Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model
Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model
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DOI：
10.1177/0022034518762381
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发表时间：
2018-07-01
影响因子：
7.6
通讯作者：
Inenaga, K.
中科院分区：
文献类型：
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作者：
Nodai, T.;Hitomi, S.;Inenaga, K.
口腔溃疡是最常见的口腔疾病，会导致进餐和说话时疼痛，降低患者的生活质量。最近使用动物模型的证据表明，口腔溃疡会诱发环氧合酶依赖性自发性疼痛和环氧合酶非依赖性机械性异常性疼痛。内皮素-1 在口腔粘膜炎症中表达上调，但尚未证明它会引起口腔溃疡疼痛。在本研究中，我们使用我们专有的检测系统在清醒的大鼠中研究了内皮素-1 信号传导与口腔溃疡引起的疼痛的关系。在局部醋酸治疗实验诱发的口腔溃疡中，内皮素-1 显着上调，而抗菌预处理则抑制了内皮素-1 的产生。通过拭子涂抹 BQ-788（ETB 受体拮抗剂）、ONO-8711（前列腺素受体 EP1 拮抗剂）和 HC-030031（TRPA1 拮抗剂）可抑制口腔溃疡模型大鼠的自发伤害行为。 BQ-788 抑制溃疡中前列腺素 E-2 的产生。模型中的机械异常性疼痛不仅可以被 BQ-788 和 HC-030031 抑制，还可以被 BQ-123（ETA 受体拮抗剂）、SB-366791（TRPV1 拮抗剂）和 RN-1734（TRPV4 拮抗剂）抑制。在幼稚大鼠中，粘膜下注射内皮素-1 引起机械异常性疼痛，该异常性疼痛对 HC-030031 和 SB-366791 敏感，但对 RN-1734 不敏感。这些结果表明，口腔细菌通过溃疡区域侵入后内皮素-1 的产生引发了 TRPA1 介导的自发性疼痛。这种疼痛可能是通过涉及 ETB 受体加速前列腺素生成的间接途径发生的。 Endothelin-1 通过伤害性纤维上的 ETA 和 ETB 受体直接引发 TRPA1 和 TRPV1 介导的机械异常性疼痛。 TRPV4 介导的异常性疼痛成分似乎与内皮素信号传导无关。这些发现强调了内皮素信号传导阻滞剂作为口腔溃疡患者有效镇痛方法的潜力。
Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ETB receptor antagonist), ONO-8711 (prostanoid receptor EP1 antagonist), and HC-030031 (TRPA1 antagonist). Prostaglandin E-2 production in the ulcers was suppressed by BQ-788. Mechanical allodynia in the model was inhibited not only by BQ-788 and HC-030031 but also by BQ-123 (ETA receptor antagonist), SB-366791 (TRPV1 antagonist), and RN-1734 (TRPV4 antagonist). In naive rats, submucosal injection of endothelin-1 caused mechanical allodynia that was sensitive to HC-030031 and SB-366791 but not to RN-1734. These results suggest that endothelin-1 production following oral bacterial invasion via ulcerative regions elicits TRPA1-mediated spontaneous pain. This pain likely occurs through an indirect route that involves ETB receptor-accelerated prostanoid production. Endothelin-1 elicits directly TRPA1- and TRPV1-mediated mechanical allodynia via both ETA and ETB receptors on nociceptive fibers. The TRPV4-mediated allodynia component seems to be independent of endothelin signaling. These findings highlight the potential of endothelin signaling blockers as effective analgesic approaches for oral ulcer patients.