Name: partial sciatic nerve ligation: a mouse model of chronic neuropathic pain to study the antinociceptive effect of novel therapies
Uploaded: 2022-10-06T14:30:00
Description: Watch this Scientific Journal Video about Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies at JoVE.com

这项研究得到了国家补充和综合健康中心[R01AT009716，2017]（M.M.I.），亚利桑那大学综合慢性疼痛和成瘾中心（M.M.I.）和亚利桑那大学医学院的医学科学家培训计划（MSTP）的支持。

所有程序均由亚利桑那大学机构动物护理和使用委员会批准，并符合美国国立卫生研究院的实验动物使用指南（NIH出版物编号80-23，1966）。将无病原体的成年C57Bl6 / J小鼠（测试重量：22-28g）饲养在气候控制房间的标准动物饲养小鼠笼（每笼五只小鼠）中，进行12小时的光照/黑暗 循环，并允许随意获取食物和水。所有行为实验均由对治疗条件不知情的实验者进行。
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<ol>
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K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+the+foot+withdrawal+response+to+noxious+radiant+heat+in+the+rat.">Characterization of the foot withdrawal response to noxious radiant heat in the rat.</a> Pain. 59 (1), 85-94 (1994).</li><li>Cheah, M., Fawcett, J. W., Andrews, M. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+thermal+pain+sensation+in+rats+and+mice+using+the+Hargreaves+test.">Assessment of thermal pain sensation in rats and mice using the Hargreaves test.</a> Bio-Protocol. 7 (16), 2506 (2017).</li><li>Hook, M. 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慢性疼痛治疗通常需要长期药物治疗，使疼痛管理具有挑战性。因此，临床前模型是评估依赖药物或非药物方法的创新疗法的潜在益处的重要工具。由于不同研究人员之间手术技术的可变性增加，慢性神经性疼痛的众多模型带来了挑战，导致可重复性降低。因此，必须在多种模型中表征新疗法的潜在抗伤害感受作用，这些模型具有良好的特征和标准化。
该报告表明，坐骨神?...

慢性疼痛是全世界一个重大的医疗保健问题，也是美国最昂贵的健康问题之一。当以多学科方式同时使用药理学和非药理学方式时，慢性疼痛可以得到更好的管理1。慢性疼痛的管理具有挑战性，在某些情况下，不能充分治疗疼痛2。因此，需要新的补充方法来改善慢性疼痛管理，动物模型对于研究创新疗法至关重要。
慢性神经性疼痛由躯体感觉系统的病变或疾病引起，包括糖尿病、感染、神经压迫或自身免疫性疾病3.神经性疼痛依赖于外周和中枢致敏机制，起源于神经病变。这种疼痛的特征是触觉和热诱发的痛觉过敏和异常性疼痛、持续疼痛以及患肢温度变化4.为了更好地了解机制并推进新的治疗方法，已经在啮齿动物中开发了几种模型来模拟神经性疼痛的症状和原因5。例如，神经性疼痛可通过化疗药物注射、脊神经结扎术 （SNL）、坐骨神经慢性收缩损伤 （CCI）、pSNL、备用神经损伤、坐骨神经横断和坐骨神经三断6 诱发。值得注意的是，坐骨神经结扎再现了在人类中观察到的神经性疼痛的多种特征，例如机械和热超敏反应，或受影响肢体的温度变化，这是复杂区域疼痛综合征（CRPS）的特征7。因此，该模型非常适合研究CRPS或任何其他诱发慢性神经性疼痛的神经损伤影响。该模型最初由Seltzer于1990年开发8，广泛用于疼痛研究，以研究新型镇痛化合物或评估慢性疼痛的认知影响9，10，11，12，13。该模型具有很高的可重复性，部分连接保留了对外周刺激的行为反应6。
许多目前使用的模型都有在pSNL中没有观察到的缺点。CCI模型根据收缩器的紧密程度，每只动物之间的损伤变异性要高得多，并且自体切开术改变了后爪手指，使模型不适合行为分析6。SNL模型是一种更复杂，更长的手术，不仅需要先进的技术技能，而且还具有严重运动缺陷的高风险3。这些缺点在pSNL模型中没有看到。易于重现、手术持续时间短以及术后运动缺陷风险降低，使该模型对于研究周围神经性疼痛很有价值8，14。然而，部分连接程序本身可能在实验者之间产生差异，导致连接神经纤维数量的一致性降低。因此，呈现手术的细节对于提高研究的可重复性至关重要。
为了诱发慢性神经病变，使用9-0不可吸收的尼龙缝合线来连接坐骨神经宽度的三分之一。手术后，对热和机械刺激的反应被夸大，从术后第 1 天开始，持续超过 50 天8。在这里，使用Hargreaves，热板和von Frey灯丝测试在28天内评估了热和机械灵敏度。所有的行为测定都证明了长期超敏反应的一致性。该模型已被证明具有吗啡和布洛芬的剂量依赖性作用，证实它非常适合临床前疼痛研究。值得注意的是，本文介绍了一种独特的手工玻璃工具的说明，称为“神经玻璃钩”。该工具用于代替镊子来操纵神经并防止手术过程中意外的额外神经损伤。

