Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund’s complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non–rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP + neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.

中文翻译：

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伤害感受器自发活动导致神经性疼痛小鼠模型中非快速动眼睡眠的碎片化

自发性疼痛是神经性疼痛患者的主要主诉，但由于在临床前模型或临床研究中都没有可靠的标志物，因此一直未能得到研究。在这里，我们对几种慢性疼痛小鼠模型的睡眠进行了全面的脑电图/肌电图分析：神经性疼痛（幸存神经损伤和慢性压迫性损伤）、炎症性疼痛（弗氏完全佐剂和角叉菜胶、足底切口）和化学性疼痛（辣椒素）。我们发现，周围轴突损伤通过增加非快速眼动睡眠（NREMS）的短暂唤醒而导致睡眠碎片化，而不会改变总睡眠量。与神经性疼痛相反，炎症性疼痛或化学性疼痛不会增加短暂的觉醒。镇痛药加巴喷丁和卡马西平可减少 NREMS 碎片，当短暂性神经病理性疼痛模型（坐骨神经挤压）中疼痛敏感性恢复正常时，NREMS 碎片就会消失。外周感觉神经元的基因沉默或 CGRP 消融+臂旁核中的神经元可以防止睡眠碎片化，而皮肤感觉纤维的药理学封锁则无效，这表明驱动唤醒的神经活动异位起源于初级伤害感受器神经元，并通过外侧臂旁核传递。这些发现将短暂唤醒引起的 NREMS 碎片确定为测量小鼠自发性神经病理性疼痛的有效指标。