Name: osteoarthritis pain model induced by intra-articular injection of mono-iodoacetate in rats
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本研究由中国浙江省自然科学基金（批准号:LY17H270016），中国国家自然科学基金（批准号:81774331，81873049和81673997）和中国浙江省中医药科学技术项目（批准号:2013ZQ007和2016ZZ011）资助。

涉及动物受试者的程序已获得浙江中医大学医学规范和伦理委员会的批准，并符合中国关于实验动物使用和护理的立法。
1.膝关节内注射单碘乙酸酯
<ol><li>适应一周后，将40只体重180-200g（4-5周龄）的雄性Sprague-Dawley大鼠随机平均分为四组（n = 10只大鼠/组）。 注意:对照组的大鼠将关节内注射50μL盐水，而实验组中的大鼠将分别用溶解在50μL盐水中的0.5，1.5或3mgMIA处理。</li>
	<li>在注射当天，新鲜制备MIA在无菌盐水（0.9%NaCl）中的溶液，浓度为15，30和60mg / mL，并在无菌盐水（0.9%NaCl）中制备10%戊巴比妥溶液。 注意:MIA对粘膜，上呼吸道，眼睛和皮肤和其他组织具有极大的破坏性作用。因此，在制备溶液时，建议戴口罩和手套。</li>
	<li>通过腹膜内注射60mg / kg的氯胺酮和5mg / kg的甲苯噻嗪（均在盐水中制备）麻醉大鼠。用镊子轻轻夹住大鼠的脚趾以确认麻醉。</li>
	<li>将老鼠背朝下放置。刮掉膝盖，用酒精擦拭膝关节周围的区域。</li>
	<li>保持膝盖成90°角，露出髌骨下方的白色髌腱。用指尖按压髌腱，找到髌骨下方的间隙。</li>
	<li>选择间隙和髌腱外侧的交界处作为注射部位。然后，将 26 G 针头垂直插入约 5 mm 的部位。当针头在关节空间时，不应感到阻力。 注意:保持针头垂直于注射部位很重要。</li>
	<li>将 50 μL 盐水或 MIA 溶液注入关节腔。慢慢拔出针头，在注射部位缠上一块纱布，以尽量减少回流和泄漏。麻醉恢复后，取下纱布。</li>
	<li>如第 2 节所述，在注射后 1、7、14、21、28 和 35 天测试疼痛相关行为。</li>
</ol>2. 行为评估
<ol><li>机械撤退阈值 注意:MWT通过冯弗雷测试13 测量，观察者对动物接受的注射不知情。<ol><li>将老鼠放在高架塑料笼子（17 cm x 11 cm x 13 cm）中，金属丝网底座悬挂在桌子上方 50 厘米处。确保测试环境安静，给大鼠30分钟适应环境。</li>
		<li>将冯弗雷针垂直按压在每只大鼠后爪的足底表面上。逐渐（约20 g / s）和线性增加压力，直到发生爪子抬起或舔爪子。</li>
		<li>使用低于上一个阈值的力，以确保阈值是最小撤回力。测试每只大鼠三次以上，至少间隔3-5分钟。</li>
		<li>记录引起爪子撤回反射的最小力。将数据平均为大鼠的MWT。</li>
	</ol></li>
	<li>热抽出延迟 （TWL） 注意:使用足底测试设备（材料表）测量TWL，观察者对动物接受的注射不知情。<ol><li>将一个有机玻璃盒（60厘米x 20厘米x 14厘米，分为6个隔间）放在3毫米厚的玻璃板上，并将老鼠放入盒子中（每个隔间一个）。确保环境安静，室温恒定。</li>
		<li>给大鼠30分钟适应测试环境。</li>
		<li>通过红外辐射计校准热刺激。将所需的红外强度设置为 70 个单位。</li>
		<li>将红外发射器/探测器放在被测爪子中心正下方的容器上。</li>
		<li>按 开始 按钮。计时器将自动启动。一旦爪子发生移动，控制器将自动关闭红外灯并完全停止计时器。</li>
		<li>记录爪子退出和爪子舔舐出现时的反应时间。 注意:测试的阳性反应被视为爪子撤回和爪子舔。如果只发生爪子撤退，则应将其视为大鼠的自愿运动，而不是积极的反应。</li>
		<li>重复测试三次以上。将数据平均为大鼠的TWL。 注意:每次辐射热暴露不应超过 20 秒。同一后爪上的红外刺激应至少间隔 3-5 分钟。</li>
	</ol></li>
	<li>步态模式分析 注意:使用成像系统（材料表）测量步态模式分析，观察者对动物接受的注射不知情。<ol><li>通过使用步行舱两端的旋钮将步行舱的长度调整为适合大鼠的长度（例如，61厘米）。</li>
		<li>在正式实验之前，将一只大鼠放入步行舱并训练大鼠以 18 厘米/秒的速度不间断地运行至少 5 个步程循环。 注意:当老鼠第一次被放置在步行舱中时，速度可以设置为大约 20 厘米/秒，并在奔跑约 2 秒时关闭。然后将速度设置为 18 厘米/秒。如果老鼠在行走过程中停下来或后退，用隔板轻轻拍打老鼠的背部。尝试将速度从 18 厘米/秒逐渐降低到 10 厘米/秒。如果大鼠最终未能进行测试，则可以选择另一只大鼠进行测试。</li>
		<li>慢慢增加跑步机的速度，直到达到目标速度（18 厘米/秒）。使用安装在透明跑步机皮带下方的高速数字摄像机捕获至少5秒的大鼠连续运动的视频。</li>
		<li>测试每只大鼠至少相隔5分钟以获得至少三次不间断的运行。</li>
		<li>在成像软件中绘制一个"边界框"来定义动物行走图像的边界，并输入每个视频的运行速度。选择视频作为一个组，并通过软件自动处理视频。处理视频后，软件将输出多个电子表格来报告步态指数，包括站姿、摆动、制动、推进、踏频、步数顺序等。</li>
		<li>计算总爪面积 （cm 2）、平均步幅 （cm） 和统一步幅。 注意:总爪面积是每组大鼠四只爪子总面积的平均值，爪面积定义为在步道周期的站立阶段与跑步机接触的最大爪面积。步幅是同一爪子在一个完整步幅中的初始接触之间的距离。单位步幅 = 平均步幅 （cm）/体长 （cm）。</li>
	</ol></li>
</ol>3. 组织病理学和免疫组织化学分析
