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

描述（由申请人提供）：肌肉骨骼疼痛是工人赔偿和残疾的最常见和最昂贵的条件。以前对工作相关的肌肉骨骼疼痛的发病机制的研究往往集中在肌肉细胞病理的可能性上;然而，很明显，慢性人体工程学肌肉疼痛可以在肌肉中没有任何细胞损伤的迹象的情况下发生。在目前的资助期间，我们已经提供了广泛的证据，在两个符合人体工程学的肌肉疼痛（振动和离心运动）的动物模型，肌肉伤害感受器是一个主要的轨迹的病理生理变化，产生慢性肌肉疼痛。此外，这些模型表现出从急性痛觉过敏到慢性痛觉过敏启动的神经可塑性转变，使我们能够研究从急性到慢性肌肉疼痛过渡的细胞机制。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，这表明伤害感受器的离散亚群在慢性人体工程学肌肉疼痛中起着关键作用，并且该亚群的独特特征（对GDNF的敏感性和IB 4的versican依赖性结合）不仅是将它们与其他亚群区分开的方便标记，而且事实上，在它们对慢性肌肉疼痛的独特贡献中起着至关重要的作用。二是鉴于突出的临床作用 压力在慢性肌肉疼痛综合征的病理生理学中起作用，我们将研究伤害感受器作为神经内分泌压力轴激活导致慢性疼痛的主要部位。PI实验室的多学科专业知识使本提案能够概述基于行为，药理学，解剖学和体内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.