不同模型上雌激素受体拮抗剂对晕动病易感性的影响
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摘要
晕动病(motion sickness,MS)又称运动病,是因机体暴露于被动运动环境中,受不适宜的运动环境刺激,引起头晕、头痛(皮层感觉性反应);上腹部不适、出冷汗、面色苍白、恶心、呕吐等前庭和自主神经反应为主的综合征。因运动环境不同而可将晕动病分为晕船病、晕车病、晕机病、宇宙晕动病、模拟器晕动病等。人群中有近2/3人因晕动病使其在陆地、海上及空中的旅行受到影响。
晕动病是前庭、视觉、本体感觉和其它感觉刺激的整合,加速运动是晕动病外因,前庭终器敏感是内因。不同的被动运动方式,通过不同的反应通路引发晕动病。晕机、晕飞船是以角加速度刺激为主,主要刺激内耳的半规管;晕船、晕车是以直线加速度刺激为主,主要刺激耳石器的椭圆囊和球囊。
要进行晕动病深入研究,离不开整体动物实验。实验性晕动病动物模型和客观评估指标是晕动病研究的关键,也是难点。人体上晕动病的反应终点是呕吐。常用实验动物中,不同种属间对晕动刺激的反应差别很大。已知啮齿目的小鼠、大鼠和豚鼠,或兔等常用实验动物没有呕吐反射,不可能诱发呕吐,没有判断晕动病反应的直接客观指标,需要通过检测其它间接指标来反映晕动病的症状。
流行病学调查、模拟器或旋转视鼓诱发的晕动病研究均表明,女性较男性易感;臭鼩、大鼠、小鼠、黑猩猩和松鼠猴等动物实验也表明雌性易诱发晕动病。晕动病易感性的男女差异仅发生在8～39岁的个体,而40岁尤其60岁以上的个体,晕动病敏感性的性别差异不明显,如绝经期的妇女与同年龄段男性相比,晕动病发病率无显著性差异。而且,患乳腺癌的两姐妹服用他莫昔芬后晕动病发生率显著降低。可见,雌激素和其受体拮抗剂他莫昔芬与晕动病的发生关系密切。
因此,要研究雌激素和雌激素受体拮抗剂与晕动病易感性的关系,建立指标明确、切实可行的实验性晕动病动物模型是重要基础。本实验尝试并建立了不同的实验性晕动病模型,如小鼠热板反应、异食癖和自发活动及其大鼠异食癖的晕动病模型,并观察了不同模型上雌激素受体拮抗剂他莫昔芬对晕动病易感性的影响。
目的:建立几种指标明确、切实可行的晕动病实验动物模型,在不同模型上观察雌激素受体拮抗剂他莫昔芬对晕动病易感性的影响。
方法和结果:
1实验性晕动病模型的建立
在250 rpm旋转1 min后,小鼠在热板中舔后足潜伏期显著延长,而未旋转小鼠没有变化;在70 rpm旋转1 h后,小鼠异食高岭土量显著高于对照组,其自发活动中总路程和活动次数显著低于对照组(P＜0.05)。另外,仿Crampton条件下旋转120min后,大鼠高岭土摄取量量显著高于未旋转组。可见,在以上旋转刺激条件下,可以诱发小鼠或大鼠晕动病,故小鼠热板潜伏期、异食癖和自发活动以及大鼠异食癖行为均可作为晕动病动物模型的客观敏感指标。
2已知有效药物检验
用目前已知临床上经典的防晕药物东莨菪碱试验,观察其对旋转后小鼠或大鼠晕动病指标的影响。结果显示,东莨菪碱0.1和0.3 mg/kg灌胃30 min后,能分别显著降低旋转后小鼠热板潜伏期和高岭土摄取量(P＜0.05);东莨菪碱1.0 mg/kg亦能显著降低旋转后大鼠高岭土摄取量(P＜0.05)。结果表明,小鼠热板反应和异食癖模型以及大鼠异食癖模型基本成立。
然而,东莨菪碱0.15～0.6 mg/kg不能抑制小鼠旋转后自发活动的总路程和活动次数等指标的变化(P＞0.05 vs对照组),可能与东莨菪碱中枢抑制作用有关,提示东莨菪碱在该模型上缺乏特异性。
3化学迷路切除(chemical labyrinthectomy)对晕动病的影响
0.3 M的NaHCO_3溶液加至100 mg/ml的对氨基苯胂酸(arsanilic acid)溶液中,调节pH中性即可形成对氨基苯胂酸钠溶液。小鼠经戊巴比妥钠麻醉后,注射针穿过鼓膜向鼓室内注射对氨基苯胂酸钠溶液0.04 ml,注射完毕后用火棉胶紧紧塞住。假损伤组用生理盐水作为对照。3 d后以接触翻正反射(contact righting reflex)和游泳法(swimming test)等行为学方法评定前庭功能。结果显示,对氨基苯胂酸溶液处理的小鼠接触翻正反射恢复时间明显延长,游泳能力显著降低,提示前庭功能已经损伤。光镜前庭组织病理学和电镜前庭上皮细胞超微螺旋结构观察,进一步证实小鼠前庭器受到对氨基苯胂酸的破坏。
化学迷路切除后,小鼠旋转后热板潜伏期显著缩短、高岭土摄取量显著降低、自发活动的总路程和活动次数等显著增加,与对照组比较均有统计学意义(P＜0.05)。结果提示,化学迷路切除拮抗了小鼠前庭刺激诱发的晕动病。这与文献中报道的迷路切除也能废除大鼠异食癖行为相一致。可见,功能正常的前庭器官是晕动病发生必不可少的因素,二者关系密切。
