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/jci15709
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发表时间：
2002-10
期刊：
影响因子：
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通讯作者：
S. Ugawa;T. Ueda;Y. Ishida;Makoto Nishigaki;Y. Shibata;S. Shimada
中科院分区：
文献类型：
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作者：
S. Ugawa;T. Ueda;Y. Ishida;Makoto Nishigaki;Y. Shibata;S. Shimada
许多疼痛的炎症和缺血性疾病，如类风湿关节炎、心脏缺血和骨骼肌衰竭，都伴有局部组织酸中毒。在这种酸中毒状态下，细胞外质子通过打开伤害感受器中的阳离子通道而引起疼痛。一般认为，香草受体亚型-1 （VR1）和酸感离子通道（ASIC）介导了哺乳动物酸致伤害感觉的大部分。在这里，我们提供了证据，证明这两个通道都参与了人类酸诱发的疼痛，并展示了它们对伤害感觉的相对贡献。在我们的心理物理实验中，将酸性溶液（pH b>或= 6.0）直接输注到人体皮肤中引起局部疼痛，这种疼痛被asic抑制剂阿米洛利（amiloride）阻断，而被VR1抑制剂capsazepine阻断。在更严重的酸化（pH 5.0）下，阿米洛利对减轻酸引起的疼痛的效果较差。此外，在这些条件下，辣椒平具有部分阻断作用。阿米洛利本身既不能阻断辣椒素引起的人类皮肤局部疼痛，也不能抑制表达vr1的爪蟾卵母细胞中质子诱导的电流。我们的研究结果表明，asic是人类痛觉感受器中主要的酸传感器，VR1主要在极酸条件下参与痛觉。
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 > or = 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.