GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain

Xiaoqing Fan; Siyu Zhang; Suling Sun; Wenxu Bi; Shuyang Li; Wei Wang; Xueran Chen; Zhiyou Fang

doi:10.1136/rapm-2023-104980

GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain

Reg Anesth Pain Med. 2023 Nov 28:rapm-2023-104980. doi: 10.1136/rapm-2023-104980. Online ahead of print.

Authors

Xiaoqing Fan^{1

2

3}, Siyu Zhang^{1

2}, Suling Sun^{1

2}, Wenxu Bi^{1

2}, Shuyang Li^{1

4}, Wei Wang^{1

4}, Xueran Chen^{5

2}, Zhiyou Fang^{5

2}

Affiliations

¹ Hefei 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 Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
³ Department 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 School of Basic Medicine, Anhui Medical University, Hefei, Anhui, People's Republic of China.
⁵ Hefei 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 xueranchen@cmpt.ac.cn z.fang@cmpt.ac.cn.

PMID: 38050183
DOI: 10.1136/rapm-2023-104980

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.

Keywords: analgesics, opioid; animal experimentation; cancer pain; pain management.