Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats

Sep 21, 2026

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Cancer-induced bone pain (CIBP) is a prevalent and severe symptom in advanced tumors, yet its underlying mechanisms are not fully defined. The CXCL12/CXCR4 axis relates to glial activation, while MAPK signaling and c-Jun (AP-1) contribute to pain development. Using a tumor cell implantation model, CXCL12/CXCR4, p-MAPKs, and p-c-Jun were up-regulated in spinal cord. Immunofluorescence showed activated microglia expressing these signals. Intrathecal CXCR4 and JNK inhibitors reduced phosphorylation and alleviated pain, and esketamine produced similar analgesic effects by suppressing the JNK-c-Jun pathway.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

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Abstract

Key findings and pathway implications

Introduction

Clinical burden of cancer-induced bone pain

Roles of CXCL12/CXCR4 and MAPK-c-Jun signaling

Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats Molecular Pain Volume 20: 1–16 © The Author(s) 2024 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions) [DOI: 10.1177/17448069241239231](DOI: 10.1177/17448069241239231)[ ](DOI: 10.1177/17448069241239231)[journals.sagepub.com/home/mpx](journals.sagepub.com/home/mpx) Chenxia Duan 1,†, Yi Zhu 1,†, Zhuoliang Zhang2,†, Tiantian Wu3, Mengwei Shen 1, Jinfu Xu3, Wenxin Gao3, Jianhua Pan 1, Lei Wei 1 􀀁, Huibin Su1, and Chenghuan Shi 1 Abstract Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the speciﬁc CIBP mechanisms remain unknown. Esketamine is a nonselective N-methyl-D-aspartic acid receptor(NMDA)inhibitor commonly used asan analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunoﬂuorescence images showed activated microglia in the spinal cord on day 14 after TCIand co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection ofthe CXCR4inhibitor AMD3100reducedJNKandc-Jun phosphorylations, and intrathecal injection oftheJNK inhibitorSP600125andesketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway. Keywords cancer-induced bone pain, X-C motif chemokine ligand 12, X-C motif chemokine receptor 4, c-Jun N-terminal kinase, c-Jun, esketamine Date Received: 8 November 2023; Revised 4 February 2024; accepted: 25 February 2024 1 Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Afﬁliated Suzhou Hospital of Nanjing Medical University, Suzhou, China 2Department of Anesthesiology, Suzhou Municipal Hospital, Xuzhou Medical University, Suzhou, China 3Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China †These authors contributed equally to this work. Corresponding Authors: Lei Wei, Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Afﬁliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Street, Suzhou 215002, China. [Email:](Email: w123-78-77@126.com)[ w123-78-77@126.com](Email: w123-78-77@126.com) Huibin Su, Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Afﬁliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Street, Suzhou 215002, China. Email: [2337125467@qq.com](2337125467@qq.com) Chenghuan Shi, Department of Anesthesiology, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, The Afﬁliated Suzhou Hospital of Nanjing Medical University, 26 Daoqian Street, Suzhou 215002, China. Email: [675874051@qq.com](675874051@qq.com) Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permits non-c

FAQs

What is the main research focus of the study?

The study investigates how esketamine relieves cancer-induced bone pain by examining signaling in the spinal dorsal horn, specifically the CXCL12/CXCR4 axis and the JNK-c-Jun pathway.

Which experimental model was used to study bone cancer pain?

A tumor cell implantation (TCI) model was used to induce cancer-related bone pain and assess molecular changes in the spinal cord.

How does esketamine affect the relevant molecular pathway?

Esketamine alleviated TCI-induced pain and reduced phosphorylation of JNK and c-Jun in microglia, indicating inhibition of the JNK-c-Jun pathway.

Sep 21, 2026

Uploaded by Finn