<ol><li>通过腹膜内注射150mg / kg的戊巴比妥钠（在盐水中制备）对大鼠实施安乐死。立即切除膝关节进行组织学分析。</li>
	<li>在10%福尔马林中固定关节24小时，在磷酸盐缓冲盐水（PBS）中用10%EDTA脱钙8周，然后将关节嵌入石蜡中。 注意:福尔马林会引起眼睛、皮肤和呼吸道刺激。它应该在引擎盖中处理。</li>
	<li>用切片机将石蜡嵌入接头切成3mm厚的接头，并漂浮在含有蒸馏水的40°C水浴中。</li>
	<li>将切片转移到载玻片上。将载玻片干燥过夜，并将载玻片储存在室温（RT）下以继续以下染色。</li>
	<li>将载玻片放入60°C烘箱中4小时以脱蜡。</li>
	<li>将载玻片分别浸入二甲苯，二甲苯，100%乙醇，100%乙醇，95%乙醇，80%乙醇和75%乙醇中，在室温下5分钟。</li>
	<li>用苏木精和伊红（H&E），safranin-O（SO）和阿尔新蓝苏木精（ABH）以及针对大鼠II型胶原蛋白（Col2），X型胶原蛋白（Col10）和基质金属蛋白酶13（MMP13）的抗体染色切片，如步骤3.8-3.12所述。</li>
	<li>H&E 染色<ol><li>用去离子H2O冲洗载玻片3分钟。用苏木精染色载玻片3-5分钟。</li>
		<li>用去离子H 2O 3x 冲洗载玻片，每次 1 分钟，直到表面上没有苏木精残留。</li>
		<li>用伊红染色载玻片30秒。然后，用去离子H2O 3x冲洗载玻片，每次1分钟，直到表面上没有曙红残留。</li>
		<li>将载玻片浸入0.1%氨中10-20秒。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟。</li>
		<li>分别将幻灯片依次浸入95%乙醇，100%乙醇，二甲苯，二甲苯和二甲苯中1分钟。</li>
		<li>用中性树脂盖玻片。</li>
	</ol></li>
	<li>SO 染色<ol><li>用去离子H2O冲洗载玻片3分钟。用苏木精染色载玻片3-5分钟。</li>
		<li>在1%酸性酒精（约3秒）中快速分化。然后，用去离子H2O 3x冲洗载玻片，每次1分钟，直到表面上没有苏木精残留。</li>
		<li>用快速绿色（FCF）溶液染色载玻片5分钟。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟。</li>
		<li>用SO染色载玻片1-2分钟。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟。</li>
		<li>用1%乙酸冲洗载玻片1-2分钟以去除残留的FCF。用去离子H2O冲洗载玻片1分钟。</li>
		<li>分别将幻灯片依次浸入95%乙醇，100%乙醇，二甲苯，二甲苯和二甲苯中1分钟。</li>
		<li>用中性树脂盖玻片。</li>
	</ol></li>
	<li>ABH 染色<ol><li>用去离子H2O冲洗载玻片3分钟。将载玻片浸入1%酸性酒精中30秒，然后在纸巾上短暂沥干（不要冲洗）。</li>
		<li>将载玻片浸入ABH中1小时。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟，直到表面上没有 ABH 残留。</li>
		<li>在1%酸性酒精（约3秒）中快速分化。用去离子H2O 3x冲洗载玻片，每次1分钟。</li>
		<li>将载玻片浸入0.5%铵水中15秒。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟。</li>
		<li>将载玻片浸入95%乙醇中1分钟。将载玻片浸入伊红/橙色G溶液中1.5分钟。</li>
		<li>分别将幻灯片依次浸入95%乙醇，100%乙醇，二甲苯，二甲苯和二甲苯中1分钟。</li>
		<li>用中性树脂盖玻片。</li>
	</ol></li>
	<li>根据曼金的评分系统14，在显微镜下检查所有载玻片，并通过双盲观察以0-13的等级进行统计评分。</li>
	<li>免疫组化<ol><li>用去离子H2O冲洗载玻片3分钟。</li>
		<li>将载玻片浸入0.1M柠檬酸钠中，并将载玻片置于60°C烘箱中4小时以取出抗原。</li>
		<li>将载玻片浸入PBS中的0.3%Triton X-100中10分钟。然后，用PBS 2x冲洗载玻片，每次3分钟。</li>
		<li>在室温下在3%H2O2 甲醇溶液中孵育切片10分钟以阻断内源性过氧化物酶活性。用PBS 2x冲洗载玻片，每次3分钟。</li>
		<li>在室温下用 5% 山羊血清在 PBS 中孵育切片 30 分钟以阻断任何非特异性结合。用PBS 2x冲洗载玻片，每次3分钟。</li>
		<li>将切片在4°C下孵育过夜，与100μLPBS稀释（1:1，000）抗大鼠II型胶原蛋白（Col2），X型胶原蛋白（Col10）和基质金属蛋白酶13（MMP13）的一抗。用PBS 2x冲洗载玻片，每次3分钟。</li>
		<li>用 100 μL PBS 稀释的 （1:1，000） 二抗（山羊抗小鼠二抗或山羊抗小鼠二抗）在室温下孵育切片 20 分钟。 用 PBS 冲洗载玻片 2x，每次 3 分钟。</li>
		<li>用 100 μL 3，3′-二氨基联苯胺 （DAB） 工作溶液孵育切片。当显色反应使表位位点变成棕色时监测反应。 注意:DAB是一种致癌物质。使用 DAB 工作时，请务必戴手套并在头罩中工作。 注意:显色时间可能从几秒钟到10分钟不等。</li>
		<li>一旦切片上出现棕色，用去离子 H2O 2x 冲洗载玻片，每次 3 分钟。</li>
		<li>将载玻片浸入苏木精中1-2分钟以复染载玻片。然后，用去离子H 2O 3x 冲洗载玻片，每次 1 分钟。</li>
		<li>分别将幻灯片依次浸入95%乙醇，100%乙醇，二甲苯，二甲苯和二甲苯中1分钟。</li>
		<li>用中性树脂盖玻片。</li>
		<li>在显微镜下观察切片中抗体染色的颜色。</li>
	</ol></li>
</ol>