4卵巢切除和他莫昔芬对晕动病易感性的影响
在小鼠热板反应和异食癖以及大鼠异食癖的晕动病模型上,观察卵巢切除(ovariectomy)或单次、重复灌胃给予雌激素受体拮抗剂他莫昔芬(tamoxifen)对晕动病易感性的影响。单次给予他莫昔芬20 mg/kg能显著降低旋转后小鼠热板潜伏期和高岭土摄取量(P＜0.05 vs对照组);连续21 d给予他莫昔芬2 mg/kg亦能显著降低旋转后热板潜伏期(P＜0.05 vs对照组)。结果提示,他莫昔芬对小鼠晕动病易感性有抑制作用。而单次或重复给予他莫昔芬15 mg/kg未能显示抑制大鼠异食癖行为。
小鼠卵巢切除后28 d,旋转后热板潜伏期显著增加,表明卵巢切除不能抑制热板反应模型中的晕动病。然而,大鼠卵巢切除30 d后,旋转后高岭土摄取量显著降低,表明雌激素水平对大鼠晕动病易感性亦有影响。可见,雌激素受体拮抗剂他莫昔芬和雌激素在不同晕动病模型上对晕动病易感性影响不同,可能与种属差异有关。
结论:小鼠热板反应、异食癖和自发活动的晕动病模型及其改进的大鼠异食癖的晕动病模型是指标明确、切实可行的晕动病实验动物模型,可用于晕动病药效及机制的研究。雌激素水平和雌激素受体拮抗剂他莫昔芬在不同模型上对晕动病易感性有不同的影响。在小鼠热板反应和异食癖模型上,雌激素受体拮抗剂他莫昔芬可以降低晕动病的易感性;卵巢切除小鼠旋转后热板潜伏期明显延长,即不能降低小鼠对晕动病的易感性。大鼠去卵巢和雌激素受体拮抗剂对晕动病的作用需重复试验验证。
Motion sickness (MS) is observed in humans exposed to unfamiliar motion. Usually, the four cardinal symptoms of cold sweating, pallor, nausea and vomiting are preceded by some combination of prodromal features such as lethargy, salivation, enhanced visceral awareness, dizziness and panting. According to different circumstances, MS includes seasickness, vehicle sickness, airsickness, space sickness and simulator sickness.
MS is the integration of vestibular, visual, proprioceptive and other sensory stimulus. Accelerating motion is exopathic causes, the sensitive vestibular end organ is the internal cause. Due to different motion models, MS is induced by different response access. Airsickness and space sickness are induced by angular accelerations, which stimulate primarily the semicircular canals. Seasickness and vehicle sickness are initiated by linear accelerations, which stimulate primarily the otolith organs.
It is required for research on MS to establish an experimental model. Vomiting is the criterion of gastrointestinal malaise in most studies dealing with MS. Since rodents are unable to vomit, they are not routinely used in studies dealing with MS. Many attempts have been made to use behavioral criteria other than emesis to detect for MS.
