Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Division of Laboratory Animal Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Nat Commun. 2017 Jul 5;8:16079. doi: 10.1038/ncomms16079.
miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia.
miR-17-92 是一个由六个不同成员组成的 microRNA 簇。在这里，我们表明 miR-17-92 簇及其各个成员调节慢性神经性疼痛。在神经损伤后，所有簇成员在初级感觉神经元中持续上调。miR-18a、miR-19a、miR-19b 和 miR-92a 簇成员的过表达会在大鼠中引起机械性痛觉过敏，而它们的阻断会减轻神经性疼痛大鼠模型中的机械性痛觉过敏。miR-17-92 簇的可能靶基因包括编码众多电压门控钾通道及其调节亚基的基因。单细胞分析显示，初级感觉神经元中广泛表达 miR-17-92 簇及其预测靶基因。miR-17-92 下调钾通道的表达，特别是 A 型电流的外向钾电流。钾通道调节剂的联合应用协同缓解神经损伤或 miR-17-92 过表达引起的机械性痛觉过敏。miR-17-92 簇似乎协同调节多种电压门控钾通道亚基的功能，持续引起机械性痛觉过敏。
