Development and Validation of a Clinically Relevant Animal Pain Model

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。这些差距主要存在于三个方面。1)构念效度。的确有 动物疼痛模型与临床疼痛模型在神经损伤部位上的根本区别。2) 内容有效性。包括三叉神经痛在内的人类神经病理性疼痛通常表现为自发性疼痛， 只有大约20%的患者报告有机械过敏。相比之下，动物模型中的疼痛通常 表现为机械和热过敏等诱发行为。除了自发性疼痛， 许多疼痛的主要临床表现，如三叉神经痛的牙痛症状，都不是 由现有的三叉神经疼痛模型概括。3)标准效度。临床疼痛评估以患者为基础 报告的症状和功能评估，考虑到疼痛引起的情感变化。 然而，在非言语动物中，疼痛评估通常是基于脊椎反射。完善标准 动物疼痛模型的有效性，必须建立客观和定量的行为指标 测量，反映功能和情感状态。在初步研究中，我们构建了一只小鼠 经裂孔注射海绵制作三叉神经根卡压模型 在老鼠的头骨底部。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比较，判断其有效性。更具体地说，Com-TN模式具有 人体三叉神经痛受压部位效应性的构建。其内容效度为 由自发的疼痛行为支持，包括过度的面部修饰，不对称的面部表情 更重要的是，躯体感觉S1皮质中自发和同步的神经元活动增加了两个- 清醒和休息状态下的光子显微镜。此外，内容效度通过总结临床得到支持。 三叉神经痛的表现，包括牙痛和痛性抑郁行为。该标准 有效性得到了几种疼痛相关行为的支持，这些行为可以客观和定量地评估 反映疼痛的功能和情感方面。数据还表明，它与卡马西平一样具有预测有效性， 三叉神经痛一线治疗，部分缓解疼痛行为。进一步开发和验证 对于Com-TN模型，我们计划进行两个阶段的研究：R61阶段-1)建立Com-TN模型 在雌性小鼠身上；2)确定舒吉海绵的最佳剂量；以及3)确定动态范围和 行为端点的可靠性。R33阶段-1)在另一个研究所建立Com-TN模型；2) 建立SD大鼠和CD1小鼠模型；3)探讨Com-TN模型的预测效度。 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 以客观和定量的方式评估。这项提案的结果将填补关键的空白 动物疼痛模型和人类疼痛之间的联系，为药物开发提供测试平台。

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.