Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
Brain. 2021 Jul 28;144(6):1711-1726. doi: 10.1093/brain/awab086.
Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Nav1.8 and CGRPα. Ablating neurons expressing Nav1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of Kv1 voltage-gated potassium channels. Thus, silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.
患有神经病理性疼痛的患者经常会感到无害的冷却也会引起剧痛。这种冷感觉过敏的细胞和分子基础知之甚少。我们使用感觉神经节的体内钙成像来研究三种神经病理性疼痛模型（奥沙利铂诱导的神经病、部分坐骨神经结扎和雪卡毒素中毒）中外周冷感觉神经元的活性如何发生改变。在对照小鼠中，冷感觉神经元数量少且体积小。在有冷感觉过敏的神经病理性动物中，一组通常沉默的大直径神经元对冷却变得敏感。这些沉默的冷感觉神经元中的许多对有害的机械刺激有反应，并表达伤害感受器标记物 Nav1.8 和 CGRPα。Nav1.8 表达神经元的消融导致冷感觉过敏减轻。在对照小鼠中，通过阻断 Kv1 电压门控钾通道，也可以激活沉默的冷感觉神经元。因此，在各种神经病理性疼痛状态下，沉默的冷感觉神经元被揭示出来，冷感觉过敏是由伤害感受器兴奋性改变引起的外周致敏引起的。
