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Original research
GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain
  1. Xiaoqing Fan1,2,3,
  2. Siyu Zhang1,2,
  3. Suling Sun1,2,
  4. Wenxu Bi1,2,
  5. Shuyang Li1,4,
  6. Wei Wang1,4,
  7. Xueran Chen1,2 and
  8. Zhiyou Fang1,2
  1. 1Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, Anhui, People's Republic of China
  2. 2Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, Anhui, People's Republic of China
  3. 3Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, Anhui, People's Republic of China
  4. 4School of Basic Medicine, Anhui Medical University, Hefei, Anhui, People's Republic of China
  1. Correspondence to Dr Xueran Chen, Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science Chinese Academy of Sciences, Hefei, Anhui, China; xueranchen{at}cmpt.ac.cn; Dr Zhiyou Fang, Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, People's Republic of China; z.fang{at}cmpt.ac.cn

Abstract

Background Cancer pain has a significant impact on patient’s quality of life. Astrocytes play an important role in cancer pain signaling. The direct targeting of astrocytes can effectively suppress cancer pain, however, they can cause many side effects. Therefore, there is an urgent need to identify the specific signaling pathways or proteins involved within astrocytes in cancer pain as targets for treating pain.

Methods A neuropathic cancer pain (NCP) model was established by inoculating mouse S-180 sarcoma cells around the right sciatic nerve in C57BL/6 mice. Spontaneous persistent pain and paw withdrawal thresholds were measured using von Frey filaments. The NCP spinal cord dorsal horn (L4–L6) and mouse astrocyte cell line MA-C were used to study protein palmitoylation using acyl-biotin exchange, real-time polymerase chain reaction, ELISA, western blotting, and immunofluorescent staining.

Results In a cancer pain model, along with tumor growth, peripheral nerve tissue invasion, and cancer pain onset, astrocytes in the dorsal horn of the spinal cord were activated and palmitoyltransferase ZDHHC23 expression was upregulated, leading to increased palmitoylation levels of GFAP and increased secretion of inflammatory factors, such as (C–X–C motif) ligand (CXCL)10 (CXCL-10), interleukin 6, and granulocyte-macrophage colony-stimulating factor. These factors in turn activate astrocytes by activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway. A competitive peptide targeting GFAP palmitoylations was designed to effectively alleviate morphine tolerance in cancer pain treatment as well as cancer pain signaling and inflammatory factor secretion.

Conclusions In a rodent model, targeting GFAP palmitoylation appears to be an effective strategy in relieving cancer pain and morphine tolerance. Human translational research is warranted.

  • analgesics, opioid
  • animal experimentation
  • pain management
  • cancer pain

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

https://doi.org/10.1136/rapm-2023-104980

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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    Footnotes

    • Contributors XQF, XRC, and ZYF conceived and designed the experiments; XQF, SYZ, SSL, WXB, SYL, and WW conducted the experiments; XQF, SYZ, SSL, and XRC analyzed the data; and XQF and SSL wrote the manuscript. All the authors have read and approved the final version of the manuscript. ZYF, and XRC acted as guarantors to accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding This research was supported by the National Natural Science Foundation of China (grant numbers 82172663, 82104208, 81872066, 81773131, and 81972635), the Innovative Program of the Development Foundation of the Hefei Center for Physical Science and Technology (grant number 2021HSC-CIP011), and CASHIPS Director's Fund (YZJJ2023QN50, and YZJJ2022QN49).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.