Experimental model of chronic pain risk: Insomnia, inflammation, central sensitization, and affective disturbance

项目摘要 慢性疼痛和抑郁症对老年人的影响不同，这两种疾病往往是棘手的， 强调需要调查可改变的风险因素，并更好地阐明这些风险因素的病理生理学， 紊乱失眠，这两种疾病的主要症状，是可以改变的，但不知道如何失眠 影响增加慢性疼痛风险的生物和中枢神经系统因素。这种知识是 对于改善失眠和慢性疼痛管理疗法以靶向中枢疼痛的改变至关重要 导致慢性疼痛风险和发病率的过程。鉴于失眠和睡眠障碍会激活 炎症信号，这项研究假设炎症是一种常见的生物基质， 动态地将失眠和情感障碍与中枢疼痛处理的两个维度的改变联系起来 与慢性疼痛风险相关，即中枢致敏（CS）和情感性疼痛调节（APM）。动物 模型表明，炎症增强疼痛敏感性，并诱导神经可塑性改变， 增加CNS伤害感受神经元对正常或阈下传入输入的反应性，即，CS. 炎症还诱导情感障碍，其可以调节和放大疼痛感知（APM）。低 剂量内毒素给药安全和短暂诱导情感障碍，新兴的研究表明， 这种炎症性刺激可能会改变CS。因此，我们将研究失眠，单独或合并 实验性炎症刺激（内毒素）改变了老年人的CS和APM。该提案协同 一项新资助的研究[（R 01 AG 051944（欧文）]，研究了抑郁症状与阴性和 积极的情绪反应是失眠和炎症的函数。我们将研究一个子集（N=148） 在这项对患有（N=74）和没有（N=74）失眠的老年人进行的母研究中， 与安慰剂相比，暴露于内毒素后疼痛处理（CS和APM）的综合评估。到 为了进一步建立这种慢性疼痛风险实验模型的转化承诺，我们将添加电子 3、6、9和12个月时每日疼痛和抑郁症状的日记评估。我们将实现四个目标： 1)评估中枢敏感化（CS）指数与失眠和实验性失眠的关系， 内毒素暴露; 2）评估作为失眠的函数的情感疼痛调节（APM）的差异， 实验性内毒素暴露，并确定内毒素诱导的情感障碍的程度 解释CS和APM的改变; 3）确定内毒素诱导的 炎症反应与CS和APM改变相关，作为失眠的函数，以及4） 确定内毒素诱导的炎症反应和/或CS、APM和 情感障碍可预测1年内每日自我报告的疼痛和抑郁症状， 失眠的功能这些数据将有助于开发新的预防和治疗方法 治疗慢性疼痛和抑郁症

PROJECT SUMMARY Chronic pain and depressive disorders differentially impact older adults and both conditions are often intractable, underscoring the need to investigate modifiable risk factors and better elucidate the pathophysiology of these disorders. Insomnia, a cardinal symptom of both disorders, is modifiable, yet it is not known how insomnia influences biological and central nervous system factors that increase risk for chronic pain. This knowledge is critical for refining insomnia and chronic pain management therapies to target alterations in central pain processing that contribute to chronic pain risk and morbidity. Given that insomnia and sleep disturbance activate inflammatory signaling, the proposed study hypothesizes that inflammation is a common biological substrate that dynamically links insomnia and affective disturbance with alterations in two dimensions of central pain processing associated with chronic pain risk, i.e. central sensitization (CS) and affective pain modulation (APM). Animal models demonstrate that inflammation heightens pain sensitivity and induces neuroplastic alterations that increase the responsivity of CNS nociceptive neurons to normal or subthreshold afferent input, i.e., CS. Inflammation also induces affective disturbances that may modulate and amplify pain perception (APM). Low dose endotoxin administration safely and transiently induces affective disturbance and emerging studies suggest this inflammatory challenge may alter CS. Hence, we will investigate whether insomnia, alone or combined with an experimental inflammatory challenge (endotoxin) alters CS and APM in older adults. This proposal synergizes with a newly funded study [(R01 AG051944 (Irwin)] of differences in depressive symptoms and negative and positive affect responding as a function of insomnia and inflammatory challenge. We will study a subset (N=148) of participants in this parent study of older adults with (N=74) and without (N=74) insomnia who will complete a comprehensive assessment of pain processing (CS and APM) following exposure to endotoxin vs. placebo. To further establish the translational promise of this experimental model of chronic pain risk, we will add electronic diary assessments of daily pain and depressive symptoms at 3, 6, 9, and 12 months. We will address four aims: 1) Evaluate differences in indices of central sensitization (CS) as a function of insomnia and experimental endotoxin exposure; 2) Evaluate differences in affective pain modulation (APM) as a function of insomnia and experimental endotoxin exposure and determine the extent to which endotoxin-induced affective disturbance accounts for alterations in CS and APM; 3) Determine whether individual differences in the endotoxin-induced inflammatory response are associated with alterations in CS and APM, as a function of insomnia and 4) Determine the extent to which the endotoxin-induced inflammatory response and/or alterations in CS, APM, and affective disturbance predict daily self-reported pain and depressive symptoms over the course of 1 year, as a function of insomnia. These data will be instrumental in developing novel prevention and treatment approaches for chronic pain and depression.