Clinical and preclinical studies have found sex-specific differences in susceptibility to MS and females are more susceptible than males. Symptoms of MS induced by an optokinetic drum were significantly different between females and males. Significant gender differences in MS were also observed in mice, rats, squirrel monkeys, chimpanzee and Suncus murinus. Gender differences in susceptivity to MS were found in human between 8-39 years old. There were less gender differences in human beyond 40 years old, especially 60 years old. In addition, after administering tamoxifen, a selective estrogen receptor antagonist, two sisters, both breast cancers, felt sick less frequently after different kinds of transport or motion. Therefore, estrogen and estrogen receptor antagonist would play an important role in genesis of MS.
In the present study, we try to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS in the different animal models for MS.
Objective: To establish the convenient and feasible animal models of MS in mice and rats for research on the mechanism of MS while to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS on these models.
Methods and results:
1. Establishment of experimental animal model for MS
Following 1 min of rotation at 250 rpm, the latency of licking a hindpaw on the hot plate in mice was significantly prolonged (P<0.05). Furthermore, following 60 min of rotation at 70 rpm, mice showed significant increase in kaolin intake, and showed significant decrease in total distances and activity of the open field test compared with unrotated mice (P<0.05). In addition, kaolin intake was also significantly increased following 120 min of rotation in rats (P<0.05). Therefore, rotation-induced analgesia, pica and spontaneous activity could be the behavioral indices of experimental MS in mice. Of course, pica have already been recognized also an index of MS in rats.
2. Examination of prophylactic-MS drugs (scopolamine) on animal model of MS
Scopolamine, the classic prophylactic-MS drugs, at dose of 0.1, 0.3 and 1.0 mg/kg (ig) significantly decreased latency of licking a hindpaw and kaolin intake in mice, and kaolin intake in rats following rotation, respectively. The results verified the feasibility of animal model of MS. So, it seems that latency of licking a hindpaw in mice and kaolin intake in rats or mice are sensitive parameters for evaluating the effects of prophylactic-MS drugs.
However, scopolamine (0.15-0.60 mg/kg) did not significantly decrease the total distances and activity in open field test following rotation. It is possible because of central inhibitory effect of scopolamine and scopolamine is lack of specificity on this model.
3. Effect of chemical labyrinthectomy on MS
Under anesthesia with 30 mg/kg intraperitoneally of sodium pentobarbital, mice received bilateral intratympanic each side 0.04 ml of the arsanilic acid solution. The needle was inserted through the tympanic membrane until resistance by the auditory ossicles was encountered, and then the solution was injected within 3-4 s. Following each side injection the ear canal was tightly packed with gelfoam to prevent against leaking of injected solution. Sham-lesioned mice received bilateral intratympanic injections of 0.04 ml of isotonic saline. It is convinced that vestibular apparatus was damaged by vestibular function evaluation using contact righting reflex and swimming test. Moreover, light and electron microscopy further confirmed the damage of vestibular apparatus.
Following rotation, mice with chemical labyrinthectomy showed decreases in the latency of licking a hindpaw and kaolin intake and increases in total distance and activity of the open field test, indicating that chemical labyrinthectomy antagonized MS induced by rotation in mice. It is consistent with labyrinthectomy abolished pica behavior in rats. Therefore, a functioning vestibular system is very necessary for the perception of MS.
4. Effects of ovariectomy and tamoxifen on susceptivity to MS
The postrotational latency of licking a hindpaw and kaolin intake in mice were significantly decreased 4 h after administratering tamoxifen at dose of 20 mg/kg (ig). In addition, the postrotational latency of licking a hindpaw in mice significantly decreased following administering intragastrally with tamoxifen at dose of 2 mg/kg once daily for 21 consecutive days. The results suggested that tamoxifen had inhibitory effect on susceptivity to MS in mice. However, tamoxifen with single or repeated administration at dose of 15 mg/kg did not decrease kaolin intake in rats following rotation.
The postrotational latency of licking a hindpaw significantly increased 28 d after ovarietomy in mice, suggesting that ovarietomy could not inhibit MS indexed as latency of licking a hindpaw. However, postrotional kaolin intake significantly decreased 30 d after ovarietomy in rats, indicating that estrogen could also influence susceptivity to MS. Thus, estrogen and selective estrogen receptor antagonist tamoxifen have different effects on susceptivity to MS on different animal models of MS.
Conclusion: It is suggested that rotation-induced hot-plate responses, pica behavior and spontaneous activity in mice and pica behavior in rats could be the convenient and feasible indices of animal model for research on the mechanism of MS. Furthermore, estrogen and tamoxifen have different effects on susceptivity to MS on different animal models of MS. Tamoxifen could reduce susceptivity to MS indexed as hot-plate responses and pica behavior in mice, whereas ovariectomy increased the postrotational hot-plate latency, suggesting increase of sensitivity to MS in mice. In addition, the effects of ovariectomy and tamoxifen on susceptivity to MS in rats await further repeated verification through experiments.
