Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain
Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain
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DOI：
10.1002/syn.22188
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发表时间：
2020-09
期刊：
影响因子：
2.3
通讯作者：
Kazumi Yoshizawa;Kota Takeuchi;Toka Nakamura;Saki Ukai;Yukino Takahashi;Akira Sato;R. Takasawa;S. Tanuma
中科院分区：
文献类型：
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作者：
Kazumi Yoshizawa;Kota Takeuchi;Toka Nakamura;Saki Ukai;Yukino Takahashi;Akira Sato;R. Takasawa;S. Tanuma
已知细胞外高迁移性组框1 （HMGB1）通过模式识别受体介导炎症反应，包括晚期糖基化终产物受体（RAGE）或toll样受体（TLRs）。本研究的目的是研究一种新型RAGE抑制剂罂粟碱是否可以抑制注射完全弗氏佐剂（CFA）引起的几个时间点后的小鼠炎症性疼痛。我们还研究了慢性炎性疼痛状态下氧化还原调节的影响。虽然罂粟碱在第7天没有抑制CFA诱导的机械异位痛，但在第14天和第28天，罂粟碱显著抑制CFA诱导的机械异位痛。相比之下，自由基清除剂N -叔丁基- α -苯基硝基酮（PBN）在第7天和第14天抑制小鼠的机械异常性疼痛，但在第28天没有。我们证明RAGE抑制剂改善慢性炎症条件下的机械性异常性痛。此外，我们还发现，高水平的活性氧（ROS）有助于CFA诱导的机械异常性疼痛的早期阶段。准确地说，在慢性状态下，较低的ROS水平通过全巯基HMGB1/RAGE信号通路促进了炎症性疼痛反应。这些发现使我们提出ROS水平通过调节二硫HMGB1或全硫醇HMGB1的浓度来调节RAGE和/或TLR4介导的炎症性异常痛。
Extracellular high‐mobility group box 1 (HMGB1) is known to mediate the inflammatory response through pattern recognition receptors, including the receptor for advanced glycation end products (RAGE) or the toll‐like receptors (TLRs). The aim of the present study was to investigate whether papaverine, a novel RAGE inhibitor, could suppress inflammatory pain in mice after several time points, which was induced by the injection of complete Freund's adjuvant (CFA). We also investigated the influence of redox modulation during a state of chronic inflammatory pain. Although papaverine did not suppress CFA‐induced mechanical allodynia on Day 7, papaverine significantly suppressed CFA‐induced mechanical allodynia on Days 14 and 28. In contrast, the radical scavenger N‐tert‐Butyl‐α‐phenylnitrone (PBN) suppressed mechanical allodynia in mice on Days 7 and 14, but not on Day 28. We demonstrated that the RAGE inhibitor improves mechanical allodynia in chronic inflammatory conditions. Moreover, we also found that high levels of reactive oxygen species (ROS) contributed to the early phase of CFA‐induced mechanical allodynia. Precisely, lower ROS levels contributed to the inflammatory pain response via the all‐thiol HMGB1/RAGE signaling pathway during the chronic state. These findings led us to propose that ROS levels modulate RAGE and/or TLR4‐mediated inflammatory allodynia by regulating the concentrations of disulfide HMGB1 or all‐thiol HMGB1.