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

• 批准号: 8680211
• 负责人: THOMAS E SCAMMELL
• 金额: $ 41.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/8680211
• 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

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.

描述（由申请人提供）：我们假设睡眠不好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睡眠不足会改变伤害性系统，使其在外周神经损伤后更容易发生适应不良的可塑性，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。为了验证这些假设，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。我们将在长达几周的时间内减少或破坏小鼠的睡眠，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促进慢性疼痛的发展。我们将重点关注疼痛相关的结果，如冷异常性疼痛和针刺痛敏，因为它们的发展是可变的C57 BL/6 j小鼠后，标准形式的外周神经损伤。我们将在外周神经损伤前产生慢性睡眠中断（部分睡眠剥夺或睡眠片段化），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致敏模型，然后我们将量化浅层背角中c-fos和p-ERK阳性神经元的数量。在目标3中，我们将在神经损伤后立即促进睡眠，并持续几天，以确定增强小鼠的睡眠是否会降低患慢性疼痛的风险。为了研究不同神经化学系统的作用，我们将使用三种作用于不同系统的催眠药物（苯二氮卓类、食欲素拮抗剂和γ-羟基丁酸酯）。我们预计，增加睡眠量和减少睡眠碎片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，因为它们应该阐明低质量的睡眠如何促进从急性疼痛到适应不良的慢性疼痛的转变，以及改善睡眠如何减轻疼痛。