Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
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DOI：
10.1371/journal.pone.0217209
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发表时间：
2019-05-24
期刊：
影响因子：
3.7
通讯作者：
Miyawaki, Takuya
中科院分区：
文献类型：
--
作者：
Miyake, Saki;Higuchi, Hitoshi;Miyawaki, Takuya
背景近年来，超极化激活的环核苷酸门控（HCN）通道在神经性疼痛和炎症性疼痛的机制中的作用以及作为治疗靶点的作用受到了广泛关注。伊伐布雷定是一种HCN通道阻滞剂，在动物模型中被证明对神经性疼痛有影响。因此，在本研究中，我们评估了伊伐布雷定对炎症性疼痛的影响，并假设伊伐布雷定可以直接影响炎症反应，我们研究了其在体内和体外study.MethodsAfter批准，从我们的机构，我们研究了8周的雄性Sprague-Dawley大鼠。通过将角叉菜胶皮下注射到大鼠后爪中来诱导外周炎症。通过用von Frey细丝对注射部位施加机械刺激来评价缩爪阈值（疼痛阈值）。伊伐布雷定与角叉菜胶联合皮下注射，评价其对痛阈的影响。此外，我们评价了伊伐布雷定对大鼠注射区域白细胞蓄积和TNF-α表达的影响。此外，我们研究了伊伐布雷定对LPS刺激的TNF-α在孵育的小鼠巨噬细胞样cells.ResultsThe除了伊伐布雷定角叉菜胶增加痛阈降低角叉菜胶注射的影响。HCN通道激活剂拉莫三嗪和毛喉素均显著逆转伊伐布雷定对痛阈的抑制作用。伊伐布雷定抑制注射区域中角叉菜胶诱导的白细胞蓄积和TNF-α表达。此外，伊伐布雷定显着抑制LPS刺激的TNF α的产生在孵育cells.ConclusionThe结果本研究表明，局部注射伊伐布雷定是有效的对角叉菜胶诱导的炎症性疼痛通过HCN通道。其作用被认为不仅涉及对周围神经的作用，而且还涉及抗炎作用。
BackgroundRecently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide- gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies.MethodsAfter approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells.ResultsThe addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNFalpha in the incubated cells.ConclusionThe results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.