Role of Stress-induced LC Dysfunction on Pain Trajectory and Disability after Surgery

压力引起的 LC 功能障碍对手术后疼痛轨迹和残疾的作用

• 批准号: 9900813
• 负责人: Christopher Michael Peters
• 金额: $ 15.25万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900813
• 关键词: Absence of pain sensation; Affect; Affective; Amygdaloid structure; Analgesics; Animal Model; Animals; Behavioral; Capsaicin; Chronic stress; Clinical; Cognitive; Engineering; Failure; Functional disorder; Growth; Hypersensitivity; Impairment; Incidence; Individual; Intervention; Ligation; Measures; Mechanics; Methods; Modeling; Neurons; Operative Surgical Procedures; Pain; Pathway interactions; Pattern; Performance; Persons; Physical Function; Population Intervention; Postoperative Pain; Postoperative Period; Public Health; Quality of life; Rattus; Recovery; Research Proposals; Resolution; Rodent; Role; Running; Sensory; Signal Pathway; Signal Transduction; Speed; Spinal; Spinal Cord; Spinal nerve structure; Stress; Testing; Time; Variant; Viral Vector; Well in self; chronic pain; conditioned pain modulation; designer receptors exclusively activated by designer drugs; disability; duloxetine; experimental study; gabapentin; high risk population; innovation; locus ceruleus structure; negative affect; noradrenergic; novel; partial recovery; postoperative recovery; prevent; receptor-mediated signaling; response; sensory stimulus; social defeat

The failure of pain to resolve after surgery has a significant impact on the physical function, emotional well- being, and overall quality of life for those affected often leading to long term disability. As a result, the identification of interventions that prevent or treat chronic pain after surgery (CPAS) has the potential to significantly impact public health. Clinically, a person’s capacity to engage endogenous analgesic circuits as well as a negative preoperative cognitive affective state have been shown to predict a higher incidence of pain and disability several months after surgery. The causal mechanisms responsible for these relationships are not understood. The central hypothesis of this research proposal is that locus coeruleus (LC) noradrenergic projections to the spinal cord and central amygdala (CeA) are important for resolution of pain and disability following surgery and increased tonic LC activity induced by chronic stress around the time of surgery disrupts noradrenergic circuits and receptor mediated signaling pathways resulting in long term disability affecting multiple behavioral domains (sensory, cognitive, affective). A barrier to the field is a lack of appropriate animal models and approaches to study the mechanisms that underlie these associations. In the current project, we use novel and innovative methods to study the interaction between LC activity, chronic stress, and recovery from pain and disability after surgery. We apply growth curve modeling to longitudinal measures of mechanical hypersensitivity and a novel non- evoked measure of disability involving running wheel performance to better characterize the resolution of postoperative pain and disability in individual rats. We recently demonstrated for the first time in an animal model that lower preoperative CPM was associated with smaller slope of recovery of hypersensitivity following surgery and spinal noradrenergic pathways were critical to both CPM and speed of recovery. Expanding on these findings, we demonstrate that exposing rats to repeat social defeat (RSD) stress reduces preoperative CPM and slows recovery of hypersensitivity and reduces mobility. As part of Aim 1, we will examine the influence of augmenting spinal noradrenergic activity on preoperative CPM and postoperative hypersensitivity and disability. Additionally, we will engineer and use DREADD containing viral vectors to selectively excite/silence noradrenergic circuits at the terminal to better understand the contribution of specific projections (to spinal cord and CeA) to aspects of recovery. As part of Aim 2, we examine how experimentally increasing LC tonic activity with RSD impacts sensory evoked LC activity and NE release to regulate recovery from surgery. In Aim 3, we will test whether preoperative tonic LC activity and CPM predicts the efficacy of systemic gabapentin and duloxetine to speed recovery from hypersensitivity and reduced mobility in individual rats. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and pain.

手术后疼痛未能解决，对身体功能有明显影响，情绪良好- 生活质量和整体生活质量的影响，往往导致长期残疾。结果导致 确定预防或治疗术后慢性疼痛（CPAS）的干预措施有可能 严重影响公共卫生。临床上，一个人参与内源性镇痛回路的能力， 以及术前消极的认知情感状态被证明预示着更高的疼痛发生率 术后几个月残疾造成这些关系的因果机制并不是 明白这项研究的中心假设是蓝斑（LC）去甲肾上腺素能神经元 向脊髓和中央杏仁核（CeA）的投射对于缓解疼痛和残疾是重要的 手术后慢性应激引起的紧张性LC活动增加， 去甲肾上腺素能回路和受体介导的信号传导途径导致长期残疾， 多个行为领域（感觉、认知、情感）。 该领域的一个障碍是缺乏适当的动物模型和方法来研究 这些关联的基础。在本项目中，我们使用新颖和创新的方法来研究 LC活动、慢性应激与手术后疼痛和残疾恢复之间的相互作用。 我们将生长曲线模型应用于机械超敏性的纵向测量，并提出了一种新的非- 诱发残疾的措施，涉及转轮性能，以更好地表征解决方案， 个体大鼠的术后疼痛和残疾。我们最近首次在动物身上展示了 模型表明，较低的术前CPM与术后超敏反应恢复的斜率较小相关， 手术和脊髓去甲肾上腺素能通路对CPM和恢复速度都至关重要。扩大对 这些发现表明，将大鼠暴露于重复社交失败（RSD）压力可降低术前 CPM和减缓恢复过敏和减少流动性。 作为目标1的一部分，我们将研究增强脊髓去甲肾上腺素能活性对术前 CPM与术后超敏反应和残疾。此外，我们将设计和使用DREADD 含有病毒载体，以选择性地激发/沉默末端的去甲肾上腺素能回路， 特定投射（对脊髓和CeA）对恢复方面的贡献。作为目标2的一部分，我们 研究如何通过实验增加RSD的LC强直活性影响感觉诱发的LC活性， NE释放以调节手术恢复。在目标3中，我们将测试术前紧张性LC活动是否 CPM预测全身性加巴喷丁和度洛沙汀加速超敏反应恢复的疗效 以及个体大鼠的活动性降低。总之，这个项目和所描述的实验可以提供 新的和重要的信息去甲肾上腺素能功能和交叉的负面影响和疼痛。