Sleep fragmentation by brief awakenings as a surrogate to measure neuropathic spontaneous pain

通过短暂觉醒来进行睡眠碎片化作为测量神经性自发性疼痛的替代方法

• 批准号: 10394220
• 负责人: Alban A Latremoliere
• 金额: $ 38.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394220
• 关键词: Acoustics; Affect; Afferent Neurons; Amyloid beta-Protein; Analgesics; Animals; Area; Axon; Behavior; C Fiber; Caliber; Carbamazepine; Cells; Cre driver; Data; Electroencephalography; Enterobacteria phage P1 Cre recombinase; Event; Fiber; Genetic; Glycine Receptors; Hypersensitivity; Injury; Label; Lateral; Lesion; Light; Link; Local Anesthetics; Measures; Modeling; Monitor; Mus; Nature; Nerve; Neurons; Neuropathy; Nociception; Outcome Measure; Pain; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral nerve injury; Pharmacology; Reporting; Rodent; Sedation procedure; Sensory; Signal Transduction; Site; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Spinal; Stimulus; Symptoms; TACR1 gene; Techniques; Testing; Tetanus Toxin; Thermal Hyperalgesias; Transgenic Mice; Trauma; Trigeminal nerve structure; awake; dorsal horn; efficacy testing; experimental study; gabapentin; genetic approach; injured; mechanical allodynia; mouse model; nerve injury; non rapid eye movement; novel; optogenetics; pain patient; pain sensitivity; painful neuropathy; poor sleep; pre-clinical research; relating to nervous system; response; sleep quality; spinal pathway; spontaneous pain

Project Summary/Abstract Most preclinical research on neuropathic pain has focused almost exclusively on mechanical allodynia and thermal hyperalgesia as endpoint readouts. While these are pertinent to assess stimulus-evoked hypersensitivity, they leave out the two top complaints reported by neuropathic pain patients: spontaneous pain and sleep disturbances. There is currently no technique to measure spontaneous pain reliably in rodents, limiting our study of the mechanisms responsible, and the nature of the sleep disturbances in neuropathic pain states are not known. We analyzed sleep and pain responses in two mouse models of peripheral neuropathic pain and found that while peripheral nerve trauma did not change total sleep amount, it caused a severe non-rapid eye movement sleep (NREMS) fragmentation in both models, which was only detected when mice also displayed signs of abnormal pain hypersensitivity and resolved when evoked pain sensitivity returned to pre-injury values. The temporal profile of the wake episodes that fragment sleep fits with the very brief sharp pain burst reported in patients with traumatic neuropathic pain (1), and also with the rare occurrence of spontaneous pain-like behavior observed in awake rodents after trigeminal nerve injury (2-4). In our pilot data, we used a combination of genetic and pharmacological approaches and found that the increase in sleep fragmentation after nerve injury originates from injured peripheral sensory neurons, does not appear to be caused by peripheral inputs and can be blocked by analgesics. In this project we hypothesize that sleep fragmentation caused by nerve injury is causally linked to the spontaneous activity in sensory fibers that activates pain pathways, and that therefore it could be used as a surrogate readout for quantifying neuropathic spontaneous pain. We propose 3 Specific Aims to test if sleep fragmentation after nerve injury is caused by ectopic activation of injured sensory neurons that activates ascending pain pathways, while it does not involve innocuous stimuli or require evoked noxious stimuli. Aim 1: Identify which peripheral sensory neurons drive NREMS fragmentation after nerve injury. Aim 2: Determine if the neural activity responsible for NREMS fragmentation is generated spontaneously at the injury site or requires external stimuli. Aim 3: Test if the spino-parabrachial pathway contributes to nerve injury-induced NREMS fragmentation Because we cannot measure spontaneous pain in live animals it has been impossible to perform mechanistic studies. Identifying a novel readout measure for neuropathic spontaneous pain would represent a fundamental breakthrough to study the underlying mechanisms and test the efficacy of potential novel analgesics.

项目摘要/摘要 关于神经性疼痛的大多数临床前研究几乎专注于机械性异常性疾病和 热过敏作为终点读数。虽然这些与评估刺激诱发有关 高敏性，他们忽略了神经性疼痛患者报告的两个主要投诉：自发疼痛 和睡眠障碍。目前尚无啮齿动物可靠地测量自发疼痛的技术， 限制我们对负责机制的研究以及神经性疼痛中睡眠障碍的性质 状态尚不清楚。 我们分析了两个小鼠神经性疼痛的小鼠模型中的睡眠和疼痛反应，发现 虽然周围神经创伤并没有改变总的睡眠量，但它引起了严重的非比重运动 两种模型中的睡眠（NREMS）碎片化，仅在小鼠也显示出迹象的迹象时才检测到 当诱发疼痛敏感性恢复到伤害前值时，异常的疼痛超敏反应并解决。这 唤醒发作的时间概况，碎片睡眠与报道的非常短的剧烈疼痛爆发适合 神经性疼痛（1）的患者，也很少发生自发性疼痛样 三叉神经损伤后在清醒啮齿动物中观察到的行为（2-4）。 在我们的飞行员数据中，我们使用了遗传和药理方法的组合，发现 神经损伤后的睡眠碎片增加起源于受伤的周围感觉神经元 似乎是由外围输入引起的，可以被镇痛药阻止。在这个项目中，我们假设 由神经损伤引起的睡眠碎片与感觉自发活动有因果关系 激活疼痛途径的纤维，因此可以用作替代读数 量化神经性自发疼痛。 我们提出了3个特定目的，以测试神经损伤后的睡眠破裂是由异位激活引起的 受伤的感觉神经元激活上升的疼痛途径，而它不涉及无害的刺激或 需要引起的有害刺激。 AIM 1：确定哪种周围感觉神经元在神经损伤后驱动NREMS分裂。 AIM 2：确定负责NREM碎片化的神经活动是否是自发产生的 伤害部位或需要外部刺激。 AIM 3：测试Spino-Parabrachial途径是否有助于神经损伤引起的NREMS分裂 因为我们无法测量活动物的自发疼痛，所以无法执行机械 研究。确定一种新颖的神经性自发疼痛的读数措施将代表一个基本 研究潜在的新型镇痛药的效力，以研究潜在的机制的突破。