Mechanisms of Sleep Disruption Hyperalgesia

描述（由申请人提供）：20%的美国人患有慢性疼痛，这是一种很难治疗的疾病，严重限制了生活质量，是医疗保健系统和经济的巨大负担。睡眠障碍是一个同样普遍存在的问题，也是与慢性疼痛相关的最常见和致残的合并症之一。睡眠障碍不仅仅是疼痛的后果，它大大增加了从急性疼痛过渡到慢性疾病的风险。虽然尚不清楚睡眠障碍是如何增加风险的，但初步证据表明，即使是部分睡眠剥夺也可能导致痛觉过敏，即对疼痛刺激的反应增强。痛觉过敏对慢性疼痛综合征的病因和维持至关重要，但促进痛觉过敏的复杂生物行为因素尚不清楚。睡眠障碍促进痛觉过敏的机制还有待研究。我们提出了一个新的研究计划来研究睡眠中断痛觉过敏（SD_HA）的机制。解决这一知识差距对慢性疼痛的病因、预防和治疗具有重要意义。我们小组的临床前研究和初步数据表明，两种可能相互关联的候选机制具有重要的临床意义：1)炎症和2)阿片能抗感觉系统损伤。我们组建了一个来自约翰霍普金斯大学和加州大学洛杉矶分校的跨学科团队，在健康的人类受试者中进行对照实验，以确定炎症在SD_HA中的作用，并研究睡眠中断和炎症对阿片类镇痛的影响。我们将采用我们团队开发的一种新颖的睡眠中断操作，使用多次强制唤醒来模拟最常见的与疼痛和失眠相关的睡眠缺失模式。在不受干扰的睡眠和睡眠中断条件下，我们将评估第二天的痛觉过敏和镇痛反应：(a)吗啡或(b)安慰剂。我们的具体目标是：1)通过评估热辣椒素疼痛模型中的实验室疼痛反应，研究实验性睡眠中断对脊柱致敏（继发性痛觉过敏）的影响；2)研究睡眠中断对阿片类镇痛的影响；3)确定睡眠中断对炎症的基因组、细胞和全身标志物的影响，并描述炎症在实验室疼痛反应和阿片类镇痛中的作用。我们假设SD_HA和阿片类镇痛的减少将通过睡眠中断操作引起的炎症增强来介导。关注炎症级联的基因组和细胞维度，阿片能功能及其相互作用将导致对慢性疼痛病理生理学的更好理解，并可能对新型疼痛治疗和预防方法的发展产生巨大影响。研究结果还将对阿片类药物成瘾和慢性疾病（如心血管疾病）等问题产生广泛影响，其中炎症导致发病率和睡眠障碍很常见。

DESCRIPTION (provided by applicant): Twenty percent of Americans suffer from chronic pain, a poorly understood condition that is refractory to treatment, severely limits quality of life, and is a tremendous burden on the healthcare system and the economy. Sleep disturbance is an equally ubiquitous problem and among the most common and disabling comorbidities associated with chronic pain. Sleep disturbance is not simply a consequence of pain, it substantially increases the risk of transitioning from acute pain to a chronic disorder. Although it is not known how sleep disturbance increases risk, preliminary evidence suggests that even partial sleep deprivation may cause hyperalgesia, i.e., enhanced responsivity to painful stimulation. Hyperalgesia is critical to the etiology and maintenance of chronic pain syndromes, but the complex biobehavioral factors that promote hyperalgesia are poorly understood. The mechanisms by which sleep disturbance promotes hyperalgesia have yet to be studied. We propose a novel research program to study the mechanisms of sleep disruption hyperalgesia (SD_HA). Addressing this knowledge gap has critical implications for the etiology, prevention and treatment of chronic pain. Pre-clinical studies and preliminary data from our groups implicate two possibly interrelated candidate mechanisms of major clinical import: 1) inflammation and 2) opioidergic antinociceptive system impairment. We have assembled an interdisciplinary team from Johns Hopkins and UCLA to conduct a controlled experiment in healthy human subjects to determine the role of inflammation in SD_HA and study the effects of sleep disruption and inflammation on opioid analgesia. We will employ a novel sleep disruption manipulation developed by our group that uses multiple, forced awakenings to mimic the pattern of sleep loss most commonly associated with pain and insomnia. Following undisturbed sleep and sleep disruption conditions, we will assess next-day hyperalgesia and analgesic response to either: (a) morphine or (b) placebo. Our specific aims are to: 1) examine the effects of experimental sleep disruption on spinal sensitization (secondary hyperalgesia) by evaluating laboratory pain responses in the heat-capsaicin pain model; 2) examine the effects of sleep disruption on opioid analgesia and 3) determine the effects of sleep disruption on genomic, cellular, and systemic markers of inflammation and characterize the role of inflammation on laboratory pain responses and opioid analgesia. We hypothesize that SD_HA and diminished opioid analgesia will be mediated by enhanced inflammation attributable to the sleep disruption manipulation. Focusing on genomic and cellular dimensions of the inflammatory cascade, opioidergic function and their interaction will lead to a better understanding of chronic pain pathophysiology and could have tremendous impact on the development of novel pain treatment and prevention methods. Findings will also have broad implications for problems such as opioid addiction and chronic medical conditions, such as cardiovascular disease in which inflammation contributes to morbidity and sleep disturbance is common. PUBLIC HEALTH RELEVANCE: The mechanisms of sleep disturbance hyperalgesia are unknown. We will determine whether sleep disruption induces spinally mediated hyperalgesia, impairs opioid analgesia, and evaluate the potential mediating role of inflammation in these processes. Findings could lead to novel pain prevention treatment approaches.