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			<td>5/0, FS-2, 30&#34; Undyed PGA Braided Polyglycolic Acid Synthetic Absorbable Suture</td>
			<td>CP Medical</td>
			<td>421A</td>
			<td>https://cpmedical.com/suturesearch/product/421a-visorb-50-fs-2-30/</td>
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			<td>6/0, P-1, 18&#34; Blue Polypropylene Monofilament Non-Absorbable Suture</td>
			<td>CP Medical</td>
			<td>8697P</td>
			<td>https://cpmedical.com/suturesearch/product/8697p-polypro-60-p-1-18/</td>
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			<td>9/0 (0.3 metric) Nylon Black Monofilament Suture</td>
			<td>Crestpoint Ophthalmics</td>
			<td>MANI 1407</td>
			<td>https://crestpointophthalmics.com/mani-1407-suture-trape-spatula-nylon-black-mono-box-of-12.html</td>
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			<td>Allodynia Software&#160;</td>
			<td>National Instruments, LabView 2015</td>
			<td></td>
			<td>Quantification of mean withdrawal thresholds (Von Frey data)</td>
		</tr>
		<tr>
			<td>C57Bl6/J mice&#160;</td>
			<td>The Jackson Laboratory, Bar Harbor, ME</td>
			<td>000664</td>
			<td>https://www.jax.org/strain/000664</td>
		</tr>
		<tr>
			<td>Castroviejo needle holder</td>
			<td>Fine Science Tools</td>
			<td>12565-14</td>
			<td>https://www.finescience.com/en-US/Products/Wound-Closure/Needle-Holders/Castroviejo-Needle-Holder/12565-14</td>
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			<td>Cold Hot Plate Test</td>
			<td>Bioseb</td>
			<td>BIO-CHP</td>
			<td>https://www.bioseb.com/en/pain-thermal-allodynia-hyperalgesia/563-cold-hot-plate-test.html</td>
		</tr>
		<tr>
			<td>Elevated metal mesh stand for Von Frey</td>
			<td>Bioseb</td>
			<td>BIO-STD2-EVF</td>
			<td>https://www.bioseb.com/en/pain-mechanical-allodynia-hyperalgesia/1689-elevated-metal-mesh-stand-30-cm-height-to-fit-up-to-2-pvf-cages.html</td>
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			<td>Extra fine Graefe forceps</td>
			<td>Fine Science Tools</td>
			<td>11152-10</td>
			<td>https://www.fishersci.com/shop/products/fisherbrand-curved-medium-point-general-purpose-forceps/16100110</td>
		</tr>
		<tr>
			<td>Fine Castroviejo needle holder</td>
			<td>Simovision/Geuder</td>
			<td>17565</td>
			<td>https://simovision.com/assets/Uploads/Brochure-Geuder-Ophthalmic-Surgical-Instruments-EN2.pdf</td>
		</tr>
		<tr>
			<td>Fine scissors (11.5 cm)</td>
			<td>Fine Science Tools</td>
			<td>14558-11</td>
			<td>https://www.finescience.com/en-US/Products/Scissors/Standard-Scissors/Fine-Scissors-Tungsten-Carbide-ToughCut%C2%AE/14558-11</td>
		</tr>
		<tr>
			<td>Fine scissors (9 cm)</td>
			<td>Fine Science Tools</td>
			<td>14558-09</td>
			<td>https://www.finescience.com/en-US/Products/Scissors/Standard-Scissors/Fine-Scissors-Tungsten-Carbide-ToughCut%C2%AE/14558-09</td>
		</tr>
		<tr>
			<td>Iris forceps</td>
			<td>Fine Science Tools</td>
			<td>11064-07</td>
			<td>https://www.finescience.com/en-US/Products/Forceps-Hemostats/Fine-Forceps/Iris-Forceps/11064-07</td>
		</tr>
		<tr>
			<td>Micro Adson forceps</td>
			<td>Fine Science Tools</td>
			<td>392487</td>
			<td>https://www.fishersci.com/shop/products/micro-adson-tissue-forceps-1x2-teeth-german-steel/13820072#?keyword=adson%20forceps</td>
		</tr>
		<tr>
			<td>Modular holder cages for rats and mice</td>
			<td>Bioseb</td>
			<td>BIO-PVF</td>
			<td>https://www.bioseb.com/en/pain-mechanical-allodynia-hyperalgesia/1206-modular-holder-cages-for-rats-and-mice.html</td>
		</tr>
		<tr>
			<td>Moretti/Effetre #240 Light Cobalt Blue glass rods 4 mm</td>
			<td>Ebay</td>
			<td>N/A</td>
			<td>https://www.ebay.com/itm/402389491328?hash=item5db0485e80:g:agYAAOS 
			w9CtfnIVJ&#38;amdata=enc 
			%3AAQAHAAAAwCoqvgWRo 
			NTe5Vq8PWOgfE4ygWeW4tL 
			k81J1AFu%2Fkcbsk6pxYtJi6 
			digE5TL9SzlgMzYUMNDr%2B 
			dku2%2B%2FEvB1qXqFmebE 
			020SGs9LPDXLL5w21un7jrM0 
			9xfWYvIzBYQYh6FRWyUJngC 
			uuA9Bkjb9lxtZoYlg5y6PyFR2P 
			34xFk5xaNC5ib65M1%2Fr%2F 
			4w2Iw45QqsSyXH2cuUKRom0 
			AGBoBaIr%2BbJw1VnlMjGuc9dtx 
			4fbPbqoBNSWjj3RbZPOPTYS8Q 
			%3D%3D%7Ctkp%3ABk9SR4q6- 
			6LfYA</td>
		</tr>
		<tr>
			<td>Plantar Test for Thermal Stimulation - Hargreaves Apparatus</td>
			<td>Ugo Basile</td>
			<td>37570</td>
			<td>https://ugobasile.com/products/categories/pain-and-inflammation/plantar-test-for-thermal-stimulation</td>
		</tr>
		<tr>
			<td>Touch-Test Sensory Evaluators, Set of 20 Monofilaments</td>
			<td>North Coast Medical</td>
			<td>NC12775-99</td>
			<td>https://www.ncmedical.com/products/touch-test-sensory-evaluators_1278.html</td>
		</tr>
		<tr>
			<td>Tying forceps</td>
			<td>Duckworth &#38; Kent</td>
			<td>2-504ER8</td>
			<td>https://duckworth-and-kent.com/product/tying-forceps-9/</td>
		</tr>
	</tbody>
</table>

