Development and Validation of a Clinically Relevant Animal Pain Model

临床相关动物疼痛模型的开发和验证

• 批准号: 10460795
• 负责人: Shiqian Shen
• 金额: $ 38.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460795
• 关键词: Development; Validation; Clinically; Relevant; Animal

One key barrier in developing safe and effective pain treatment drugs is that there are critical gaps between animal pain models and pain in humans. These gaps lie in three main categories. 1) Construct validity. There is fundamental difference in the site of nerve injury between animal pain models and clinical pain conditions. 2) Content validity. Human neuropathic pain including trigeminal neuralgia often presents with spontaneous pain, with only about 20% of patients reporting mechanical hypersensitivity. In contrast, pain in animal models often manifests as evoked behaviors such as mechanical and thermal hypersensitivities. Besides spontaneous pain, many key clinical presentations of pain, such as dental pain symptoms in trigeminal neuralgia, are not recapitulated by existing trigeminal pain models. 3) Criterion validity. Clinical pain assessment is based on patient reported symptoms and functional assessment, with a consideration of pain-induced affective changes. Whereas, in non-verbalizing animals, pain assessment is typically based on spinal reflexes. To improve criterion validity of animal pain models, it is imperative to establish behavioral indices that allow objective and quantitative measurements, reflecting both functional and affective status. In preliminary studies, we constructed a mouse model of trigeminal nerve root compression (Com-TN) by administering surgifoam through the foramen lacerum at the skull base of mice. Our data indicate that the Com-TN model provides improved construct, content, and criterion validities when compared with infraorbital nerve ligation model. More specifically, Com-TN model has construct validity as the site of compression mimics which in human trigeminal neuralgia. Its content validity is supported by spontaneous pain behaviors including excessive facial grooming, asymmetrical facial grimaces and, more importantly, spontaneous and synchronized neuronal activities in somatosensory S1 cortex by two- photon microscopy in awake and resting state. Additionally, content validity is supported by recapitulating clinical presentations of trigeminal neuralgia, including dental pain and pain-induced depression behavior. The criterion validity is supported by several pain-related behaviors, which can be assessed objectively and quantitively to reflect functional and affective aspects of pain. Data also suggest that it has predictive validity as carbamazepine, a first-line treatment for trigeminal neuralgia, partially alleviated pain behaviors. To further develop and validate the Com-TN model, we plan to carry out two phases of studies: R61 phase - 1) to establish the Com-TN model in female mice; 2) to establish the optimal dose of surgifoam; and 3) to determine the dynamic ranges and reliability of the behavior endpoints. R33 Phase - 1) to establish the Com-TN model in another institute; 2) to establish the model in SD rats and CD1 mice; and 3) to investigate the predictive validity of the Com-TN model. Successful execution of this proposal will establish a pain model which enables multi-dimensional pain assessment in an objective and quantitative manner. The outcomes of this proposal will fill in the critical gaps between animal pain models and pain in humans, to provide a testing platform for drug development.

开发安全有效的疼痛治疗药物的一个关键障碍是 动物疼痛模型和人类疼痛。这些差距分为三个主要类别。 1）构造有效性。有 动物疼痛模型和临床疼痛状况之间神经损伤部位的基本差异。 2） 内容有效性。包括三叉神经痛在内的人类神经性疼痛通常会出现自发疼痛， 报告只有20％的患者报告机械性超敏反应。相反，动物模型的疼痛经常 表现为诱发行为，例如机械性和热超敏反应。除了自发疼痛， 疼痛的许多关键临床表现，例如三叉神经痛的牙齿疼痛症状，不是 由现有的三叉神经疼痛模型概括。 3）标准有效性。临床疼痛评估是基于患者 报告的症状和功能评估，考虑到疼痛引起的情感变化。 鉴于在非语言动物中，疼痛评估通常基于脊柱反射。提高标准 动物疼痛模型的有效性，必须建立允许客观和定量的行为指数 测量，反映了功能和情感状态。在初步研究中，我们构建了一只小鼠 三叉神经根压缩（COM-TN）的模型通过通过孔杆进行施用外科手术 在小鼠的头骨基础上。我们的数据表明，COM-TN模型提供了改进的结构，内容和 标准有效性与眶下神经连接模型相比。更具体地说，Com-TN模型具有 构建有效性作为压缩模拟部位的位点，在人类三叉神经痛中。它的内容有效性是 由自发疼痛行为支持，包括过度的面部修饰，不对称的面部饰边 而且，更重要的是，两种体感S1皮层中的自发和同步神经元活性 光子显微镜在清醒和静止状态下。此外，通过概括临床来支持内容有效性 三叉神经痛的表现，包括牙齿疼痛和疼痛诱发的抑郁行为。标准 有效性得到了几种与疼痛相关的行为的支持，可以客观地和定量地评估这些行为 反映疼痛的功能和情感方面。数据还表明，它具有作为卡马西平的预测有效性， 三叉神经痛的一线治疗，部分缓解了疼痛行为。进一步发展和验证 COM-TN模型，我们计划进行两个研究阶段：R61阶段-1）建立COM-TN模型 在雌鼠中； 2）建立最佳的外科手术剂量； 3）确定动态范围和 行为终点的可靠性。 R33阶段-1）在另一家学院建立COM -TN模型； 2）到 在SD大鼠和CD1小鼠中建立模型； 3）研究COM-TN模型的预测有效性。 该提案的成功执行将建立一个疼痛模型，以使多维疼痛 以客观和定量的方式进行评估。该提案的结果将填补关键空白 在动物疼痛模型和人类疼痛之间，为药物开发提供了测试平台。