Indoxacarb is a newly developed insecticide with high insecticidal activity and low toxicity to non-target organisms. Its metabolite, DCJW, is known to block compound action potentials in insect nerves and to inhibit sodium currents in cultured insect neurons. However, little is known about the effects of these compounds on the sodium channels of mammalian neurons. We compared the effects of indoxacarb and DCJW on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons by using the whole-cell patch clamp technique. Indoxacarb and DCJW at 1-10 microM slowly and irreversibly blocked both TTX-S and TTX-R sodium channels in a voltage-dependent manner. The sodium channel activation kinetics were not significantly modified by 1 microM indoxacarb or 1 microM DCJW. The steady-state fast and slow inactivation curves were shifted in the hyperpolarization direction by 1 microM indoxacarb or 1 microM DCJW indicating a higher affinity of the inactivated sodium channels for these insecticides. These shifts resulted in an enhanced block at more depolarized potentials, thus explaining voltage-dependent block, and an apparent difference in the sensitivity of TTX-R and TTX-S channels to indoxacarb and DCJW near the resting potential. Indoxacarb and its metabolite DCJW cause toxicity through their action on the sodium channels.

中文翻译：

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恶二嗪类杀虫剂茚虫威及其代谢物DCJW对哺乳动物神经元钠通道的电压依赖性阻断。

茚虫威是一种新开发的杀虫剂，对非目标生物具有高杀虫活性和低毒性。已知其代谢产物DCJW可以阻止昆虫神经中的复合动作电位，并抑制培养的昆虫神经元中的钠电流。但是，关于这些化合物对哺乳动物神经元钠通道的作用了解甚少。我们通过使用全细胞膜片钳技术，比较了茚虫威和DCJW对大鼠背根神经节神经元中河豚毒素敏感（TTX-S）和河豚毒素抗性（TTX-R）钠通道的影响。1-10 microM的茚虫威和DCJW以电压依赖性方式缓慢且不可逆地阻断TTX-S和TTX-R钠通道。1 microM茚虫威或1 microM DCJW并未明显改变钠通道的活化动力学。稳态快慢灭活曲线在超极化方向上移动了1 microM茚虫威或1 microM DCJW，表明灭活的钠通道对这些杀虫剂的亲和力更高。这些移动导致在更多去极化电势下增强了传导阻滞，从而解释了电压依赖性传导阻滞，以及在静息电位附近，TTX-R和TTX-S通道对茚虫威和DCJW的敏感性存在明显差异。茚虫威及其代谢产物DCJW通过作用于钠通道而引起毒性。从而解释了电压依赖性传导阻滞，以及在静息电位附近，TTX-R和TTX-S通道对茚虫威和DCJW敏感性的明显差异。茚虫威及其代谢产物DCJW通过作用于钠通道而引起毒性。从而解释了电压依赖性传导阻滞，以及在静息电位附近，TTX-R和TTX-S通道对茚虫威和DCJW敏感性的明显差异。茚虫威及其代谢产物DCJW通过作用于钠通道而引起毒性。