partial sciatic nerve ligation: a mouse model of chronic neuropathic pain to study the antinociceptive effect of novel therapies

直到今天，慢性疼痛的管理仍然具有挑战性，目前的治疗与不良反应有关，包括耐受性和成瘾。慢性神经性疼痛由躯体感觉系统的病变或疾病引起。为了研究减少副作用的潜在疗法，动物疼痛模型是临床前研究的金标准。因此，特征明确且描述良好的模型对于创新疗法的开发和验证至关重要。 
坐骨神经部分结扎术（pSNL）是一种诱发小鼠慢性神经性疼痛的手术，其特征是机械和热超敏反应，持续疼痛和肢体温度变化，使该模型非常适合临床前研究神经性疼痛。pSNL是研究神经性疼痛的有利模型，因为它再现了在患有神经性疼痛的人类中观察到的许多症状。此外，外科手术相对快速且直接执行。单侧 pSNL 可比较同侧和对侧爪，以及评估中枢致敏。 
为了诱导慢性神经性超敏反应，使用9-0不可吸收的尼龙线连接坐骨神经的背侧三分之一。本文描述了外科手术，并通过多种常用的行为测试来表征慢性神经性疼痛的发展。由于现在正在研究大量用于治疗慢性疼痛的创新疗法，本文提供了标准化的关键概念，并准确描述了诱发神经性疼痛所需的手术。

