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，药物之间存在着重大差距。 动物疼痛模型和人类疼痛。这些差距主要分为三个类别。 1）构建效度。有 动物疼痛模型和临床疼痛状况之间神经损伤部位的根本区别。 2） 内容有效性。人类神经性疼痛，包括三叉神经痛，通常表现为自发性疼痛， 只有约 20% 的患者报告机械过敏。相比之下，动物模型中的疼痛通常 表现为诱发行为，例如机械和热超敏反应。除了自发性疼痛外， 许多关键的疼痛临床表现，例如三叉神经痛的牙痛症状，并不 由现有的三叉神经疼痛模型概括。 3）标准有效性。临床疼痛评估基于患者 报告症状和功能评估，并考虑疼痛引起的情感变化。 然而，在非语言动物中，疼痛评估通常基于脊髓反射。改进标准 为了验证动物疼痛模型的有效性，有必要建立客观、定量的行为指标 测量，反映功能和情感状态。在初步研究中，我们构建了小鼠 通过撕裂孔施用外科泡沫来建立三叉神经根受压模型 (Com-TN) 在小鼠的颅底。我们的数据表明 Com-TN 模型提供了改进的结构、内容和 与眶下神经结扎模型相比，标准的有效性。更具体地说，Com-TN 模型具有 将有效性构建为模拟人类三叉神经痛的压迫部位。其内容效度为 自发性疼痛行为支持，包括过度修饰面部、不对称的面部鬼脸 更重要的是，体感 S1 皮层的自发和同步神经元活动由两个- 清醒和休息状态下的光子显微镜。此外，内容的有效性得到了临床重现的支持。 三叉神经痛的表现，包括牙痛和疼痛引起的抑郁行为。标准 有效性由几种与疼痛相关的行为支持，可以客观、定量地评估这些行为 反映疼痛的功能和情感方面。数据还表明它与卡马西平具有预测有效性， 三叉神经痛的一线治疗，部分缓解疼痛行为。进一步开发和验证 Com-TN模型，我们计划开展两个阶段的研究： R61阶段 - 1）建立Com-TN模型 在雌性小鼠中； 2) 确定手术泡沫的最佳剂量； 3) 确定动态范围和 行为终点的可靠性。 R33阶段 - 1）在另一个研究所建立Com-TN模型； 2）到 建立SD大鼠和CD1小鼠模型； 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能够实现多维疼痛的疼痛模型 客观、定量地进行评估。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进行研究，为药物开发提供测试平台。