音猬因子信号通路通过激活大鼠脑源性神经营养因子/酪氨酸激酶受体B通路促进开胸术后慢性疼痛
Sonic Hedgehog Signaling Contributes to Chronic Post-Thoracotomy Pain via Activating BDNF/TrkB Pathway in Rats.
作者信息
Yang Yitian, Wang Xiaoyan, Zhang Xuan, You Shaohua, Feng Long, Zhang Yunliang, Shi Yizheng, Xu Yuhai, Zhang Hong
机构信息
Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, People's Republic of China.
Department of Anesthesiology, The Fourth Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100037, People's Republic of China.
出版信息
J Pain Res. 2020 Jul 10;13:1737-1746. doi: 10.2147/JPR.S245515. eCollection 2020.
PURPOSE
Some patients undergoing thoracotomy may suffer from chronic post-thoracotomy pain (CPTP). Treatment of CPTP has been a clinical challenge and the underlying mechanisms of CPTP remain elusive. Recently, sonic hedgehog (Shh) signaling has been shown to be associated with various pain states but its role in the pathogenesis of CPTP is still unclear.
METHODS
CPTP was induced in rats by thoracotomy. Rats were divided into CPTP group and non-CPTP group based on the mechanical withdrawal threshold (MWT). Rats were administered with Shh signaling inhibitor cyclopamine and activator smoothened agonist (SAG), and then evaluated by MWT and cold allodynia testing. The expressions of Shh signaling (Shh ligand, patched and smoothened receptor, Gli transcription factors), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor B (Trk-B), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in rat T4-5 spinal cord dorsal horn (SDH) were detected by Western blotting and immunohistochemistry.
RESULTS
The expression of Shh signaling significantly increased and the BDNF/TrkB pathway was activated in T4-5 SDH of CPTP rats. Cyclopamine attenuated hyperalgesia and down-regulated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt in CPTP rats. SAG induced hyperalgesia in non-CPTP rats and elevated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt.
CONCLUSION
Shh signaling may contribute to CPTP via activating BDNF/TrkB signaling pathway, and inhibition of Shh signaling may effectively alleviate CPTP.
目的
一些接受开胸手术的患者可能会遭受慢性开胸术后疼痛（CPTP）。CPTP的治疗一直是一项临床挑战，其潜在机制仍不清楚。最近，音猬因子（Shh）信号通路已被证明与多种疼痛状态有关，但其在CPTP发病机制中的作用仍不明确。
方法
通过开胸手术在大鼠中诱导CPTP。根据机械撤针阈值（MWT）将大鼠分为CPTP组和非CPTP组。给大鼠施用Shh信号抑制剂环杷明和激活剂平滑激动剂（SAG），然后通过MWT和冷痛觉过敏测试进行评估。通过蛋白质印迹法和免疫组织化学检测大鼠T4-5脊髓背角（SDH）中Shh信号通路（Shh配体、patched和smoothened受体、Gli转录因子）、脑源性神经营养因子（BDNF）、原肌球蛋白相关激酶受体B（Trk-B）、磷脂酰肌醇3激酶（PI3K）和蛋白激酶B（Akt）的表达。
结果
CPTP大鼠的T4-5 SDH中Shh信号通路的表达显著增加，BDNF/TrkB通路被激活。环杷明减轻了CPTP大鼠的痛觉过敏，并下调了Gli1、BDNF、p-TrkB、p-PI3K和p-Akt的表达。SAG在非CPTP大鼠中诱导痛觉过敏，并提高了Gli1、BDNF、p-TrkB、p-PI3K和p-Akt的表达。
结论
Shh信号通路可能通过激活BDNF/TrkB信号通路导致CPTP，抑制Shh信号通路可能有效缓解CPTP。
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