弱酸感受离子通道抑制剂（如苯并咪唑和 APETx2）在大鼠炎症痛模型中诱发部分且高度可变的抗痛觉过敏作用。
Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain.
机构信息
UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia.
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.
出版信息
Br J Pharmacol. 2018 Jun;175(12):2204-2218. doi: 10.1111/bph.14089. Epub 2018 Jan 3.
BACKGROUND AND PURPOSE
Acid-sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor, but its analgesic activity has not been assessed.
EXPERIMENTAL APPROACH
We determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage-clamp electrophysiology of Xenopus oocytes expressing ASICs 1-3. Its peripheral analgesic activity was then assessed relative to APETx2, an ASIC3 inhibitor, and morphine, in a Freund's complete adjuvant (FCA)-induced rat model of inflammatory pain.
KEY RESULTS
Diminazene inhibited homomeric rat ASICs with IC values of ~200-800 nM, via an open channel and subtype-dependent mechanism. In rats with FCA-induced inflammatory pain in one hindpaw, diminazene and APETx2 evoked more potent peripheral antihyperalgesia than morphine, but the effect was partial for APETx2. APETx2 potentiated rat ASIC1b at concentrations 30-fold to 100-fold higher than the concentration inhibiting ASIC3, which may have implications for its use in in vivo experiments.
CONCLUSIONS AND IMPLICATIONS
Diminazene and APETx2 are moderately potent ASIC inhibitors, both inducing peripheral antihyperalgesia in a rat model of chronic inflammatory pain. APETx2 has a more complex ASIC pharmacology, which must be considered when it is used as a supposedly selective ASIC3 inhibitor in vivo. Our use of outbred rats revealed responders and non-responders when ASIC inhibition was used to alleviate inflammatory pain, which is aligned with the concept of number-needed-to-treat in human clinical studies.
LINKED ARTICLES
This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
背景与目的
酸敏离子通道（ASICs）是哺乳动物中主要的酸感受器，ASIC1b 和 ASIC3 亚型参与外周伤害感受。抗寄生虫药物地美硝唑是一种中等效力的 ASIC 抑制剂，但尚未评估其镇痛活性。
实验方法
我们使用表达 ASICs 1-3 的非洲爪蟾卵母细胞电压钳电生理学来确定地美硝唑的 ASIC 亚型选择性及其抑制 ASIC 的机制。然后，相对于 APETx2（一种 ASIC3 抑制剂）和吗啡，在弗氏完全佐剂（FCA）诱导的大鼠炎症性疼痛模型中评估其外周镇痛活性。
主要结果
地美硝唑通过开放通道和亚型依赖性机制，以约 200-800 nM 的 IC 值抑制同源大鼠 ASICs。在一只后爪患有 FCA 诱导的炎症性疼痛的大鼠中，地美硝唑和 APETx2 引起的外周抗痛觉过敏作用比吗啡更强，但 APETx2 的作用是部分的。APETx2 在比抑制 ASIC3 浓度高 30 至 100 倍的浓度下增强大鼠 ASIC1b，这可能对其在体内实验中的应用有影响。
结论和意义
地美硝唑和 APETx2 是中等效力的 ASIC 抑制剂，均可在大鼠慢性炎症性疼痛模型中诱导外周抗痛觉过敏。APETx2 具有更复杂的 ASIC 药理学，当它作为体内所谓的选择性 ASIC3 抑制剂使用时，必须考虑到这一点。我们使用杂交大鼠发现，当使用 ASIC 抑制减轻炎症性疼痛时，存在有反应者和无反应者，这与人类临床研究中所需治疗人数的概念一致。
相关文章
本文是针对“靶向离子通道治疗慢性疼痛的最新进展”专题的一部分。要查看本专题中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.。
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