Activation of Tetrodotoxin-Resistant Sodium Channel NaV1.9 in Rat Primary Sensory Neurons Contributes to Melittin-Induced Pain Behavior
Activation of Tetrodotoxin-Resistant Sodium Channel NaV1.9 in Rat Primary Sensory Neurons Contributes to Melittin-Induced Pain Behavior
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DOI：
10.1007/s12017-012-8211-0
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发表时间：
2013-03
影响因子：
3.5
通讯作者：
Yao-Qing Yu;Zhen-Yu Zhao;Xue-Feng Chen;Fang-Mei Xie;Yan Yang;Jun Chen
中科院分区：
文献类型：
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作者：
Yao-Qing Yu;Zhen-Yu Zhao;Xue-Feng Chen;Fang-Mei Xie;Yan Yang;Jun Chen
背根神经节（dorsal root ganglion，DRG）神经元河豚毒素抗性（Tetrodotoxin resistant，TTX-R）钠通道NaV1.8和NaV1.9在病理性疼痛中起重要作用。我们最近报道，蜂毒肽，整个蜂毒的主要毒素，诱导动作电位放电的DRG神经元，即使在高浓度（500 nM）的TTX的存在下，表明TTX-R钠通道的贡献。这一假设是充分调查在本研究中。皮下注射蜂毒肽后，NaV1.8和NaV1.9显著上调mRNA和蛋白表达，相关钠电流也增加。双重免疫组化结果显示，NaV1.8阳性神经元主要为中型和小型神经元，而NaV1.9阳性神经元仅为小型神经元。用NaV1.8和NaV1.9为靶点的反义寡核苷酸（AS ODNs）评价TTX-R钠通道表达增加的功能意义。行为测试表明，靶向NaV1.9而非NaV1.8的AS ODN逆转蜂毒肽诱导的热超敏反应。NaV1.8AS ODN和NaV1.9AS ODN均不影响蜂毒肽诱导的机械超敏反应。这些结果提供了先前未知的证据，即在小尺寸DRG神经元中NaV1.9而不是NaV1.8的上调有助于蜂毒肽诱导的热超敏性。蜂毒肽诱导的生物学效应为研究TTX-R钠通道特性提供了一种新的思路。
Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in dorsal root ganglion (DRG) neurons play important roles in pathological pain. We recently reported that melittin, the major toxin of whole bee venom, induced action potential firings in DRG neurons even in the presence of a high concentration (500 nM) of TTX, indicating the contribution of TTX-R sodium channels. This hypothesis is fully investigated in the present study. After subcutaneous injection of melittin, NaV1.8 and NaV1.9 significantly upregulate mRNA and protein expressions, and related sodium currents also increase. Double immunohistochemical results show that NaV1.8-positive neurons are mainly medium- and small-sized, whereas NaV1.9-positive ones are only small-sized. Antisense oligodeoxynucleotides (AS ODNs) targeting NaV1.8 and NaV1.9 are used to evaluate functional significance of the increased expressions of TTX-R sodium channels. Behavioral tests demonstrate that AS ODN targeting NaV1.9, but not NaV1.8, reverses melittin-induced heat hypersensitivity. Neither NaV1.8 AS ODN nor NaV1.9 AS ODN affects melittin-induced mechanical hypersensitivity. These results provide previously unknown evidence that upregulation of NaV1.9, but not NaV1.8, in small-sized DRG neurons contributes to melittin-induced heat hypersensitivity. Furthermore, melittin-induced biological effect indicates a potential strategy to study properties of TTX-R sodium channels.