晕动病是前庭、视觉、本体感觉和其它感觉刺激的整合,加速运动是晕动病外因,前庭终器敏感是内因。不同的被动运动方式,通过不同的反应通路引发晕动病。晕机、晕飞船是以角加速度刺激为主,主要刺激内耳的半规管;晕船、晕车是以直线加速度刺激为主,主要刺激耳石器的椭圆囊和球囊。
要进行晕动病深入研究,离不开整体动物实验。实验性晕动病动物模型和客观评估指标是晕动病研究的关键,也是难点。人体上晕动病的反应终点是呕吐。常用实验动物中,不同种属间对晕动刺激的反应差别很大。已知啮齿目的小鼠、大鼠和豚鼠,或兔等常用实验动物没有呕吐反射,不可能诱发呕吐,没有判断晕动病反应的直接客观指标,需要通过检测其它间接指标来反映晕动病的症状。
流行病学调查、模拟器或旋转视鼓诱发的晕动病研究均表明,女性较男性易感;臭鼩、大鼠、小鼠、黑猩猩和松鼠猴等动物实验也表明雌性易诱发晕动病。晕动病易感性的男女差异仅发生在8～39岁的个体,而40岁尤其60岁以上的个体,晕动病敏感性的性别差异不明显,如绝经期的妇女与同年龄段男性相比,晕动病发病率无显著性差异。而且,患乳腺癌的两姐妹服用他莫昔芬后晕动病发生率显著降低。可见,雌激素和其受体拮抗剂他莫昔芬与晕动病的发生关系密切。
因此,要研究雌激素和雌激素受体拮抗剂与晕动病易感性的关系,建立指标明确、切实可行的实验性晕动病动物模型是重要基础。本实验尝试并建立了不同的实验性晕动病模型,如小鼠热板反应、异食癖和自发活动及其大鼠异食癖的晕动病模型,并观察了不同模型上雌激素受体拮抗剂他莫昔芬对晕动病易感性的影响。
目的:建立几种指标明确、切实可行的晕动病实验动物模型,在不同模型上观察雌激素受体拮抗剂他莫昔芬对晕动病易感性的影响。
方法和结果:
1实验性晕动病模型的建立
在250 rpm旋转1 min后,小鼠在热板中舔后足潜伏期显著延长,而未旋转小鼠没有变化;在70 rpm旋转1 h后,小鼠异食高岭土量显著高于对照组,其自发活动中总路程和活动次数显著低于对照组(P＜0.05)。另外,仿Crampton条件下旋转120min后,大鼠高岭土摄取量量显著高于未旋转组。可见,在以上旋转刺激条件下,可以诱发小鼠或大鼠晕动病,故小鼠热板潜伏期、异食癖和自发活动以及大鼠异食癖行为均可作为晕动病动物模型的客观敏感指标。
2已知有效药物检验
用目前已知临床上经典的防晕药物东莨菪碱试验,观察其对旋转后小鼠或大鼠晕动病指标的影响。结果显示,东莨菪碱0.1和0.3 mg/kg灌胃30 min后,能分别显著降低旋转后小鼠热板潜伏期和高岭土摄取量(P＜0.05);东莨菪碱1.0 mg/kg亦能显著降低旋转后大鼠高岭土摄取量(P＜0.05)。结果表明,小鼠热板反应和异食癖模型以及大鼠异食癖模型基本成立。
然而,东莨菪碱0.15～0.6 mg/kg不能抑制小鼠旋转后自发活动的总路程和活动次数等指标的变化(P＞0.05 vs对照组),可能与东莨菪碱中枢抑制作用有关,提示东莨菪碱在该模型上缺乏特异性。
3化学迷路切除(chemical labyrinthectomy)对晕动病的影响
0.3 M的NaHCO_3溶液加至100 mg/ml的对氨基苯胂酸(arsanilic acid)溶液中,调节pH中性即可形成对氨基苯胂酸钠溶液。小鼠经戊巴比妥钠麻醉后,注射针穿过鼓膜向鼓室内注射对氨基苯胂酸钠溶液0.04 ml,注射完毕后用火棉胶紧紧塞住。假损伤组用生理盐水作为对照。3 d后以接触翻正反射(contact righting reflex)和游泳法(swimming test)等行为学方法评定前庭功能。结果显示,对氨基苯胂酸溶液处理的小鼠接触翻正反射恢复时间明显延长,游泳能力显著降低,提示前庭功能已经损伤。光镜前庭组织病理学和电镜前庭上皮细胞超微螺旋结构观察,进一步证实小鼠前庭器受到对氨基苯胂酸的破坏。
化学迷路切除后,小鼠旋转后热板潜伏期显著缩短、高岭土摄取量显著降低、自发活动的总路程和活动次数等显著增加,与对照组比较均有统计学意义(P＜0.05)。结果提示,化学迷路切除拮抗了小鼠前庭刺激诱发的晕动病。这与文献中报道的迷路切除也能废除大鼠异食癖行为相一致。可见,功能正常的前庭器官是晕动病发生必不可少的因素,二者关系密切。
4卵巢切除和他莫昔芬对晕动病易感性的影响
在小鼠热板反应和异食癖以及大鼠异食癖的晕动病模型上,观察卵巢切除(ovariectomy)或单次、重复灌胃给予雌激素受体拮抗剂他莫昔芬(tamoxifen)对晕动病易感性的影响。单次给予他莫昔芬20 mg/kg能显著降低旋转后小鼠热板潜伏期和高岭土摄取量(P＜0.05 vs对照组);连续21 d给予他莫昔芬2 mg/kg亦能显著降低旋转后热板潜伏期(P＜0.05 vs对照组)。结果提示,他莫昔芬对小鼠晕动病易感性有抑制作用。而单次或重复给予他莫昔芬15 mg/kg未能显示抑制大鼠异食癖行为。
小鼠卵巢切除后28 d,旋转后热板潜伏期显著增加,表明卵巢切除不能抑制热板反应模型中的晕动病。然而,大鼠卵巢切除30 d后,旋转后高岭土摄取量显著降低,表明雌激素水平对大鼠晕动病易感性亦有影响。可见,雌激素受体拮抗剂他莫昔芬和雌激素在不同晕动病模型上对晕动病易感性影响不同,可能与种属差异有关。