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Correlation of morphology with biochemical and metabolic data.</a> Journal of Bone and Joint Surgery. 53 (3), 523-537 (1971).</li><li>Yan, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chondroprotective+effects+of+platelet+lysate+towards+monoiodoacetate-induced+arthritis+by+suppression+of+TNF-&#945;-induced+activation+of+NF-&#312;B+pathway+in+chondrocytes.">Chondroprotective effects of platelet lysate towards monoiodoacetate-induced arthritis by suppression of TNF-&#945;-induced activation of NF-&#312;B pathway in chondrocytes.</a> Aging. 11 (9), 2797-2811 (2019).</li><li>Yan, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intra-Articular+Injection+of+Extract+Attenuates+Pain+Behavior+and+Cartilage+Degeneration+in+Mono-Iodoacetate+Induced+Osteoarthritic+Rats.">Intra-Articular Injection of Extract Attenuates Pain Behavior and Cartilage Degeneration in Mono-Iodoacetate Induced Osteoarthritic Rats.</a> Frontiers in Pharmacology. 9, 1360 (2018).</li><li>Wang, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Agkistrodon+ameliorates+pain+response+and+prevents+cartilage+degradation+in+monosodium+iodoacetate-induced+osteoarthritic+rats+by+inhibiting+chondrocyte+hypertrophy+and+apoptosis.">Agkistrodon ameliorates pain response and prevents cartilage degradation in monosodium iodoacetate-induced osteoarthritic rats by inhibiting chondrocyte hypertrophy and apoptosis.</a> Journal of Ethnopharmacology. 231, 545-554 (2019).</li><li>Yamada, E. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+monosodium+iodoacetate+dosage+to+induce+knee+osteoarthritis:+Relation+with+oxidative+stress+and+pain.">Evaluation of monosodium iodoacetate dosage to induce knee osteoarthritis: Relation with oxidative stress and pain.</a> International Journal of Rheumatic Diseases. 22 (3), 399-410 (2019).</li><li>Schuelert, N., McDougall, J. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrophysiological+evidence+that+the+vasoactive+intestinal+peptide+receptor+antagonist+VIP6-28+reduces+nociception+in+an+animal+model+of+osteoarthritis.">Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP6-28 reduces nociception in an animal model of osteoarthritis.</a> Osteoarthritis and Cartilage. 14 (11), 1155-1162 (2006).</li><li>Lee, S. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Choline,+an+alpha7+nicotinic+acetylcholine+receptor+agonist,+alleviates+hyperalgesia+in+a+rat+osteoarthritis+model.">Choline, an alpha7 nicotinic acetylcholine receptor agonist, alleviates hyperalgesia in a rat osteoarthritis model.</a> Neuroscience Letters. 548, 291-295 (2013).</li><li>Piesla, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Abnormal+gait,+due+to+inflammation+but+not+nerve+injury,+reflects+enhanced+nociception+in+preclinical+pain+models.">Abnormal gait, due to inflammation but not nerve injury, reflects enhanced nociception in preclinical pain models.</a> Brain Research. 1295, 89-98 (2009).</li><li>Udo, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Monoiodoacetic+acid+induces+arthritis+and+synovitis+in+rats+in+a+dose-+and+time-dependent+manner:+proposed+model-specific+scoring+systems.">Monoiodoacetic acid induces arthritis and synovitis in rats in a dose- and time-dependent manner: proposed model-specific scoring systems.</a> Osteoarthritis and Cartilage. 24 (7), 1284-1291 (2016).</li><li>Guingamp, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mono-iodoacetate-induced+experimental+osteoarthritis:+a+dose-response+study+of+loss+of+mobility,+morphology,+and+biochemistry.">Mono-iodoacetate-induced experimental osteoarthritis: a dose-response study of loss of mobility, morphology, and biochemistry.</a> Arthritis &amp; Rheumatism. 40 (9), 1670-1679 (1997).</li><li>Jeong, J. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Eupatilin+Exerts+Antinociceptive+and+Chondroprotective+Properties+in+a+Rat+Model+of+Osteoarthritis+by+Downregulating+Oxidative+Damage+and+Catabolic+Activity+in+Chondrocytes.">Eupatilin Exerts Antinociceptive and Chondroprotective Properties in a Rat Model of Osteoarthritis by Downregulating Oxidative Damage and Catabolic Activity in Chondrocytes.</a> PLoS ONE. 10 (6), 0130882 (2015).</li><li>Cook, J. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+cartilage+repair.">Animal models of cartilage repair.</a> Bone &amp; Joint Research. 3 (4), 89-94 (2014).</li><li>Little, C. B., Zaki, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=What+constitutes+an+"animal+model+of+osteoarthritis"--the+need+for+consensus.">What constitutes an "animal model of osteoarthritis"--the need for consensus.</a> Osteoarthritis and Cartilage. 20 (4), 261-267 (2012).</li></ol>

