Resolution of postoperative pain by complementary approaches

摘要 在美国，每年有数以百万计的人因医学上必要的疾病和 有发展为慢性疼痛的风险，特别是在骨科手术等创伤性手术之后。 过度的炎症和未解决的疼痛仍然是发病率的主要原因，特别是在 不断增长的老年人口。我们的长期目标是确定急性转化为 持续的术后疼痛，并提供安全有效的方法来减少这种潜在的 具有毁灭性的复杂性。在拟议的研究中，我们将使用临床相关的模型来模拟术后疼痛 骨科手术(胫骨骨折)合并应力的模式，这对几乎每个患者都是常见的 正在接受大手术。本项目中提出的工作的总体目标是评估 补充和综合的健康方法，以减少，并可能解决，术后疼痛。我们的 中心假说是，手术引起的神经炎症对术后疼痛的调节至关重要， 并因紧张的事件而变得更糟。靶向促分辨和迷走神经介导的信号可以逆转 这种持续的疼痛。这一假设是基于申请者实验室获得的初步数据，并且 将通过追求3个具体目标进行测试：1)分析压力和性别对手术诱导的影响 神经炎症和疼痛行为；2)确定包括二十二碳六烯酸在内的天然化合物的效果 酸、薄荷脑和桉油醇对骨科手术后神经炎症和疼痛行为的影响； 描述生物电子方法(电针和迷走神经刺激)降低 骨科手术后疼痛和神经炎症。这些模型和技术的可行性一直是 在申请者手中确立。在这种创新的方法中，新的互补生物电子策略， 包括微创迷走神经刺激，电路标测方法，以及对 澄清的组织将与严格的免疫表型和行为测试相结合，以定义和 调节手术后疼痛相关的信号。这项拟议研究的基本原理是 完成这项工作将促进和扩大我们对多种互补和综合健康如何 治疗方法影响与疼痛信号和围手术期恢复相关的基本分子机制。 这种知识非常重要，因为它有可能改善手术结果，减少阿片类药物 要求，并提高美国数百万患者的生活质量。

Abstract Millions of individuals in the United States undergo surgery every year for medically necessary conditions and are at risk for developing chronic pain especially following traumatic procedures like orthopedic surgery. Excessive inflammation and unresolved pain remain leading causes of morbidity, in particular among the rapidly growing elderly population. Our long-term goal is to define the mechanisms that underlie the conversion of acute to persistent postoperative pain, and to provide safe and effective approaches to reduce this potentially devastating complication. In the proposed study, we will model postoperative pain using a clinically relevant model of orthopedic surgery (tibial fracture) combined with stress, which is a common to virtually every patient undergoing major surgery. The overall objective of the work proposed in this project is to evaluate the role of complementary and integrative health approaches to reduce, and possibly resolve, postoperative pain. Our central hypothesis is that surgery-induced neuroinflammation is crucial to the modulation of postoperative pain, and is exacerbated by a stressful event. Targeting of pro-resolving and vagal-mediated signaling can reverse this persistent pain. This hypothesis is based on preliminary data acquired in the applicants’ laboratories, and will be tested by pursuing 3 specific aims: 1) Analyze the effects of stress and sex on surgery-induced neuroinflammation and pain behavior; 2) Determine the effects of natural compounds including docosahexaenoic acids, menthol, and eucalyptol, on neuroinflammation and pain behavior after orthopedic surgery; and 3) Characterize the ability of bioelectronic approaches (electroacupuncture and vagus nerve stimulation) to reduce pain and neuroinflammation after orthopedic surgery. Feasibility for these models and techniques has been established in the applicants’ hands. In this innovative approach, novel complementary bioelectronic strategies, including minimally invasive vagus nerve stimulation, circuit mapping methods, and postmortem analyses of clarified tissues will be combined with rigorous immunophenotyping and behavioral testing to define and modulate pain-related signaling after surgery. The rationale for the proposed research is that successful completion will advance and expand our understanding of how multiple complementary and integrative health approaches affect fundamental molecular mechanisms of relevance to pain signaling and perioperative recovery. Such knowledge is highly significant because it has the potential to improve surgical outcome, reduce opioid requirements, and enhance quality of life for millions of patients in the United States.