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

疼痛是一种复杂的主观现象，会导致身体和情感上的不适；在宠物身上，它通常被低估和治疗。在过去的50年里，几乎没有出现有效的慢性疼痛治疗方法，这在很大程度上是因为这些疾病的机制还不完全清楚。当我们考虑到在西方社会，慢性骨关节炎(OA)疼痛影响大约20%的成年猫狗种群时，这种缺乏洞察力是令人震惊的。当我们面临临床疼痛问题时，我们会遵循一套久经考验的技术。这涉及到对解剖基础的理解，在疼痛医学中，解剖基础是“疼痛生成器”。我们进一步探讨了问题背后的病因-病理生理学(或原因和过程)：神经递质/调节器(配体和受体)和其他参与疼痛产生、传播和调制的化学物质。这是目前兽医临床疼痛的状态。神经科学的进步现在使人们有可能推测与疼痛发生和维持有关的各种神经网络。如果不了解这些网络，我们就无法完全解决痛苦问题。在分子水平上理解疼痛增加了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世纪相对较新和迅速发展的研究领域，有助于传统的研究工具。我们已经开发并验证了一套疼痛行为评估组件，该组件专注于OA大鼠的生物力学和躯体感觉敏感性的变化。这使得可以表征神经生理学的每个层次的骨性关节炎疼痛过程，即外周敏感性、脊髓敏感化和下行(上级)抑制控制。此外，我们还建立了与骨性关节炎相关的脊髓神经肽组改变。基于我们最近的发现，我们的目标是继续研究骨性关节炎疼痛过程中的神经肽学/基因组学串扰，以确定宠物动物骨性骨性关节炎疼痛调控的新的分子靶点。我们的具体目标将是：1)利用我们先前的OA研究中建立的大鼠外科骨性关节炎疼痛模型，检测三种最相关神经肽的细胞来源和功能；ii)对选定的神经肽，即P物质、生长抑素和转甲状腺素产生特异性的基因沉默，并研究它们对已建立的大鼠慢性骨性关节炎疼痛表型的影响；以及iii)将大鼠模型中最有趣的发现扩展到自然发生的猫性骨性关节炎。我们有一个独特的通道，可以接触到自然受到OA影响的宠物动物群体。因此，根据神经蛋白质组/基因组学结果确定的、在大鼠模型中被证明有效的外周伤害性感受器和中枢递质的药物遗传沉默(或调制)将在OA猫身上进行测试。

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.