作者没有什么可透露的。

MIA诱导的OA大鼠模型是一种成熟且广泛使用的模型。关节内注射MIA最初引起严重和急性炎症，这导致OA的更长和退行性阶段17，18。在这项研究中，我们通过MWT和TWL测量了伤害敏感性，并使用成像系统评估了步态改变。先前的报告发现，注射MIA可以提高传入膝关节纤维的敏感性，导致伤害感受，这反映在热痛觉过敏和降低的机械阈值19<sup...

骨关节炎（OA）是世界上最常见的关节疾病，估计影响成人10-12%的人口1。最普遍受累的关节是膝关节，OA在老年人中发病率较高，尤其是女性2。作为一种慢性疾病，OA在几十年内逐渐发展为关节衰竭，症状包括软骨丢失，滑膜炎症，骨癣菌病，功能下降和慢性疼痛3。根据世界卫生组织（WHO）的数据，OA是女性中第四大最普遍的疾病，也是男性中第八大最流行的疾病。到2020年，OA可能成为人类第四大致残性疾病4。然而，目前可用的OA疗法仅解决症状，并延长关节置换手术的时间5。
人类患者的自发性OA往往需要很长时间才能产生关节相关疼痛等临床症状6。在OA的早期阶段，疼痛通常是间歇性的，并且随着疾病的进展变得更加频繁和严重，使其成为患者的主要主诉7。因此，在过去的半个世纪中，已经开发了广泛的OA疼痛动物模型来促进疼痛缓解疗法。OA模型通常分为自发模型和诱导模型。自发模型包括自然发生的模型和转基因模型，它们可以更密切地模拟人类原发性OA的过程8。诱导模型一般可分为两类:1）手术或其他创伤诱导的创伤后OA;或2）关节内注射软骨毒性或促炎物质3。这些模型为OA的病理生理学研究奠定了基础，并为开发减轻疼痛和增加功能的药物做出了巨大贡献。
最近，OA建模最广泛使用的诱导剂是单碘乙酸酯（MIA）。MIA是甘油醛-3-磷酸脱氢酶的抑制剂，可引起软骨基质的变化、降解、软骨流失、滑膜炎等变化，与人类骨关节炎的病理变化相似9.已经注意到，关节内注射MIA在MIA给药后28天引起持续疼痛，表明MIA模型可能有助于研究慢性伤害性疼痛10，11，12。在这项研究中，雄性Sprague-Dawley大鼠接受关节内注射，膝关节中含有0.5、1.5或3mg的MIA。通过注射后1、7、14、21、28和35天的机械和热敏感性评估来测量MIA诱导的关节疼痛的严重程度。在此基础上，选择1.5mg的MIA作为最终浓度，以评估注射后28天的步态模式和组织学变化。