结论:小鼠热板反应、异食癖和自发活动的晕动病模型及其改进的大鼠异食癖的晕动病模型是指标明确、切实可行的晕动病实验动物模型,可用于晕动病药效及机制的研究。雌激素水平和雌激素受体拮抗剂他莫昔芬在不同模型上对晕动病易感性有不同的影响。在小鼠热板反应和异食癖模型上,雌激素受体拮抗剂他莫昔芬可以降低晕动病的易感性;卵巢切除小鼠旋转后热板潜伏期明显延长,即不能降低小鼠对晕动病的易感性。大鼠去卵巢和雌激素受体拮抗剂对晕动病的作用需重复试验验证。
Motion sickness (MS) is observed in humans exposed to unfamiliar motion. Usually, the four cardinal symptoms of cold sweating, pallor, nausea and vomiting are preceded by some combination of prodromal features such as lethargy, salivation, enhanced visceral awareness, dizziness and panting. According to different circumstances, MS includes seasickness, vehicle sickness, airsickness, space sickness and simulator sickness.
MS is the integration of vestibular, visual, proprioceptive and other sensory stimulus. Accelerating motion is exopathic causes, the sensitive vestibular end organ is the internal cause. Due to different motion models, MS is induced by different response access. Airsickness and space sickness are induced by angular accelerations, which stimulate primarily the semicircular canals. Seasickness and vehicle sickness are initiated by linear accelerations, which stimulate primarily the otolith organs.
It is required for research on MS to establish an experimental model. Vomiting is the criterion of gastrointestinal malaise in most studies dealing with MS. Since rodents are unable to vomit, they are not routinely used in studies dealing with MS. Many attempts have been made to use behavioral criteria other than emesis to detect for MS.
Clinical and preclinical studies have found sex-specific differences in susceptibility to MS and females are more susceptible than males. Symptoms of MS induced by an optokinetic drum were significantly different between females and males. Significant gender differences in MS were also observed in mice, rats, squirrel monkeys, chimpanzee and Suncus murinus. Gender differences in susceptivity to MS were found in human between 8-39 years old. There were less gender differences in human beyond 40 years old, especially 60 years old. In addition, after administering tamoxifen, a selective estrogen receptor antagonist, two sisters, both breast cancers, felt sick less frequently after different kinds of transport or motion. Therefore, estrogen and estrogen receptor antagonist would play an important role in genesis of MS.
