Acute-to-Chronic Transition in Ergonomic Muscle Pain: Nociceptor Mechanisms

描述(由申请人提供)：肌肉骨骼疼痛是最常见和最昂贵的工人补偿和残疾情况。以前对工作相关肌肉骨骼疼痛的发病机制的研究往往集中在肌肉细胞的病理可能性上；然而，很明显，慢性人体工程学肌肉疼痛可以发生，而肌肉中没有任何细胞损伤的迹象。在目前的资助期间，我们在两个人体工学肌肉疼痛的动物模型(振动和偏心运动)中提供了广泛的证据，表明肌肉伤害性感受器是产生慢性肌肉疼痛的主要病理生理变化的场所。此外，这些模型显示了从急性痛觉过敏到慢性痛觉过敏的神经可塑性转变，使我们能够研究从急性肌肉痛到慢性肌肉痛转变的细胞机制。基于这些发现，该提案概述了一个项目，该项目将采用两种创新方法来促进我们对慢性肌肉疼痛的潜在细胞机制的理解。首先，我们将继续我们的初步观察，表明一个离散的伤害性感受器亚群在慢性人体工学肌肉疼痛中起着关键作用，并且这个亚群的独特特征(对GDNF的敏感性和依赖于万能的IB4结合)不仅是区分它们与其他亚群的便捷标记，而且实际上，在它们对慢性肌肉疼痛的独特贡献中发挥着关键作用。第二，针对突出的临床作用 应激在慢性肌肉痛综合征的病理生理学中起作用，我们将研究伤害性感受器作为神经内分泌应激轴激活促进慢性疼痛的主要部位。PI实验室的多学科专业知识使这项建议能够勾勒出一个基于行为、药理学、解剖学和活体电生理学和体外神经生理学方法的协调使用的研究计划。

DESCRIPTION (provided by applicant): Musculoskeletal pain is the most frequent and expensive condition for worker compensation and disability. Previous investigations into the pathogenesis of work- related musculoskeletal pain have tended to focus on the possibility of pathology in muscle cells; however, it is clear that chronic ergonomic muscle pain can occur without any signs of cellular injury in the muscle. During the current funding period we have provided extensive evidence, in two animal models of ergonomic muscle pain (vibration and eccentric exercise) that the muscle nociceptor is a primary locus of pathophysiological changes that produce chronic muscle pain. Furthermore, these models exhibit a neuroplastic shift from acute hyperalgesia to chronic hyperalgesic priming that enables us to study the cellular mechanisms of the transition from acute to chronic muscle pain. Based on those findings, this proposal outlines a project that will employ two innovative approaches to advance our understanding of the underlying cellular mechanisms of chronic muscle pain. First, we will pursue our preliminary observations which suggest a discrete subpopulation of nociceptors plays a critical role in chronic ergonomic muscle pain, and that distinctive features of this subpopulation (sensitivity to GDNF and versican-dependent binding of IB4) are not just convenient markers to distinguish them from other subpopulations, but in fact, play a crucial role in their unique contribution to chronic muscle pain. Second, in view of the prominent clinical role stress plays in the pathophysiology of chronic muscle pain syndromes, we will investigate the nociceptor as a primary site at which activation of neuroendocrine stress axes contributes to chronic pain. The multi-disciplinary expertise of the PI's laboratory enables this proposal to outline a research plan based on the concerted use of behavioral, pharmacological, anatomical, and in vivo electrophysiological and in vitro neurophysiological methods.