Sleep disturbance as a risk factor for developing chronic pain

睡眠障碍是发生慢性疼痛的危险因素

基本信息

批准号：
8368585
负责人：
THOMAS E SCAMMELL
金额：
$ 43.87万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-26 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8368585
关键词：
Acute Acute Pain Affect Animals Award Behavior Behavioral Benzodiazepines Capsaicin Chronic Clinical Clinical Data Collaborations Data Development Environmental Risk Factor FOS gene Future Hyperalgesia Injection of therapeutic agent Injury Laboratories Lead Left Light Maintenance Measures Modeling Mus Nature Nerve Nerve Crush Neurobiology Neuronal Plasticity Neurons Nociception Outcome Outcome Measure Pain Pain Threshold Patients Peripheral nerve injury Pharmaceutical Preparations Predisposition Reporting Risk Risk Factors Role Secondary Hyperalgesias Severities Sleep Sleep Deprivation Sleep Fragmentations Sleep disturbances Stimulus Symptoms Synaptic plasticity System Testing allodynia central sensitization chronic pain clinically relevant dorsal horn forging gamma hydroxybutyrate hypnotic hypocretin improved indexing injured mouse model multidisciplinary nerve injury neurochemistry novel novel strategies pain behavior painful neuropathy pre-clinical prevent relating to nervous system research study response sciatic nerve

项目摘要

DESCRIPTION (provided by applicant): We hypothesize that poor sleep increases the likelihood of transitioning from acute to chronic pain. Specifically, we propose that disrupted or insufficient sleep alters the nociceptive system, making it more susceptible to maladaptive plasticity after peripheral nerve injury, resulting in chronic pain. Conversely, we hypothesize tha promoting restorative sleep will reduce the risk of developing persistent neuropathic pain. To test these hypotheses, we propose three aims: In Aim 1, we will test if moderate, chronic sleep disturbance increases acute nociceptive pain sensitivity. We will reduce or fragment sleep in mice for periods up to several weeks and measure pain sensitivity before, during and after the sleep disruption. In Aim 2, we will examine how sleep disruption contributes to the development of chronic pain. We will focus on pain-related outcomes such as cold allodynia and pinprick hyperalgesia because their development is variable in C57BL/6j mice after standard forms of peripheral nerve injury. We will produce chronic sleep disruption (partial sleep deprivation or sleep fragmentation) before peripheral nerve injury, and we will then measure the onset, intensity and duration of pain related behavior. We anticipate that sleep disruption will increase neuropathic pain behavior. To determine if sleep disruption affects CNS synaptic plasticity, we will also measure secondary hyperalgesia caused by intraplantar injection of capsaicin as a model of central sensitization, and we will then quantify the number of c-fos and p-ERK positive neurons in the superficial dorsal horn. In Aim 3, we will pharmacologically promote sleep immediately after nerve injury and for several days to determine whether enhancing sleep in mice reduces the risk of developing chronic pain. To examine the roles of distinct neurochemical systems, we will administer three classes of hypnotic drugs that act on different systems (benzodiazepines, orexin antagonists, and gamma hydroxybutyrate). We expect that increasing the amount of sleep and reducing sleep fragmentation will reduce the risk of developing chronic pain. These multidisciplinary experiments have substantial scientific and clinical implications as they should shed light on how poor quality sleep promotes the transition from acute pain to maladaptive, chronic pain, and how improved sleep can reduce pain. PUBLIC HEALTH RELEVANCE: Patients often report that poor sleep worsens their pain. We will examine how insufficient sleep and fragmented sleep contribute to the development of chronic pain after peripheral nerve injury in mice. Understanding how poor sleep affects the development of chronic pain should lead to better strategies for preventing and treating chronic pain.

描述（由申请人提供）：我们假设睡眠不佳会增加从急性疼痛转变为慢性疼痛的可能性。具体来说，我们认为睡眠中断或不足会改变伤害感受系统，使其在周围神经损伤后更容易出现适应不良的可塑性，从而导致慢性疼痛。相反，我们假设促进恢复性睡眠将降低发生持续性神经性疼痛的风险。为了检验这些假设，我们提出了三个目标：在目标 1 中，我们将测试中度、慢性睡眠障碍是否会增加急性伤害性疼痛敏感性。我们将减少或中断小鼠的睡眠长达数周，并在睡眠中断之前、期间和之后测量疼痛敏感性。在目标 2 中，我们将研究睡眠中断如何导致慢性疼痛的发生。我们将重点关注与疼痛相关的结果，例如冷异常性疼痛和针刺痛觉过敏，因为在标准形式的周围神经损伤后，它们的发展在 C57BL/6j 小鼠中是可变的。我们将在周围神经损伤之前产生慢性睡眠中断（部分睡眠剥夺或睡眠碎片化），然后我们将测量疼痛相关行为的发作、强度和持续时间。我们预计睡眠中断会增加神经性疼痛行为。为了确定睡眠中断是否影响中枢神经系统突触可塑性，我们还将测量足底注射辣椒素引起的继发性痛觉过敏作为中枢敏化模型，然后量化背侧浅层 c-fos 和 p-ERK 阳性神经元的数量喇叭。在目标 3 中，我们将在神经损伤后立即通过药物促进睡眠并持续几天，以确定增强小鼠的睡眠是否可以降低发生慢性疼痛的风险。为了检查不同神经化学系统的作用，我们将使用三类作用于不同系统的催眠药物（苯二氮卓类药物、食欲素拮抗剂和γ-羟基丁酸盐）。我们预计，增加睡眠量和减少睡眠碎片化将降低患慢性疼痛的风险。这些多学科实验具有重大的科学和临床意义，因为它们应该揭示低质量的睡眠如何促进从急性疼痛向适应不良的慢性疼痛的转变，以及改善睡眠如何减轻疼痛。公共健康相关性：患者经常报告睡眠不足会加剧疼痛。我们将研究睡眠不足和睡眠碎片如何导致小鼠周围神经损伤后慢性疼痛的发展。了解睡眠不足如何影响慢性疼痛的发展应该有助于制定更好的预防和治疗慢性疼痛的策略。