通过C57Bl6 / J雄性小鼠坐骨神经的部分结扎诱导慢性神经性疼痛（图1A）。使用冯弗雷灯丝和“上下”方法评估机械灵敏度。使用哈格里夫斯和热板测试评估对热的热敏感性。所有数据均通过重复测量的双向方差分析与盖瑟温室校正进行分析，以比较pSNL手术随时间推移对假动物的影响或不同剂量吗啡和布洛芬的影响。
与假动物相比，接受pSNL手术的小鼠在...

Watch this Scientific Journal Video about Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies at JoVE.com

Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies

坐骨神经部分结扎可诱发长期慢性神经性疼痛，其特征是对热和机械刺激的夸张反应。这种神经性疼痛的小鼠模型通常用于研究疼痛管理的创新疗法。本文详细介绍了提高标准化和可重复性的外科手术。

部分坐骨神经结扎术：慢性神经性疼痛的小鼠模型，用于研究新疗法的抗伤害感受作用

Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. ...

由于现在正在研究大量用于治疗慢性疼痛的创新疗法，我们的协议为诱导神经性疼痛所需的手术标准化提供了关键概念。部分坐骨神经结扎术（PSNL）是研究神经性疼痛的有利模型，因为它再现了在患有神经性疼痛的人类中观察到的许多症状。由于PSNL再现了在患有神经性疼痛的人类中观察到的许多症状，因此该协议为研究和开发新的疼痛管理疗法提供了关键概念。演示该程序的将是Kevin Cheng，我实验室的医学博士候选人。首先，在测试之前，将小鼠放在与测试室同一房间的金属丝网上的透明有机玻璃盒中，使小鼠习惯于Von Frey测试设备一小时。将一系列校准的细单丝垂直于悬挂在吊丝网笼中的动物的PSNL同侧后爪的播种机表面。通过依次增加或减少对应于灯丝尺寸的刺激强度来确定退出阈值。当反应为负时增加细丝的大小，当动物收回爪子时减小细丝的大小。在数据表中报告阴性和阳性响应，并在第一次阳性响应后用不同的细丝测试同一爪子四次。在测试之前，通过将小鼠放置在与测试室相同的房间的透明有机玻璃盒中，使小鼠习惯于哈格里夫斯测试装置一小时。使用哈格里夫斯设备建立基线爪子撤回延迟。将辐射热源聚焦到PSNL同侧后爪的花盆表面并开始刺激。当动物收回爪子时，等待运动检测器停止刺激并停止计时器。调整热源的强度以获得大约 10 秒的爪子撤回延迟基线。接下来，将提款时间记录在表格中。将热板设置为 52 摄氏度。将动物放入测试室并启动计时器。观察伤害性行为，并在观察到伤害性行为后立即停止计时器。然后将动物从腔室中取出并记录此行为的延迟。确保清洁每只测试动物之间的任何尿液，以避免影响热刺激的温度。在动物之间用70%乙醇清洁测试室，以减少气味的行为影响。要制作神经玻璃钩，请打开本生燃烧器。用一只手将玻璃棒的一端放在火上。当这根玻璃棒熔化时，用另一只手用另一根玻璃棒引导和拉动第一根玻璃棒上的熔化玻璃。从火中取出第一根玻璃棒，让熔化部分的末端自然向内滚动，使用第二根玻璃棒形成小球形。用镊子捏住后爪上的脚趾以确保没有爪反射，并在涂抹润滑性眼药膏之前检查角膜眨眼反射。在选择在哪一侧进行手术时，将动物的后腿围绕大腿区域，下部朝向髌骨，上部朝向髋部和股骨上方。接下来，用氯己定沿一个方向擦拭三次，用三个单独的纱布与温热的无菌盐水交替擦拭。然后将腿滑过 10 x 10 厘米无菌窗帘制成的缝隙，在所选腿周围形成无菌区域。使用精细的手术剪刀在大腿外侧的中线切开两毫米的小切口。将剪刀以圆周运动滑入皮肤下以突破筋膜并产生间隙，从而扩大切口空间。接下来，使用绑钳在大腿肌肉上以 90 度角垂直创建一个尖锐的 1 厘米深切口。然后将细小剪刀也以90度角插入同一切口，并轻轻张开以分离肌肉，直到看到坐骨神经。定位平行于垂直大腿的坐骨神经，沿髋关节至膝关节的方向。在继续之前，将绑钳中的剪刀从身体上取下。使用神经玻璃钩中的超细镊子将神经与下方隔离。小心地将神经从股骨转子附近的结缔组织中解放出来，该部位最靠近髋部，离膝盖最远。让神经停留在玻璃棒上，并确保杆的末端防止神经滚落。在将坐骨神经分成腓总神经、胫神经和腓肠神经分支之前，使用九个零尼龙缝合线打一个手术结，以系住坐骨神经宽度的三分之一。打结完成后，小心地将神经从玻璃棒上滑落，并将其塞回分离肌肉下方水平的原始位置。接下来，使用可吸收的聚乙醇酸五零缝合缝合肌肉切口。另外，使用不可吸收的聚丙烯六零缝合缝合皮肤。然后记录手术和麻醉停止时间。让鼠标在恢复笼中独自醒来，然后再将其放回新的干净笼子。使用冯弗雷、哈格里夫斯或热板测试来评估热和机械超敏反应及其潜在的逆转。与假动物相比，接受PSNL手术的小鼠在28天内表现出较低的机械刺激阈值。热超敏反应评估也获得了类似的结果。PSNL动物暴露于辐射热刺激后的爪子撤回延迟增加，当动物放在52摄氏度的平板上时，退出延迟增加。注射两种不同剂量吗啡的组显示出持续一到两个小时的超敏反应逆转。机械超敏反应在注射吗啡后4小时恢复到基线。当腹膜内向小鼠注射两种不同剂量的布洛芬时，结果表明与注射盐水的小鼠相比，机械超敏反应降低。限制对神经的额外损伤至关重要，因为它会影响疼痛感觉阈值。实验者应特别注意并使用玻璃钩以减少意外损坏 在该程序之后，这种慢性神经性疼痛模型可用于识别和表征药物的抗伤害感受作用，从而导致开发新的疼痛管理疗法。

