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

项目总结 慢性疼痛和抑郁障碍对老年人的影响不同，这两种疾病通常都很难治疗， 强调需要调查可改变的危险因素并更好地阐明这些危险因素的病理生理学 精神错乱。失眠是这两种疾病的主要症状，是可以改变的，但目前还不知道失眠是如何发生的 影响生物和中枢神经系统因素，增加慢性疼痛的风险。这一知识是 对于改善失眠和慢性疼痛治疗以针对中枢性疼痛的改变至关重要 导致慢性疼痛风险和发病率的加工。鉴于失眠和睡眠障碍被激活 炎症信号，这项拟议的研究假设炎症是一种常见的生物底物 失眠和情感障碍与中枢疼痛处理的两个维度的变化动态联系起来 与慢性疼痛风险相关，即中枢敏感化(CS)和情感性疼痛调制(APM)。动物 模型表明，炎症会增强疼痛敏感性，并诱导神经可塑性改变，从而 增加中枢伤害性神经元对正常或阈值下传入信息的反应性，即CS。 炎症还会引起情感障碍，从而调节和放大痛觉(APM)。低 安全和短暂地给予内毒素剂量会导致情感障碍，新的研究表明 这一炎症性挑战可能会改变CS。因此，我们将调查失眠是否单独或合并 实验性炎症刺激(内毒素)改变了老年人的CS和APM。这项建议能使 与一项新资助的研究[(R01 AG051944(欧文)])的抑郁症状的差异和阴性和 积极的情绪反应是失眠和炎症挑战的一种功能。我们将研究一个子集(N=148) 在这项父母研究中，有(N=74)有失眠和没有失眠(N=74)的老年人将完成 对暴露于内毒素和安慰剂后的疼痛处理(CS和APM)进行全面评估。至 进一步建立这一慢性疼痛风险实验模型的翻译承诺，我们将添加电子 在3、6、9和12个月时对日常疼痛和抑郁症状进行日记评估。我们将实现四个目标： 1)评估中枢敏感化指数(CS)作为失眠和实验的函数的差异 内毒素暴露；2)评估情感疼痛调制(APM)作为失眠和 实验性内毒素暴露并确定内毒素引起的情感障碍的程度 解释CS和APM的改变；3)确定内毒素诱导的个体差异 炎症反应与CS和APM的改变有关，这是失眠的一个功能和4) 确定内毒素诱导的炎症反应和/或CS、APM和 情感障碍可以在一年内预测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.