Wnt5a mediates chronic post-thoracotomy pain by regulating non-canonical pathways, nerve regeneration, and inflammation in rats
Wnt5a mediates chronic post-thoracotomy pain by regulating non-canonical pathways, nerve regeneration, and inflammation in rats
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Wnt5a 通过调节大鼠的非经典途径、神经再生和炎症来介导慢性开胸术后疼痛
DOI：
10.1016/j.cellsig.2018.01.017
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发表时间：
2018
影响因子：
4.8
通讯作者：
Huang Yuguang
中科院分区：
文献类型：
--
作者：
Zhu Afang;Shen Le;Xu Li;Chen Weiyun;Huang Yuguang
Wnts作为神经发生的重要配体，在疼痛的发病机制中具有重要的作用。我们先前的初步研究表明，鞘内抑制Wnt 5a而不是Wnt，减轻大鼠的慢性开胸术后疼痛（CPTP）。本研究旨在进一步探讨Wnt 5a在CPTP形成中的调控机制。从术后第7天（POD）至POD 21天，在胸背根神经节中发现Wnt 5a、跨膜受体Ror 2和活化的非经典Wnt通路成员的蛋白水平增加。然而，典型的Wnt通路成员的水平显示没有变化的逆转录酶-PCR。此外，从POD 7至POD 21检测到神经再生升高、活化的促炎因子和神经胶质细胞。此外，鞘内Wnt 5a阻断在早期阶段（POD 0至POD 9）显着增加痛阈值，并在后期阶段（POD 14至POD 16）的干预减轻疼痛，但镇痛反应不如在早期阶段有效。此外，早期而非晚期Wnt 5a阻断显著逆转了CPTP诱导的非经典Wnt通路激活、神经再生和炎症。相比之下，Wnt 5a激动剂降低了幼稚和无痛大鼠的痛阈。这些结果表明，Wnt 5a通过激活非经典Wnt通路、神经再生和炎症来促进CPTP的发展。以Wnt 5a为靶点的治疗性干预可能是预防和治疗CPTP的有效策略。
As well-characterized ligands involved in neurogenesis, Wnts are emerging as promising targets in pain pathogenesis. Our previous pilot study showed that intrathecal inhibition of Wnt5a, but not Wnts, relieves chronic post-thoracotomy pain (CPTP) in rats. In the present study, we aimed to further explore the regulatory mechanism of Wnt5a in CPTP development. Increased protein levels of Wnt5a, transmembrane receptor Ror2, and activated non-canonical Wnt pathway members were found in the thoracic dorsal root ganglions from postoperative day (POD) 7 to POD 21. However, the levels of canonical Wnt pathway members showed no change by reverse transcriptase-PCR. In addition, elevated nerve regeneration, activated pro-inflammatory factors, and glial cells were detected from POD 7 to POD 21. Furthermore, intrathecal Wnt5a blockade during the early phase (POD 0 to POD 9) significantly increased the pain threshold, and intervention in the late phase (POD 14 to POD 16) alleviated pain; however, the analgesic response was not as effective as that in the early phase. Additionally, early but not late Wnt5a blockade significantly reversed CPTP-induced activation of the non-canonical Wnt pathways, nerve regeneration, and inflammation. In contrast, a Wnt5a agonist decreased the pain threshold in both naïve and painless rats. These results suggest that Wnt5a promotes the development of CPTP by activating non-canonical Wnt pathways, nerve regeneration, and inflammation. Therapeutic intervention by targeting Wnt5a may represent an effective strategy for preventing and treating CPTP.