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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A-803467, a potent and selective Na_v1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat
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A-803467, a potent and selective Na_v1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

机译：A-803467，一种有效的选择性Na_v1.8钠通道阻滞剂，可减轻大鼠的神经性和炎性疼痛

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摘要

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonu-cleotide studies directed against Na_v1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC_(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na_v1.8 (IC_(50) = 8 nM) and was > 100-fold selective vs. human Na_v1.2, Na_v1.3, Na_v1.5, and Na_v1.7 (IC_(50) values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED_(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED_(50) = 85 mg/kg, i.p.), capsa-icin-induced secondary mechanical allodynia (ED_(50) ≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED_(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na_v1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
机译：抗河豚毒素的钠通道的激活有助于神经元中动作电位的电生成。针对Na_v1.8的反义寡核苷酸研究表明，该通道有助于实验性炎性和神经性疼痛。我们在这里报告A-803467的发现，这是一种钠通道阻滞剂，可有效阻断河豚毒素抗性电流（IC_（50）= 140 nM）并在大鼠背根神经节神经元体外产生自发和电诱发的动作电位。在重组细胞系中，A-803467有效地阻断了人类Na_v1.8（IC_（50）= 8 nM），并且相对于人类Na_v1.2，Na_v1.3，Na_v1.5和Na_v1.7具有选择性> 100倍的选择性（ IC_（50）值≥1μM）。 A-803467（20 mg / kg，i.v.）阻断了大鼠脊髓背角机械诱发广泛动态范围神经元的放电。在各种大鼠疼痛模型中，A-803467还可以剂量依赖性地减少机械性异常性疼痛，包括：脊髓神经结扎（ED_（50）= 47 mg / kg，腹膜内），坐骨神经损伤（ED_（50）= 85 mg / kg， ip），辣椒素诱导的继发性机械性异常性疼痛（ED_（50）≈100 mg / kg，ip）和足底内完全弗氏佐剂注射后的热痛觉过敏（ED_（50）= 41 mg / kg，ip）。 A-803467对福尔马林引起的伤害感受以及急性热痛和术后疼痛无活性。这些数据表明，在神经性和炎性疼痛的动物模型中，体内Na_v1.8钠通道的急性和选择性药理阻断作用产生了显着的抗伤害感受。

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