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

项目总结/摘要 大多数关于神经性疼痛的临床前研究几乎完全集中在机械性异常性疼痛上， 热痛觉过敏作为终点读数。虽然这些与评估刺激诱发的 他们忽略了神经性疼痛患者报告的两大主诉：自发性疼痛 和睡眠障碍目前还没有可靠地测量啮齿动物自发性疼痛的技术， 这限制了我们对神经性疼痛中睡眠障碍的机制和性质的研究 国家不知道。 我们分析了两种周围神经性疼痛小鼠模型的睡眠和疼痛反应，发现 而周围神经损伤并不改变总睡眠量，它引起了严重的非快速眼动 睡眠（NREMS）片段，这仅在小鼠也显示出 异常的疼痛敏感性，并在诱发的疼痛敏感性恢复到损伤前值时消退。的 碎片睡眠的觉醒事件的时间轮廓与在中报道的非常短暂的剧痛爆发相吻合。 创伤性神经病理性疼痛患者（1例），同时伴有罕见的自发性疼痛样 在清醒的啮齿动物中观察到三叉神经损伤后的行为（2 - 4）。 在我们的试验数据中，我们使用了遗传和药理学方法的组合，发现 神经损伤后睡眠碎片的增加源于受损的外周感觉神经元， 似乎是由外围输入引起的，可以被止痛药阻断。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神经元的自发活动有因果关系。 激活疼痛通路的纤维，因此它可以用作 定量神经性自发性疼痛。 我们提出了3个具体的目的来测试神经损伤后的睡眠片段化是否是由异位激活引起的。 受伤的感觉神经元激活上行疼痛通路，而它不涉及无害的刺激， 需要诱发有害刺激。 目的1：确定神经损伤后哪些外周感觉神经元驱动NREMS碎裂。 目的2：确定负责NREMS碎片化的神经活动是否自发产生， 或需要外部刺激。 目的3：测试脊髓-臂旁通路是否有助于神经损伤诱导的NREMS碎裂 因为我们无法测量活体动物的自发性疼痛， 问题研究识别神经性自发性疼痛的新读出测量将代表一个基本的 研究潜在的机制和测试潜在的新型镇痛药的功效的突破。

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.