In the present study, we try to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS in the different animal models for MS.
Objective: To establish the convenient and feasible animal models of MS in mice and rats for research on the mechanism of MS while to investigate the effects of estrogen and estrogen receptor antagonist tamoxifen on susceptivity to MS on these models.
Methods and results:
1. Establishment of experimental animal model for MS
Following 1 min of rotation at 250 rpm, the latency of licking a hindpaw on the hot plate in mice was significantly prolonged (P<0.05). Furthermore, following 60 min of rotation at 70 rpm, mice showed significant increase in kaolin intake, and showed significant decrease in total distances and activity of the open field test compared with unrotated mice (P<0.05). In addition, kaolin intake was also significantly increased following 120 min of rotation in rats (P<0.05). Therefore, rotation-induced analgesia, pica and spontaneous activity could be the behavioral indices of experimental MS in mice. Of course, pica have already been recognized also an index of MS in rats.
2. Examination of prophylactic-MS drugs (scopolamine) on animal model of MS
Scopolamine, the classic prophylactic-MS drugs, at dose of 0.1, 0.3 and 1.0 mg/kg (ig) significantly decreased latency of licking a hindpaw and kaolin intake in mice, and kaolin intake in rats following rotation, respectively. The results verified the feasibility of animal model of MS. So, it seems that latency of licking a hindpaw in mice and kaolin intake in rats or mice are sensitive parameters for evaluating the effects of prophylactic-MS drugs.
However, scopolamine (0.15-0.60 mg/kg) did not significantly decrease the total distances and activity in open field test following rotation. It is possible because of central inhibitory effect of scopolamine and scopolamine is lack of specificity on this model.
3. Effect of chemical labyrinthectomy on MS
Under anesthesia with 30 mg/kg intraperitoneally of sodium pentobarbital, mice received bilateral intratympanic each side 0.04 ml of the arsanilic acid solution. The needle was inserted through the tympanic membrane until resistance by the auditory ossicles was encountered, and then the solution was injected within 3-4 s. Following each side injection the ear canal was tightly packed with gelfoam to prevent against leaking of injected solution. Sham-lesioned mice received bilateral intratympanic injections of 0.04 ml of isotonic saline. It is convinced that vestibular apparatus was damaged by vestibular function evaluation using contact righting reflex and swimming test. Moreover, light and electron microscopy further confirmed the damage of vestibular apparatus.
Following rotation, mice with chemical labyrinthectomy showed decreases in the latency of licking a hindpaw and kaolin intake and increases in total distance and activity of the open field test, indicating that chemical labyrinthectomy antagonized MS induced by rotation in mice. It is consistent with labyrinthectomy abolished pica behavior in rats. Therefore, a functioning vestibular system is very necessary for the perception of MS.
4. Effects of ovariectomy and tamoxifen on susceptivity to MS
The postrotational latency of licking a hindpaw and kaolin intake in mice were significantly decreased 4 h after administratering tamoxifen at dose of 20 mg/kg (ig). In addition, the postrotational latency of licking a hindpaw in mice significantly decreased following administering intragastrally with tamoxifen at dose of 2 mg/kg once daily for 21 consecutive days. The results suggested that tamoxifen had inhibitory effect on susceptivity to MS in mice. However, tamoxifen with single or repeated administration at dose of 15 mg/kg did not decrease kaolin intake in rats following rotation.
The postrotational latency of licking a hindpaw significantly increased 28 d after ovarietomy in mice, suggesting that ovarietomy could not inhibit MS indexed as latency of licking a hindpaw. However, postrotional kaolin intake significantly decreased 30 d after ovarietomy in rats, indicating that estrogen could also influence susceptivity to MS. Thus, estrogen and selective estrogen receptor antagonist tamoxifen have different effects on susceptivity to MS on different animal models of MS.
Conclusion: It is suggested that rotation-induced hot-plate responses, pica behavior and spontaneous activity in mice and pica behavior in rats could be the convenient and feasible indices of animal model for research on the mechanism of MS. Furthermore, estrogen and tamoxifen have different effects on susceptivity to MS on different animal models of MS. Tamoxifen could reduce susceptivity to MS indexed as hot-plate responses and pica behavior in mice, whereas ovariectomy increased the postrotational hot-plate latency, suggesting increase of sensitivity to MS in mice. In addition, the effects of ovariectomy and tamoxifen on susceptivity to MS in rats await further repeated verification through experiments.
引文
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