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，会引起身体和情绪上的不适；在宠物动物中，它通常被诊断和治疗不足。在过去的50年里，很少有有效的治疗慢性疼痛的方法出现，很大程度上是因为这些疾病的机制还不完全清楚。当我们考虑到慢性骨关节炎（OA）疼痛影响着西方社会大约20%的成年猫和狗时，这种缺乏洞察力是令人震惊的。当我们遇到临床疼痛问题时，我们会遵循一套久经考验的技术。这涉及到对解剖学基础的理解，在疼痛医学中，这是“疼痛发生器”。我们进一步探讨了问题背后的病理生理学（或原因和过程）：神经递质/调节剂（配体和受体）和其他化学物质参与疼痛的产生、传播和调节。这是兽医学临床疼痛的现状。神经科学的进步使我们有可能假设不同的神经网络参与疼痛的发展和维持。如果不了解这些网络，我们就无法完全解决疼痛的问题。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世纪相对较新的和迅速发展的研究领域，并有助于传统的研究工具。我们已经开发并验证了一种专注于OA大鼠生物力学和躯体感觉敏感性变化的疼痛行为评估方法。这允许表征神经生理OA疼痛过程的每个水平，即外周敏感性，脊柱敏化和下行（高级）抑制控制。此外，我们已经确定了与OA疾病相关的脊髓神经肽丘改变。基于我们最近的发现，我们的目标是继续研究OA疼痛过程中的神经肽组学/基因组学串音，以确定宠物OA疼痛调节的新分子靶点。我们的具体目标是：(1)使用大鼠手术OA疼痛模型来检测在我们之前的OA研究中建立的三种最相关神经肽的细胞来源和功能；ii)在我们建立的大鼠慢性OA疼痛模型中，对选定的神经肽（即P物质、生长抑素和甲状腺转甲状腺素）产生特异性基因沉默，并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体内自然发生的OA。我们有一个独特的途径来接触受OA影响的宠物。因此，基于神经蛋白质组学/基因组学发现确定的外周伤害感受器和中枢递质的药理学沉默（或调节），并在大鼠模型中证明是有效的，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.