<table><tbody><tr><td>Anti-Collagen II antibody</td><td>Abcam(UK)</td><td>34712</td><td>Primary antibody for immunohistochemistry (IHC)</td></tr><tr><td>Anti-Collagen X (Col10) antibody</td><td>Abcam(UK)</td><td>49945</td><td>Primary antibody for IHC</td></tr><tr><td>DigiGait Imaging System</td><td>Mouse Specifics (Boston, MA, USA)</td><td></td><td>Equipment for gait patterns analyses</td></tr><tr><td>Eosin</td><td>Sigma-Aldrich</td><td>861006</td><td>The dye for HE staining</td></tr><tr><td>Fast Green FCF</td><td>Sigma-Aldrich</td><td>F7252</td><td>The dye for SO staining</td></tr><tr><td>Goat anti-mouse antibody</td><td>ZSGQ-BIO (Beijing, China)</td><td>PV-9002</td><td>Secondary antibody for IHC</td></tr><tr><td>Goat anti-rabbit antibody</td><td>ZSGQ-BIO (Beijing, China)</td><td>PV-9001</td><td>Secondary antibody for IHC</td></tr><tr><td>Hematoxylin</td><td>Sigma-Aldrich</td><td>H3163</td><td>The dye for HE staining</td></tr><tr><td>MIA</td><td>Sigma-Aldrich</td><td>I4386-10G</td><td>powder</td></tr><tr><td>MMP13</td><td>Cell Signaling Technology, Inc. (Danvers, MA, USA)</td><td>69926</td><td>Primary antibody for IHC</td></tr><tr><td>Modular tissue embedding center</td><td>Thermo Fisher Scientific (USA)</td><td>EC 350</td><td>Produce paraffin blocks.</td></tr><tr><td>Plantar Test apparatus</td><td>UgoBasile (Italy)</td><td>37370</td><td>Equipment for TWL assay</td></tr><tr><td>PrimeScript RT reagent Kit (Perfect Real Time)</td><td>TaKaRa Biotechnology Co. Ltd. (Dalian, China)</td><td>RR037A</td><td>Extracte total RNA from cultured cells</td></tr><tr><td>Rotary and Sliding Microtomes</td><td>Thermo Fisher Scientific (USA)</td><td>HM325</td><td>Precise paraffin sections.</td></tr><tr><td>Safranin-O</td><td>Sigma-Aldrich</td><td>S2255</td><td>The dye for SO staining</td></tr><tr><td>Tissue-Tek VIP 5 Jr</td><td>Sakura (Japan)</td><td></td><td>Vacuum Infiltration Processor</td></tr></tbody></table>

osteoarthritis pain model induced by intra-articular injection of mono-iodoacetate in rats

目前的骨关节炎（OA）动物模型可分为自发模型和诱导模型，两者都旨在模拟人类OA的病理生理变化。但是，疼痛作为OA晚期的主要症状，影响患者的日常生活，可用的模型并不多。单碘乙酸（MIA）诱导模型是应用最广泛的OA疼痛模型，主要用于啮齿动物。MIA是甘油醛-3-磷酸脱氢酶的抑制剂，可导致软骨细胞死亡，软骨变性，骨赘和动物行为的可测量变化。此外，在MIA诱导的模型中可以检测到基质金属蛋白酶（MMP）和促炎细胞因子（IL1 β和TNF α）的表达变化。这些变化与人类OA病理生理状况一致，表明MIA可以诱导可测量和成功的OA疼痛模型。本研究旨在描述大鼠关节内注射MIA的方法，并讨论由此产生的疼痛相关行为和组织病理学变化。

通过这种方法，我们在大鼠中建立了OA疼痛模型并检测了由此产生的变化。MWT和TWL分别反映机械性异常性疼痛和热痛觉过敏。如图 1所示，MIA诱导的机械性异常性疼痛和热痛觉过敏以剂量依赖性方式存在。值得注意的是，MWT的下降从21 d达到峰值至28 d，然后反弹，表明现阶段可能发生关节修复，但3 mg MIA组的MWT仍处于较低水平。TWL的变化与MWT大致一致（图2</stron...