Research

JoVE Journal

Medicine

Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy

主动脉原位移植大鼠模型，研究慢性血管病变的发展

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant ...

科研

医学

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

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 ...

Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

脓毒症动物模型，用于评估新型草药疗法

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several ...

Breathing-controlled Electrical Stimulation (BreEStim) for Management of Neuropathic Pain and Spasticity

Breathing-controlled Electrical Stimulation BreEStim for Management of Neuropathic Pain and Spasticity

呼吸控制电气的刺激（BreEStim）的神经性疼痛和痉挛的管理

Electrical stimulation (EStim) refers to the application of electrical current to muscles or nerves in order to achieve functional and therapeutic goals. ...

Urinary Bladder Distention Evoked Visceromotor Responses as a Model for Bladder Pain in Mice

膀胱胀诱发内脏运动反应为膀胱疼痛小鼠模型

Approximately 3-8 million people in the United States suffer from interstitial cystitis/bladder pain syndrome (IC/BPS), a debilitating condition ...

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

神经病理性疼痛小鼠坐骨神经掴型号

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in ...

Chronic Constriction Injury of the Rat's Infraorbital Nerve (IoN-CCI) to Study Trigeminal Neuropathic Pain

Chronic Constriction Injury of the Rat's Infraorbital Nerve IoN-CCI to Study Trigeminal Neuropathic Pain

老鼠的眶下神经（ION-CCI）研究三叉神经性疼痛性损伤

Animal models are important tools to study the pathophysiology and pharmacology of neuropathic pain. This manuscript describes the surgical and behavioral ...

The Monoiodoacetate Model of Osteoarthritis 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 Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration

骨科手术的小鼠模型研究术后认知功能障碍与组织再生

Surgery is commonly used to improve and maintain quality of life. Unfortunately, in vulnerable patients such as the elderly, complications may occur and ...

Isometric Contractility Measurement of the Mouse Mesenteric Artery Using Wire Myography

用线 Myography 测定小鼠肠系膜动脉的等轴收缩力

The wire myograph technique is used to assess the contractility of vascular smooth muscles in response to depolarization, GPCR agonists/inhibitors and ...