Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors
Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors
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DOI：
10.1172/jci200215709
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发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Shimada, S
中科院分区：
文献类型：
--
作者：
Ugawa, S;Ueda, T;Shimada, S
许多疼痛的炎症和缺血情况，如类风湿性关节炎、心肌缺血和骨骼肌疲惫，都伴随着局部组织酸中毒。在这种酸性状态下，细胞外质子通过打开伤害性感受器上的阳离子通道来刺激疼痛。一般认为，在哺乳动物中，香草素受体亚型1(VR1)和酸敏感离子通道(ASIC)介导了酸诱导的大部分伤害性感受。在这里，我们提供了这两种通道参与人类酸诱发疼痛的证据，并显示了它们对伤害性感受的相对贡献。在我们的心理物理实验中，将酸性溶液(pH大于或等于6.0)直接注入人体皮肤会引起局部疼痛，这种疼痛可以被ASICs的抑制剂阿米洛利阻断，但不能被VR1的抑制剂卡萨西平所阻断。在较严重的酸化条件下(pH 5.0)，阿米洛利的止痛效果较差。此外，卡萨西平在此条件下具有部分阻断作用。阿米洛利本身既不能阻断辣椒素在人皮肤上引起的局部疼痛，也不能抑制表达VR1的非洲爪哇卵母细胞中质子诱导的电流。我们的结果表明，ASICs是人类伤害性感受器的主要酸感受器，VR1主要在极端酸性条件下参与伤害性感受。
Many painful inflammatory and ischemic conditions such as rheumatoid arthritis, cardiac ischemia, and exhausted skeletal muscles are accompanied by local tissue acidosis. In such acidotic states, extracellular protons provoke the pain by opening cation channels in nociceptors. It is generally believed that a vanilloid receptor subtype-1 (VR1) and an acid-sensing ion channel (ASIC) mediate the greater part of acid-induced nociception in mammals. Here we provide evidence for the involvement of both channels in acid-evoked pain in humans and show their relative contributions to the nociception. In our psychophysical experiments, direct infusion of acidic solutions (pH greater than or equal to 6.0) into human skin caused localized pain, which was blocked by amiloride, an inhibitor of ASICs, but not by capsazepine, an inhibitor of VR1. Under more severe acidification (pH 5.0) amiloride was less effective in reducing acid-evoked pain. In addition, capsazepine had a partial blocking effect under these conditions. Amiloride itself neither blocked capsaicin-evoked localized pain in human skin nor inhibited proton-induced currents in VR1-expressing Xenopus oocytes. Our results suggest that ASICs are leading acid sensors in human nociceptors and that VR1 participates in the nociception mainly under extremely acidic conditions.