Pain Sensitization and Habituation in a Model of Experimentally-Induced Insomnia Symptoms

实验诱发的失眠症状模型中的疼痛敏化和习惯

• 批准号: 8861618
• 负责人: MONIKA HAACK
• 金额: $ 64.57万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8861618
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Blood; Chronic; Complex; Deterioration; Development; Dinoprostone; Equilibrium; Exacerbated Insomnia; Exposure to; Future; General Population; Goals; Health; Heating; High Prevalence; Hospitals; Hour; Impairment; Individual; Inflammation; Inflammatory Response; Interleukin-6; Investigation; Length of Stay; Measures; Modeling; Nociception; Pain; Pain Threshold; Pain intensity; Participant; Pathway interactions; Pattern; Play; Process; Recovery; Research; Research Design; Resolution; Role; Sampling; Signal Transduction; Sleep; Sleeplessness; Stimulus; Symptoms; System; Test Result; Testing; Urine; Woman; biological systems; central sensitization; chronic pain; design; experience; habituation; indexing; inflammatory marker; inflammatory pain; insight; lipid mediator; men; novel; novel strategies; pain inhibition; pressure; prevent; protective effect; public health relevance; response; sleep onset; sleep regulation; stressor

 DESCRIPTION (provided by applicant): Healthy sleep of good quantity and quality is increasingly viewed as a protective factor against the development and/or exacerbation of pain. However, deficient sleep, such as insomnia, is increasingly common in the general population and is highly co-morbid with chronic pain conditions. Though there is an established relationship between the presence of insomnia and the onset or worsening of pain symptoms, the mechanisms underlying this relationship are unknown. The goal of this proposal is to investigate two promising mechanistic candidates underlying the insomia-to-pain directionality: (1) Inflammation: Pro-inflammatory markers (interleukin-6, prostaglandin E2) increase and anti- inflammatory markers (resolvins) decrease when sleep is deficient, and contribute to the sensitization of the nociceptive system (i.e., increased responsiveness to pain signals). (2) Pain inhibition: The capacity to inhibit pain, a central process to control incoming pain signals, is deteriorated when sleep is deficient, thus preventing habituation to pain (decreased responsivness to pain signals). These two mechanistic candidates will be tested in a novel model of repeated exposure to experimentally-induced insomnia, characterized by (1) induction of typical insomnia symptoms (delayed sleep onset, sleep disruption, early morning awakening) and (2) repeated induction of such simulated insomnia episodes, which allows for the investigation of a key feature of many biological systems, i.e. the ability of systems to adapt to repeated stressor or challenge, such as pain. We hypothezise that repeated exposure to insomnia increases vulnerability to chronic pain by promoting two processes: (1) sensitization of the nociceptive system via a progressive increase of the inflammatory response and (2) decreased habituation to pain via a progressive deterioration of the pain-inhibitory response. Twenty-six healthy women and men will undergo two intra-individual balanced 17- day in-hospital stays (insomnia symptoms induction vs control sleep condition), in which frequent blood and urine sampling and a complex pain testing battery will be utilized to investigate the following aims: Aim 1 postulates a progressive increase of the inflammatory response (IL-6, PGE2, resolvins) to repeated exposure to experimentally-induced insomnia symptoms, leading to sensitization of the nociceptive system as manifested by lower pain thresholds to pressure and heat, as well as increased temporal summation of pain (an index of central sensitization). Aim 2 postulates a progressive deterioration of the pain-inhibitory response (measured by the conditioned pain modulation test), contributing to less habituation to pain. Aim 3 postulates a progressive impairment of the ability of the inflammatory and pain-inhibitory system to return to baseline upon repeated exposure to experimentally-induced insomnia symptoms. This research is fundamental for the future development of novel strategies targeting specific mechanisms to prevent or reduce pain exacerbated by insomnia.

 描述（由申请人提供）：数量和质量良好的健康睡眠越来越被视为防止疼痛发生和/或加剧的保护因素。然而，睡眠不足，例如失眠，在普通人群中越来越常见，并且与慢性疼痛状况高度共存。尽管失眠的存在与疼痛症状的发生或恶化之间存在确定的关系，但这种关系背后的机制尚不清楚。该提案的目标是研究失眠与疼痛方向性背后的两个有前景的候选机制：（1）炎症：当睡眠不足时，促炎标记物（白细胞介素 6、前列腺素 E2）增加，抗炎标记物（消退素）减少，并有助于伤害感受系统的敏化（即对疼痛信号的反应性增加）。 (2) 疼痛抑制：当睡眠不足时，抑制疼痛的能力（控制传入疼痛信号的核心过程）会恶化，从而阻止对疼痛的习惯（对疼痛信号的反应性降低）。这两种机制候选者将在反复暴露于实验诱导的失眠的新模型中进行测试，其特征是（1）诱导典型的失眠症状（延迟入睡、睡眠中断、清晨醒来）和（2）重复诱导此类模拟失眠发作，这使得可以研究许多生物系统的一个关键特征，即系统适应重复压力源的能力 或挑战，例如疼痛。我们假设，反复失眠会通过促进两个过程来增加对慢性疼痛的脆弱性：（1）通过炎症反应的逐渐增加而使伤害性系统变得敏感；（2）通过疼痛抑制反应的逐渐恶化来减少对疼痛的习惯。 26 名健康的女性和男性将接受两次个体内平衡的 17 天住院治疗（失眠症状诱导与控制睡眠状况），其中将利用频繁的血液和尿液采样以及复杂的疼痛测试电池来调查以下情况 目标：目标 1 假设反复暴露于实验诱发的失眠症状时，炎症反应（IL-6、PGE2、消退素）逐渐增加，导致伤害感受系统变得敏感，表现为对压力和热的疼痛阈值降低，以及疼痛的时间总和增加（中枢敏感化指数）。目标 2 假设疼痛抑制反应（通过条件性疼痛调节测试测量）逐渐恶化，从而减少对疼痛的习惯。目标 3 假设炎症和疼痛抑制系统在反复暴露于实验诱发的失眠症状后恢复到基线的能力逐渐受损。这项研究对于未来开发针对特定机制的新策略以预防或减轻失眠加剧的疼痛至关重要。