulp model has complex operation, specificity is not higher shortcomings, to establish a simple, easy and reliable animal model is necessary.
[Objective] To establish a simple, easy, and reliable animal model of trigeminal neuralgia.
[Methods]
Experiment1:Forty Wistar rats were randomly divided into two groups, along the eyebrow upper margin arc incision, revealed in the medial orbital at the bottom of the infraorbital nerve, to the rat infraorbital nerve trunk injection of venom (concentration of0.1mg· L-1) or saline6u1. On the3day before surgery and after3,6,9,12,15,20,25,30,40,50,60,70,80and90days of mechanical threshold behavior determination. Observed the rat infraorbital nerve innervation area of pain threshold and pain reaction behavior of mechanical stimulation manifestations.
Experiment2:Thirty Wistar rats, respectively, venom injection group was20and10in the control group only, along the eyebrow upper margin arc incision, revealed in the medial orbital at the bottom of the infraorbital nerve, to the rat infraorbital nerve trunk injection of venom (concentration of0.1mg· L-1) or saline6u1. We use video recording behavior of rats3days before surgery and3、7、14days。 We recorded the rats exploratory behavior, static behavior, grasping the face behavior, head shaking behavior, number and time licking hind behavior and lick the behavior of the body, we will be a camera is placed in front of the cage1meters.
Experiment3:Four Wistar rats, venom injection group was2and2in the control group only. We produce venom trigeminal neuralgia model according to the method of experiment1. We cut the nerve tissue of rat medulla oblongata and infraorbital, and make electron microscopic section, to observe the medulla oblongata and infraorbital nerve tissue in the electron microscope。
Experiment4:Two Wistar rats, one side femoral vein infusion of5%Evans blue dye, when the rat body turn blue about a few minutes later, ION nerve sheath to inject venom or saline, observation of ION dominant regional vascular permeability to Evans blue leakage.
Experiment5:We select the production has been completed venom model group16rats in experiment2. were randomly divided into treatment group and control group, with8rats in each group. Pregabalin treatment group take gastric lavage, drug dissolved in physiological saline solution, each perfusion30mg/kg, continuous infusion for6days,1daysbefore taking medicine and after taking medicine1,2,3,4,5,6,14days of ethology determination. We recorded the rats exploratory behavior, static behavior, grasping the face behavior, head shaking behavior, number and time licking hind behavior and lick the behavior of the body, we will be a camera is placed in front of the cage1meters.
[results]
1, Group of the experimental rats with mechanical pain threshold was significantly lower compared with the preoperative and group of the control。in infraorbital innervation area after three days(P<0.01)。 compared to rats with irritable, scratching the face or aggressive behavior. The pain threshold decreased mechanical continued to60days after operation, then gradually recovered, after90days to fully recover the preoperative.
2, The experimental group rats with exploratory behavior, static behavior, grasping the face behavior, shook his head behavior,compared with the preoperative and the control group had significant changes in the behavior after three days(P<0.01), behavior of Licking hind legs and licking body had no obvious change3day after surgery。 exploratory behavior, static behavior, grasping the face behavior, behavior change greatly shook his head, compared with the preoperative and the control group had significant changes in behavior. behavior of Licking hind legs and licking body had no obvious change and before operation and compared with the control group had no significant changes in the behavior of,7and14days after surgery。
3,Group of venom modle, bulbar neurons appeared loose, myelin demyelination and axonal density, uneven distribution of change. Snake venom model group infraorbital nerve cells, demyelination changes of myelin loose solution.
4, We inject venom in the rat infraorbital nerve sheath, after15minutes, the blue plaque around the nose lips. leakage of Evans blue significantly, while the control group almost no leakage of Evans blue.
5, The experimental group rats with exploratory grasping the face behavior, shook his head behavior,compared with the preoperative and the control group had significant changes in the behavior, exploratory behavior, static behaviors, licking hind, licking behavior without significant change in body. Changes in the pregabalin group rats in second days feeding after grasping the face, head, static behavior, compared with the preoperative and the control group had significant changes in the behavior of exploratory behavior, licking hind, no significant change in body, licking behavior. Pregabalin group rats in third days feeding after grasping the face, head, change static behavior, exploratory behavior, compared with the preoperative and the control group had significant changes in the behavior, and no significant change of licking hind, licking behavior of the body. Pregabalin group rats in medicine,5,6, fourth and14days were grasping the face, head, static behavior, exploratory behavior, compared with the preoperative and the control group had significant changes in the behavior, and no significant change of licking hind legs, licking behavior of the body.
[Conclusion] We injected the venom in the infraorbital nerve can cause allodynia in area supplied by the infraorbital nerve, spontaneous pain and related behavioral changes, medulla oblongata and infraorbital nerve demyelination changes, increased vascular permeability. This model gives the pregabalin Hello clothing, behavior changes of rats is inhibited, the above research results proved that the model can be used as animal model of trigeminal neuralgia.
引文
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