Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangdong, China.
Nat Commun. 2019 Dec 12;10(1):5678. doi: 10.1038/s41467-019-13536-0.
As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8 cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8 neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8 cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8 sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8 cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.
作为一种保护机制，角膜对有害刺激很敏感。在这里，我们发现在小鼠中，相当一部分角膜 TRPM8 冷感觉纤维表达热敏 TRPV1 通道。尽管 TRPV1 对冷不敏感，但它增强了冷刺激时 TRPM8 神经元的膜电位变化和电发放。这种升高的神经元兴奋性导致小鼠眼部冷痛觉过敏增强。在干眼症模型中，TRPM8 冷感觉纤维中 TRPV1 的表达增加，导致严重的冷超敏反应。TRPM8 感觉神经元中 TRPV1 的过表达导致角膜和非角膜组织的冷超敏反应，而不影响其热敏感性。TRPV1 依赖性神经元致敏促进神经肽 P 物质从 TRPM8 冷感觉神经元释放，以响应冷刺激信号传递伤害性感受。我们的研究确定了角膜冷痛觉过敏的机制，并为眼部疼痛的治疗提供了一个潜在的靶点。
