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）：我们假设睡眠不足会增加从急性到慢性疼痛过渡的可能性。具体而言，我们提出，睡眠中断或不足会改变伤害性系统，使其在周围神经损伤后更容易受到适应不良的可塑性，从而导致慢性疼痛。相反，我们假设促进恢复性睡眠将减少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AIM 1中，我们将测试中度，慢性睡眠障碍是否会增加急性伤心疼痛敏感性。我们将在小鼠中减少或碎片睡眠长达几周，并在睡眠中断之前，之中和之后测量疼痛敏感性。在AIM 2中，我们将研究睡眠干扰如何有助于慢性疼痛的发展。我们将重点关注与疼痛相关的结果，例如冷异常性疾病和针刺性痛觉过敏，因为它们在标准形式的周围神经损伤之后的C57BL/6J小鼠中的发育是可变的。我们将在周围神经损伤之前产生慢性睡眠破坏（部分睡眠剥夺或睡眠碎片），然后我们将测量与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。为了确定睡眠破坏是否影响CNS突触可塑性，我们还将测量由辣椒蛋白注射辣椒素作为中央敏化模型引起的次要痛觉过敏，然后我们将量化表面肩horn中C-FOS和P-ERK阳性神经元的数量。在AIM 3中，我们将在神经损伤后立即在药理学上促进睡眠，并确定增强小鼠睡眠是否会降低慢性疼痛的风险。为了检查不同的神经化学系统的作用，我们将管理三类催眠药物，这些药物作用于不同的系统（苯二氮卓类药物，奥蛋白拮抗剂和γ羟基丁酸）。我们预计增加睡眠量并减少睡眠破碎化将减少慢性疼痛的风险。这些多学科实验具有很大的科学和临床意义，因为它们应该阐明质量差的睡眠如何促进从急性疼痛到适应不良，慢性疼痛以及改善睡眠的过渡可以减轻疼痛。