Polysulfide evokes acute pain through the activation of nociceptive TRPA1 in mouse sensory neurons.
Polysulfide evokes acute pain through the activation of nociceptive TRPA1 in mouse sensory neurons.
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多硫化物通过在小鼠感觉神经元中激活伤害性TRPA1引起急性疼痛。
DOI：
10.1186/s12990-015-0023-4
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发表时间：
2015-05-02
期刊：
影响因子：
3.3
通讯作者：
Ohta T
中科院分区：
文献类型：
--
作者：
Hatakeyama Y;Takahashi K;Tominaga M;Kimura H;Ohta T
硫化氢（H2S）被氧化成多硫化物。最近的报告表明，这种硫化合物调节各种生物功能。我们已经报道了H2S参与小鼠的炎性疼痛。另一方面，对多硫化物在感觉神经元中的功能作用知之甚少。在这里，我们表明，多硫化物选择性地刺激伤害性TRPA 1和诱发急性疼痛，使用TRPA 1基因缺陷小鼠（TRPA 1（-/-）），异源表达系统和TRPA 1表达细胞系。在野生型小鼠感觉神经元中，多硫化物以剂量依赖性方式升高细胞内Ca浓度（[Ca 2 +]i）。多硫化物的半数最大有效浓度（EC 50）小于H2S的十分之一。[Ca ~（2+）]i对多硫化物的反应在对TRPA 1激动剂有反应的神经元中观察到，并且被TRPA 1的阻断剂抑制，但不被TRPV 1的阻断剂抑制。多硫化物未能引起TRPA 1（−/−）小鼠神经元[Ca 2 +]i增加。在组成性表达大鼠TRPA 1的RIN-14 B细胞中，多硫化物诱发的[Ca 2 +]i以与感觉神经元相同的EC 50值增加。异源表达的小鼠TRPA 1被多硫化物激活，并被二硫苏糖醇抑制。TRPA 1突变体通道的分析表明，位于内部结构域的半胱氨酸残基与对多硫化物的敏感性有关。将多硫化物足底注射到小鼠后爪中引起的急性疼痛和水肿明显低于TRPA 1（−/−）小鼠。目前的数据表明，多硫化物功能的原伤害性物质通过激活TRPA 1的感觉神经元。由于多硫化物的效力高于亲本H2S，并且该硫化合物在病理生理条件下产生，因此建议多硫化物充当TRPA 1的内源性配体。因此，TRPA 1可能是一个有前途的治疗靶点内源性硫化合物相关的痛觉作用。
Hydrogen sulfide (H2S) is oxidized to polysulfide. Recent reports show that this sulfur compound modulates various biological functions. We have reported that H2S is involved in inflammatory pain in mice. On the other hand, little is known about the functional role of polysulfide in sensory neurons. Here we show that polysulfide selectively stimulates nociceptive TRPA1 and evokes acute pain, using TRPA1-gene deficient mice (TRPA1(−/−)), a heterologous expression system and a TRPA1-expressing cell line. In wild-type mouse sensory neurons, polysulfide elevated the intracellular Ca concentration ([Ca2+]i) in a dose-dependent manner. The half maximal effective concentration (EC50) of polysulfide was less than one-tenth that of H2S. The [Ca2+]i responses to polysulfide were observed in neurons responsive to TRPA1 agonist and were inhibited by blockers of TRPA1 but not of TRPV1. Polysulfide failed to evoke [Ca2+]i increases in neurons from TRPA1(−/−) mice. In RIN-14B cells, constitutively expressing rat TRPA1, polysulfide evoked [Ca2+]i increases with the same EC50 value as in sensory neurons. Heterologously expressed mouse TRPA1 was activated by polysulfide and that was suppressed by dithiothreitol. Analyses of the TRPA1 mutant channel revealed that cysteine residues located in the internal domain were related to the sensitivity to polysulfide. Intraplantar injection of polysulfide into the mouse hind paw induced acute pain and edema which were significantly less than in TRPA1(−/−) mice. The present data suggest that polysulfide functions as pronociceptive substance through the activation of TRPA1 in sensory neurons. Since the potency of polysulfide is higher than parental H2S and this sulfur compound is generated under pathophysiological conditions, it is suggested that polysulfide acts as endogenous ligand for TRPA1. Therefore, TRPA1 may be a promising therapeutic target for endogenous sulfur compound-related algesic action.
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