Understanding and treating osteoarthritic pain in pet animals: An approach based on neurogenomics and neuropeptidomics manipulation

了解和治疗宠物骨关节炎疼痛：基于神经基因组学和神经肽组学操作的方法

• 批准号: RGPIN-2019-05512
• 负责人: Troncy, Eric
• 金额: $ 4.01万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746071
• 关键词: Understanding; treating; osteoarthritic; pain; pet

Pain is a complex, subjective phenomenon that causes feelings of physical and emotional discomfort; It is commonly underdiagnosed and under treated in pet animals. Within the last 50 years, few effective treatments for chronic pain have emerged, largely because the mechanisms of these disorders are incompletely understood. This lack of insight is astounding when we consider that chronic osteoarthritis (OA) pain affects approximately 20% of the adult feline and canine population in Western societies. When we are posed with a clinical pain problem, we follow a set of time-tested techniques. This involves understanding the anatomic substrate, which, in pain medicine is the `pain generator'. We further probe into the etio-pathophysiology (or cause and process) underlying the problem: neural transmitters/ modulators (ligands and receptors) and other chemicals involved in the generation, propagation and modulation of pain. This is the current state of clinical pain in veterinary medicine. Advances in neuroscience now make it possible to postulate the various neural networks involved in pain development and maintenance. Without an understanding of these networks, we are unable to address the issue of pain fully. Comprehending pain at a molecular level increases the effectiveness of already established network level knowledge. Genomics and proteomics are relatively new and rapidly expanding research areas in the 21st century, and contribute to conventional research tools. We have developed and validated a pain behavior assessment battery focusing on biomechanical and somato-sensory sensitivity alterations in OA rats. This allows to characterize every level of the neurophysiological OA pain process, namely peripheral sensitivity, spinal sensitization, and descending (superior) inhibitory control. In addition, we have established spinal neuropeptidome changes associated with the OA disease. Based on our recent discoveries, our aim is to pursue investigations on the neuro-peptidomics/ genomics crosstalk in the OA pain process, to determine new molecular targets of OA pain modulation in pet animals. Our specific objectives will be i) to use a rat surgical OA pain model to detect the cellular source and the function of the three most relevant neuropeptides established in our previous OA studies; ii) to generate specific gene silencing of selected neuropeptides, i.e., substance P, somatostatin and transthyretin, and characterize their consequences on pain phenotype in our established chronic OA pain model in rats; and iii) to extend the most interesting finding in the rat model to naturally-occurring OA in cats. We have a unique access to colony of pet animals naturally-affected by OA. Therefore, the pharmacogenetic silencing (or modulation) of peripheral nociceptors, central transmitters, determined on the basis of neuro-proteomic/ genomic findings, and demonstrated as efficient in the rat model, will be tested on OA cats.

疼痛是一种复杂的主观现象，会导致身体和情绪上的不适感。在宠物中，这种疾病通常诊断不足且治疗不足。在过去的 50 年里，几乎没有出现针对慢性疼痛的有效治疗方法，很大程度上是因为这些疾病的机制尚不完全清楚。当我们考虑到慢性骨关节炎 (OA) 疼痛影响着西方社会大约 20% 的成年猫科动物和犬科动物时，这种洞察力的缺乏是令人震惊的。当我们遇到临床疼痛问题时，我们会遵循一套经过时间考验的技术。这涉及到了解解剖学基础，在疼痛医学中，解剖学基础是“疼痛发生器”。我们进一步探讨问题背后的病因病理生理学（或原因和过程）：神经递质/调节剂（配体和受体）以及参与疼痛产生、传播和调节的其他化学物质。这就是兽医临床疼痛的现状。 神经科学的进步现在使得假设涉及疼痛发展和维持的各种神经网络成为可能。如果不了解这些网络，我们就无法完全解决疼痛问题。在分子水平上理解疼痛可以提高已经建立的网络水平知识的有效性。基因组学和蛋白质组学是 21 世纪相对较新且迅速扩展的研究领域，为传统研究工具做出了贡献。我们开发并验证了一套疼痛行为评估系统，重点关注 OA 大鼠的生物力学和体感敏感性变化。这使得能够表征神经生理学 OA 疼痛过程的每个级别，即外周敏感性、脊柱敏化和下行（上级）抑制控制。此外，我们还确定了与 OA 疾病相关的脊髓神经肽组变化。基于我们最近的发现，我们的目标是对 OA 疼痛过程中的神经肽组学/基因组学串扰进行研究，以确定宠物动物 OA 疼痛调节的新分子靶点。我们的具体目标是 i) 使用大鼠手术 OA 疼痛模型来检测我们之前 OA 研究中建立的三种最相关的神经肽的细胞来源和功能； ii) 产生选定神经肽（即 P 物质、生长抑素和运甲状腺素蛋白）的特异性基因沉默，并在我们建立的大鼠慢性 OA 疼痛模型中表征它们对疼痛表型的影响； iii) 将大鼠模型中最有趣的发现扩展到猫中自然发生的 OA。我们拥有独特的途径接触自然受 OA 影响的宠物群体。因此，根据神经蛋白质组/基因组研究结果确定的外周伤害感受器、中枢递质的药物遗传学沉默（或调节），并在大鼠模型中证明有效，将在 OA 猫上进行测试。