Mechanisms of Sleep Disruption Hyperalgesia

睡眠中断痛觉过敏的机制

• 批准号: 8471684
• 负责人: Michael R Irwin
• 金额: $ 53.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471684
• 关键词: Absence of pain sensation; Acute Pain; Address; American; Analgesics; Animals; Attenuated; Behavioral; Biology; Capsaicin; Cardiovascular Diseases; Chronic; Chronic Disease; Clinical; Comorbidity; Complement Factor B; Complex; Data; Development; Dimensions; Etiology; Functional disorder; Genetic Transcription; Genomics; Healthcare Systems; Heating; Hyperalgesia; Impairment; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Investigation; Knowledge; Laboratories; Lead; Maintenance; Measures; Mediating; Medical; Messenger RNA; Methods; Modeling; Mononuclear; Morbidity - disease rate; Morphine; Mus; Neurons; Nuclear; Opiate Addiction; Opioid; Pain; Pain Threshold; Participant; Pathway interactions; Pattern; Pharmaceutical Preparations; Placebos; Prevalence; Prevention; Primary Hyperalgesias; Process; Production; Psychoneuroimmunology; Quality of life; Randomized; Refractory; Relative (related person); Research; Risk; Role; Secondary Hyperalgesias; Sensory; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Spinal; Syndrome; System; TNF gene; Testing; Tumor Necrosis Factor-alpha; analog; animal data; base; biobehavior; chronic pain; cytokine; endogenous opioids; human subject; indexing; inflammatory marker; neurobehavioral; novel; opioid misuse; pain inhibition; preclinical study; programs; public health relevance; research study; response; spontaneous pain; transcription factor

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.

描述（由申请人提供）：20％的美国人患有慢性疼痛，一种对治疗难治性的疾病鲜为人知，严重限制了生活质量，并且对医疗保健系统和经济是一个巨大的负担。睡眠障碍是一个普遍存在的问题，也是与慢性疼痛相关的最常见和残疾合并症之一。睡眠障碍不仅仅是疼痛的结果，它大大增加了从急性疼痛转变为慢性疾病的风险。尽管尚不清楚睡眠障碍如何增加风险，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，即增强对疼痛刺激的反应性。 Hypergersia对于慢性疼痛综合征的病因和维持至关重要，但是对促进痛觉过敏的复杂生物行为因素知之甚少。睡眠障碍促进痛觉过敏的机制尚未研究。我们提出了一个新的研究计划，以研究睡眠破坏痛觉过敏的机理（SD_HA）。解决这一知识差距对慢性疼痛的病因，预防和治疗具有关键意义。我们小组的临床前研究和初步数据暗示了两种可能相互关联的主要临床进口候选机制：1）炎症和2）阿片类抗伤害感住系统障碍。我们已经组建了一个来自约翰·霍普金斯和加州大学洛杉矶分校的跨学科团队，以对健康人类受试者进行受控实验，以确定炎症在SD_HA中的作用，并研究睡眠破坏和炎症对阿片类镇痛的影响。我们将采用由我们小组开发的新型睡眠破坏操作，该操作使用多种，强迫觉醒来模仿最常见的与疼痛和失眠有关的睡眠损失模式。在不受干扰的睡眠和睡眠中断条件下，我们将评估下一天的痛觉过敏和对要么的镇痛反应：（a）吗啡或（b）安慰剂。我们的具体目的是：1）检查实验睡眠破坏对脊柱敏化（继发性痛觉过敏）的影响，通过评估热蛋白疼痛模型中的实验室疼痛反应； 2）检查睡眠破坏对阿片类镇痛的影响，3）确定睡眠破坏对炎症基因组，细胞和全身标志物的影响，并表征炎症对实验室疼痛反应和阿片类镇痛的作用。我们假设SD_HA和减少的阿片类镇痛将通过归因于睡眠破坏操作的增强炎症来介导。侧重于炎症性级联反应的基因组和细胞维度，阿片类功能及其相互作用将使人们更好地了解慢性疼痛病理生理学，并可能对新型疼痛治疗和预防方法的发展产生巨大影响。调查结果还将对诸如阿片类药物成瘾和慢性病等问题（例如心血管疾病）具有广泛的影响，其中炎症会导致发病和睡眠障碍。