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

描述（由申请人提供）：肌肉骨骼疼痛是工伤赔偿和残疾最常见和最昂贵的疾病。先前对与工作有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在没有任何肌肉细胞损伤迹象的情况下发生。在目前的资助期内，我们已经提供了广泛的证据，在两种符合人体工程学的肌肉疼痛动物模型（振动和偏心运动）中，肌肉伤害感受器是产生慢性肌肉疼痛的病理生理变化的主要位点。此外，这些模型显示了从急性痛觉过敏到慢性痛觉过敏启动的神经可塑性转变，这使我们能够研究从急性到慢性肌肉疼痛转变的细胞机制。基于这些发现，本提案概述了一个项目，该项目将采用两种创新方法来推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，这些观察表明，一个离散的伤害感受器亚群在慢性人体工程肌肉疼痛中起着关键作用，而这个亚群的独特特征（对GDNF的敏感性和对IB4的versican依赖性结合）不仅是区分它们与其他亚群的方便标记，而且实际上，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。第二，鉴于临床作用的突出

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.