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

 描述（由申请人提供）：数量和质量良好的健康睡眠越来越多地被视为防止疼痛发展和/或加剧的保护因素。然而，睡眠不足，如失眠，在一般人群中越来越常见，并且与慢性疼痛状况高度共病。虽然失眠的存在与疼痛症状的发作或恶化之间存在既定的关系，但这种关系的机制尚不清楚。该提议的目标是研究失眠至疼痛方向性的两个有希望的机制候选者：（1）炎症：当睡眠不足时，促炎标志物（白介素-6、前列腺素E2）增加而抗炎标志物（消退素）减少，并且有助于伤害感受系统的敏化（即，增加对疼痛信号的反应性）。(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中枢过程）会恶化，从而防止对疼痛的习惯化（对疼痛信号的反应性降低）。这两个机制的候选人将在一个新的模型中进行测试，该模型反复暴露于实验诱导的失眠，其特征在于（1）诱导典型的失眠症状（延迟的睡眠开始、睡眠中断、清晨觉醒）和（2）重复诱导这种模拟失眠发作，这允许研究许多生物系统的关键特征，即系统适应重复的压力或挑战（例如疼痛）的能力。我们假设，反复暴露于失眠通过促进两个过程增加对慢性疼痛的易感性：（1）通过炎症反应的进行性增加使伤害性系统敏感化，（2）通过疼痛抑制反应的进行性恶化降低对疼痛的习惯化。26名健康女性和男性将接受两个个体内平衡的17天住院治疗（失眠症状诱导vs对照睡眠条件），其中将使用频繁的血液和尿液采样以及复杂的疼痛测试组合来研究以下内容 目的：目的1假设反复暴露于实验诱导的失眠症状的炎症反应（IL-6、PGE 2、消退素）的进行性增加，导致伤害感受系统的敏化，如通过对压力和热的较低疼痛阈值以及增加的疼痛时间总和（中枢敏化的指标）所表现的。目的2假设疼痛抑制反应（通过条件性疼痛调制测试测量）的进行性恶化，导致对疼痛的习惯性降低。目的3假定在反复暴露于实验诱导的失眠症状后，炎症和疼痛抑制系统恢复到基线的能力的进行性损害。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少失眠加剧的疼痛至关重要。

 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.