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Sonic Hedgehog Signaling Contributes to Chronic Post-Thoracotomy Pain via Activating BDNF/TrkB Pathway in Rats

Authors Yang Y, Wang X, Zhang X, You S, Feng L, Zhang Y, Shi Y, Xu Y, Zhang H

Received 10 January 2020

Accepted for publication 16 June 2020

Published 10 July 2020 Volume 2020:13 Pages 1737—1746

DOI https://doi.org/10.2147/JPR.S245515

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Dr E Alfonso Romero-Sandoval


Yitian Yang,1,* Xiaoyan Wang,2,* Xuan Zhang,3 Shaohua You,1 Long Feng,1 Yunliang Zhang,1 Yizheng Shi,1 Yuhai Xu,4 Hong Zhang1

1Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, People’s Republic of China; 2Department of Anesthesiology, The Fourth Medical Center of Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100037, People’s Republic of China; 3Department of Anesthesiology, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300060, People’s Republic of China; 4Department of Anesthesiology, Air Force Medical Center, Beijing 100142, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hong Zhang; Yitian Yang Email mazuimao301@163.com; yangyitiansdu@126.com

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.

Keywords: sonic hedgehog, chronic post-thoracotomy pain, brain-derived neurotrophic factor, spinal cord dorsal horn, PI3K, Akt

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