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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738340
• 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，导致身体和情绪不适的感觉;它通常在宠物动物中诊断不足和治疗不足。在过去的50年里，很少有有效的治疗慢性疼痛的方法出现，主要是因为这些疾病的机制还不完全清楚。当我们考虑到慢性骨关节炎（OA）疼痛影响西方社会大约20%的成年猫和犬时，这种缺乏洞察力的情况令人震惊。当我们面临临床疼痛问题时，我们遵循一套经过时间考验的技术。这涉及了解解剖学基础，在疼痛医学中，解剖学基础是“疼痛发生器”。我们进一步探讨了问题的病因病理生理学（或原因和过程）：神经递质/调节剂（配体和受体）和其他参与疼痛产生，传播和调节的化学物质。这是兽医临床疼痛的现状。 神经科学的进步使得我们有可能假设参与疼痛发展和维持的各种神经网络。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，并有助于传统的研究工具。我们已经开发并验证了疼痛行为评估电池集中在OA大鼠的生物力学和躯体感觉敏感性的改变。这允许表征神经生理学OA疼痛过程的每个水平，即外周敏感性、脊髓致敏性和下行（上级）抑制控制。此外，我们已经建立了与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。我们的具体目标将是i）使用大鼠手术OA疼痛模型来检测我们先前OA研究中建立的三种最相关神经肽的细胞来源和功能; ii）产生所选神经肽的特异性基因沉默，即，P物质，生长抑素和甲状腺素运载蛋白，并在我们建立的慢性OA疼痛模型大鼠的疼痛表型的后果进行表征;和iii）在大鼠模型中最有趣的发现，以自然发生的OA猫。我们有一个独特的访问殖民地的宠物动物自然受到OA影响。因此，基于神经蛋白质组学/基因组学结果确定并证明在大鼠模型中有效的外周伤害感受器（中枢递质）的药物遗传学沉默（或调节）将在OA猫中进行检测。