Watch this Scientific Journal Video about Osteoarthritis Pain Model Induced by Intra-Articular Injection of Mono-Iodoacetate in Rats at JoVE.com

Osteoarthritis Pain Model Induced by Intra-Articular Injection of Mono-Iodoacetate in Rats

本研究描述了大鼠关节内注射单碘乙酸酯的方法，并讨论了由此产生的疼痛相关行为和组织病理学变化，为今后的应用提供参考。

大鼠关节内注射单碘乙酸酯诱导的骨关节炎疼痛模型

The current animal models of osteoarthritis (OA) can be divided into spontaneous models and induced models, both of which aim to simulate the ...

osteoarthritis-pain-model-induced-intra-articular-injection-mono

Research

JoVE Journal

Medicine

8.1K 次观看.  Zhejiang Chinese Medical University. 本研究描述了大鼠关节内注射单碘乙酸酯的方法，并讨论了由此产生的疼痛相关行为和组织病理学变化，为今后的应用提供参考。

视频: Osteoarthritis Pain Model Induced by Intra-Articular Injection of Mono-Iodoacetate in Rats

Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of the population1,2. Symptoms include spontaneous (tingling, burning, electric-shock like) pain, dysaesthesia, paraesthesia, allodynia (pain resulting from normally non-painful stimuli) and hyperalgesia (an increased response to painful stimuli). The sensory symptoms are co-morbid with behavioural disabilities, such as insomnia and depression. To study chronic neuropathic pain several animal models mimicking peripheral nerve injury have been developed, one of the most widely used is Bennett and Xie's (1988) unilateral sciatic nerve chronic constriction injury (CCI)3 (Figure 1). Here we present a method for performing CCI and testing pain hypersensitivity.
CCI is performed under anaesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Four chromic gut ligatures are tied loosely around the sciatic nerve at 1 mm intervals, to just occlude but not arrest epineural blood flow. The wound is closed with sutures in the muscle and staples in the skin. The animal is then allowed to recover from surgery for 24 hrs before pain hypersensitivity testing begins.
For behavioural testing, rats are placed into the testing apparatus and are allowed to habituate to the testing procedure. The area tested is the mid-plantar surface of the hindpaw (Figure 2), which falls within the sciatic nerve distribution. Mechanical withdrawal threshold is assessed by mechanically stimulating both injured and uninjured hindpaws using an electronic dynamic plantar von Frey aesthesiometer or manual von Frey hairs4. The mechanical withdrawal threshold is the maximum pressure exerted (in grams) that triggers paw withdrawal. For measurement of thermal withdrawal latency, first described by Hargreaves et al (1988), the hindpaw is exposed to a beam of radiant heat through a transparent glass surface using a plantar analgesia meter5,6. The withdrawal latency to the heat stimulus is recorded as the time for paw withdrawal in both injured and uninjured hindpaws. Following CCI, mechanical withdrawal threshold, as well as thermal withdrawal latency in the injured paw are both significantly reduced, compared to baseline measurements and the uninjured paw (Figure 3). The CCI model of peripheral nerve injury combined with pain hypersensitivity testing provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain. In our laboratory, we utilise CCI alongside thermal and mechanical sensitivity of the hindpaws to investigate the role of neuro-immune interactions in the pathogenesis and treatment of neuropathic pain.

Due to the simplicity of surgery and the robust behavioural outcome, chronic constriction of the sciatic nerve is one of the pre-eminent animal models of neuropathic pain. Within 24 hrs following surgery, pain hypersensitivity is established and can be quantitatively measured using a von Frey aesthesiometer (mechanical test) and plantar analgesia meter (thermal test).

慢性缩窄大鼠坐骨神经疼痛过敏测试

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of ...

科研

医学

Retinal Detachment Model in Rodents by Subretinal Injection of Sodium Hyaluronate

Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD). However, the height and duration of RD or the occurrence of subretinal hemorrhage can affect photoreceptor cell death in the detached retina. Hence, it is advantageous to create reproducible RDs without subretinal hemorrhage for evaluating photoreceptor cell death. We modified a previously reported method to create bullous and persistent RDs in a reproducible location with rare occurrence of subretinal hemorrhage. The critical step of this modified method is the creation of a self-sealing scleral incision, which can prevent leakage of sodium hyaluronate after injection into the subretinal space. To make the self-sealing scleral incision, a scleral tunnel is created, followed by scleral penetration into the choroid with a 30 G needle. Although choroidal hemorrhage may occur during this step, astriction with a surgical spear reduces the rate of choroidal hemorrhage. This method allows a more reproducible and reliable model of photoreceptor death in diseases that involve RD such as rhegmatogenous RD, retinopathy of prematurity, diabetic retinopathy, central serous chorioretinopathy, and age-related macular degeneration (AMD).

Creating experimental retinal detachments with a reproducible and sustained height of detachment, and without subretinal hemorrhage, is important for studying the pathophysiology of photoreceptor cell loss in retinal disease and evaluating potential therapeutic interventions. Here, we report such a method in detail.

视网膜脱离模型鼠害由透明质酸钠的视网膜下注射

Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD). However, the height and duration of RD or the ...

Experimental Glaucoma Induced by Ocular Injection of Magnetic Microspheres

Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye.

We present a method for inducing elevated intraocular pressure (IOP), by injecting magnetic microspheres into the rat eye, to model glaucoma. This leads to strong pressure rises, and extensive neuronal death. This protocol is easy to perform, does not require repeat injections, and produces stable long-lasting IOP rises.

实验诱发青光眼通过磁性微球注射眼

Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present ...

Inflammatory TMJ Pain Mouse Model: Bite Force and Von Frey Filament Assessments

Temporomandibular Joint Pain Measurement by Bite Force and Von Frey Filament Assays in Mice

Temporomandibular joint (TMJ) pain and osteoarthritis (OA) are common and debilitating disorders that impair patients' quality of life. The mechanisms driving diseases-related pain are poorly understood, and current treatments fail to provide effective and long-term therapeutic effects. Additionally, pain assessment in research, particularly orofacial pain, poses several challenges that complicate studies in both clinical and basic science settings. Therefore, we have established an inflammatory TMJ pain mouse model via intra-articular injection of CFA (Complete Freund's Adjuvant) and evaluated pain behaviors by bite force measurement and the von Frey filament test. Mice with CFA injection exhibited orofacial pain behaviors compared to PBS injection, including reduced bite force and head withdrawal threshold in the von Frey filament test. These methods are relatively easy to execute to have reproducible results and can be potentially extended to pain studies for other disease models related to TMJ disorders. Together, bite force, and the von Frey filament tests are reliable in measuring orofacial pain, as demonstrated in CFA injection-induced painful TMJOA mouse models.

This protocol describes how measuring bite force and head withdrawal threshold can capture pain behavior in Complete Freund's Adjuvant (CFA)-induced inflammatory temporomandibular joint (TMJ) pain.

Temporomandibular joint (TMJ) pain and osteoarthritis (OA) are common and debilitating disorders that impair patients' quality of life. The mechanisms ...

行为学

The Monoiodoacetate Model of Osteoarthritis Pain in the Mouse

A major symptom of patients with osteoarthritis (OA) is pain that&#160;is triggered by peripheral as well as central changes within the pain pathways. The current treatments for OA pain such as NSAIDS or opiates are neither sufficiently effective nor devoid of detrimental side effects. Animal models of OA are being developed to improve our understanding of OA-related pain mechanisms and define novel pharmacological targets for therapy. Currently available models of OA in rodents include surgical and chemical interventions into one knee joint. The monoiodoacetate (MIA) model has become a standard for modelling joint disruption in OA in both rats and mice. The model, which is easier to perform in the rat, involves injection of MIA into a knee joint that induces rapid pain-like responses in the ipsilateral limb, the level of which can be controlled by injection of different doses. Intra-articular injection of MIA disrupts chondrocyte glycolysis by inhibiting glyceraldehyde-3-phosphatase dehydrogenase and results in chondrocyte death, neovascularization, subchondral bone necrosis and collapse, as well as inflammation. The morphological changes of the articular cartilage and bone disruption are reflective of some aspects of patient pathology. Along with joint damage, MIA injection induces referred mechanical sensitivity in the ipsilateral hind paw and weight bearing deficits that are measurable and quantifiable. These behavioral changes resemble some of the symptoms reported by the patient population, thereby validating the MIA injection in the knee as a useful and relevant pre-clinical model of OA pain.
The aim of this article is to describe the methodology of intra-articular injections of MIA and the behavioral recordings of the associated development of hypersensitivity with a mind to highlight the necessary steps to give consistent and reliable recordings.

Osteoarthritis (OA), or degenerative joint disease, is a debilitating condition associated with pain that remains only partially controlled by available analgesics. Animal models are being developed to improve our understanding of OA-related pain mechanisms. Here we describe the methodology for the monoiodoacetate model of OA pain in the mouse.

骨关节炎疼痛的鼠标Monoiodoacetate模式

A major symptom of patients with osteoarthritis (OA) is pain that&#160;is triggered by peripheral as well as central changes within the pain pathways. The ...

A Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice

The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known risk factor for glaucoma. This protocol demonstrates a step-by-step guide on this technique in Long Evans rats and C57BL/6 mice. Under general anesthesia, a "purse-string" suture is applied on the conjunctiva, around the equator and behind the limbus of the eye. The fellow eye serves as an untreated control. Over the duration of our study, which was a period of 8 weeks for rats and 12 weeks for mice, IOP remained elevated, as measured regularly by rebound tonometry in conscious animals without topical anesthesia. In both species, the sutured eyes showed electroretinogram features consistent with preferential inner retinal dysfunction. Optical coherence tomography showed selective thinning of the retinal nerve fiber layer. Histology of the rat retina in cross-section found reduced cell density in the ganglion cell layer, but no change in other cellular layers. Staining of flat-mounted mouse retinae with a ganglion cell specific marker (RBPMS) confirmed ganglion cell loss. The circumlimbal suture is a simple, minimally invasive and cost-effective way to induce ocular hypertension that leads to ganglion cell injury in both rats and mice.

Chronic ocular hypertension is induced by applying a circumlimbal suture in rats and mice, leading to functional and structural deterioration of the retinal ganglion cells consistent with glaucoma.

Circumlimbal 缝合法诱导大鼠和小鼠青光眼模型的建立

The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known ...

Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain

Pain is the main cause of disability from arthritis. There is currently an unmet need for adequate treatments for arthritis pain. Pre-clinical models are necessary and useful for studying the mechanisms of pain and for evaluating efficacy of arthritis therapies. Measuring pain in animal models of arthritis is challenging. We have developed methods for measuring evoked and spontaneous pain in three models of murine arthritis. We quantitate the evoked pain responses of mice subjected to firm palpation of a painful knee. We also evaluate spontaneous pain by the proportion of weight and the amount of time placed on each of their 4 limbs after induction of arthritis pain in one knee. Joint pain in these mouse models produces a significant increase in evoked pain responses and an alteration in weight bearing. Since mice are quadrupeds, they offload the painful limb to the contralateral limb, to the forelimbs, or some combination. These methods are simple, require minimal equipment, and are reproducible and sensitive for detecting pain. They are useful for studying both disease-modifying arthritis treatments and analgesics in mice.

We have developed an evoked measure of arthritis pain and coupled it with a standardized method for measuring spontaneous pain in different murine models of chemically induced arthritis. These measures are sensitive and reproducible for different types of joint pain.

单关节膝关节疼痛小鼠模型疼痛的自发性和诱发性测量

Pain is the main cause of disability from arthritis. There is currently an unmet need for adequate treatments for arthritis pain. Pre-clinical models are ...

The Lower Body Positive Pressure Treadmill for Knee Osteoarthritis Rehabilitation

Here, based on a clinician&rsquo;s point-of-view, we propose a two-model lower body positive pressure (LBPP) protocol (walking and squatting models) in addition to a clinical, functional assessment methodology, including details for further encouragement of the development of non-drug surgical intervention strategies in knee osteoarthritis patients. However, we only present the effect of LBPP training in improvement of pain and knee function in one patient through three-dimensional gait analysis. The exact, long-term effects of this approach should be explored in future studies.

Here, based on a clinician&#8217;s point-of-view, we propose a two-model lower body positive pressure (LBPP) protocol (walking and squatting models) in addition to a clinical, functional assessment methodology, including details for further encouragement of the development of non-drug surgical intervention strategies in knee osteoarthritis patients. However, we only present the effect of LBPP training in improvement of pain and knee function in one patient through three-dimensional gait analysis. The exact, long-term effects of this approach should be explored in future studies.

下体正压跑步机用于膝关节骨关节炎康复

Here, based on a clinician&rsquo;s point-of-view, we propose a two-model lower body positive pressure (LBPP) protocol (walking and squatting models) in ...

使用改进的 Videman 方法在兔子中建立 KOA 模型

Application of Acupotomy in a Knee Osteoarthritis Model in Rabbit

Knee osteoarthritis (KOA) is one of the most frequently encountered diseases in the orthopedic department, which seriously reduces the quality of life of people with KOA. Among several pathogenic factors, the biomechanical imbalance of the knee joint is one of the main causes of KOA. Acupotomology believes that restoring the mechanical balance of the knee joint is the key to treating KOA. Clinical studies have shown that acupotomy can effectively reduce pain and improve knee mobility by reducing adhesion, contracture of soft tissues, and stress concentration points in muscles and tendons around the knee joint. 
In this protocol, we used the modified Videman method to establish a KOA model by immobilizing the left hindlimb in a straight position. We have outlined the method of operation and the precautions related to acupotomy in detail and evaluated the efficacy of acupotomy in conjunction with the theory of "Modulating Muscles and Tendons to Treat Bone Disorders" through the detection of the mechanical properties of quadriceps femoris and tendon, as well as cartilage mechanics and morphology. The results show that acupotomy has a protective effect on cartilage by adjusting the mechanical properties of the soft tissues around the knee joint, improving the cartilage stress environment, and delaying cartilage degeneration.

作者聚焦:研究针尖切开术治疗膝骨关节炎的作用机制

In this protocol, a knee osteoarthritis model was prepared using the modified Videman method, and the operation procedures and precautions of acupotomy are detailed. The effectiveness of acupotomy has been demonstrated by testing the mechanical properties of quadriceps femoris and tendon and the mechanical and morphological properties of cartilage.

针灸术在兔膝骨关节炎模型中的应用

Knee osteoarthritis (KOA) is one of the most frequently encountered diseases in the orthopedic department, which seriously reduces the quality of life of ...

大鼠关节内注射单碘乙酸酯诱导的骨关节炎疼痛模型

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慢性缩窄大鼠坐骨神经疼痛过敏测试

视网膜脱离模型鼠害由透明质酸钠的视网膜下注射

实验诱发青光眼通过磁性微球注射眼

Temporomandibular Joint Pain Measurement by Bite Force and Von Frey Filament Assays in Mice

骨关节炎疼痛的鼠标Monoiodoacetate模式

Circumlimbal 缝合法诱导大鼠和小鼠青光眼模型的建立

单关节膝关节疼痛小鼠模型疼痛的自发性和诱发性测量

下体正压跑步机用于膝关节骨关节炎康复

针灸术在兔膝骨关节炎模型中的应用

针灸术在兔膝骨关节炎模型中的应用