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Esketamine attenuates bone cancer pain by suppressing MAPK signaling and glial activation in the spinal dorsal horn of rats
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  • Published: 02 February 2026

Esketamine attenuates bone cancer pain by suppressing MAPK signaling and glial activation in the spinal dorsal horn of rats

  • Liang Cheng1,
  • Dongjie Wang2,
  • Zhiqiang Zhang1,
  • Yu Zhang1,
  • Yunyun Tang1,
  • Kuibin Bao1,
  • Bin Guo1,
  • Kaijing Zhang1,
  • Yu Chen1,
  • Hui Ren1,
  • Chengfei Xu2,3 &
  • …
  • Huadong Ni2 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Drug discovery
  • Neurology
  • Neuroscience

Abstract

Bone cancer pain (BCP) is a debilitating condition driven by spinal neuroinflammation and glial activation. Esketamine (ESK), an NMDA receptor antagonist, exhibits analgesic effects beyond receptor blockade, but its mechanisms in BCP remain unclear. Here, a rat BCP model was established by intramedullary injection of Walker 256 cells, followed by intrathecal ESK administration (20, 40, 60 µg). Pain behavior was assessed using Von Frey, Hargreaves, CatWalk, and open field tests. While histology confirmed tumor-induced osteolysis, ESK did not prevent bone destruction. Instead, ESK significantly reduced mechanical and thermal hypersensitivity, improved gait and anxiety-like behaviors, and suppressed microglial and astrocytic activation in the spinal dorsal horn. This was accompanied by reduced pro-inflammatory cytokine levels and inhibition of MAPK pathway activation. Pharmacological blockade of glia (fluorocitrate, minocycline) or MAPK signaling (SB203580, SP600125) reproduced these effects, confirming the contribution of glia-MAPK interactions. These findings indicate that ESK alleviates BCP by suppressing glial-driven neuroinflammation and MAPK signaling, highlighting its potential as a multimodal analgesic.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.

Funding

This work was supported by the Key Speciality of Anhui Province (2022-AH-105), Scientific research project of Anhui Provincial Health Commission (AHWJ2023A30069), Bengbu Science and Technology Bureau project (20220115), Natural Science Key Program of Bengbu Medical University (2023byzd113, 2024byzd475), Research Project on the Inheritance and Innovation of Traditional Chinese Medicine of Anhui Province (2024CCCX272), Research Project of Anhui Natural Science for Colleges and Universities (2024AH051215), National Science Foundation for Young Scientists of China (82171216, 81901124), the National Clinical Key Specialty Construction Project-Oncology department (2023-GJZK-001), the Clinical Key Specialty of Zhejiang Province Anesthesiology (2023ZJZK001), the Key Supported Discipline of Jiaxing Medical Science-Anesthesiology (2023-ZC-001), the Zhejiang Province Compact yet High-performing Clinical Innovation Team (CXTD202502014), and the Mindray Joint Fund of Zhejiang Provincial Natural Science Foundation of China under Grant No.LMRZ26H090001.

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Authors and Affiliations

  1. Department of Anesthesiology, The Third People’s Hospital of Bengbu, 38 Shengli Middle Road, Bengbu, 233000, China

    Liang Cheng, Zhiqiang Zhang, Yu Zhang, Yunyun Tang, Kuibin Bao, Bin Guo, Kaijing Zhang, Yu Chen & Hui Ren

  2. Department of Anesthesiology and Pain Research Center, The Affiliated Hospital of Jiaxing University, 1882 Zhonghuan South Road, Jiaxing, 314001, China

    Dongjie Wang, Chengfei Xu & Huadong Ni

  3. Department of Anesthesiology, Bengbu Third People’s Hospital Affiliated to Bengbu Medical University, Bengbu, 233000, China

    Chengfei Xu

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Contributions

LC and CX designed the study. DW, ZZ, YZ, YT, KB, BG, KZ, YC, and HR performed the experiments. CX and HN analyzed the data. LC and DW drafted and revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Chengfei Xu or Huadong Ni.

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Cheng, L., Wang, D., Zhang, Z. et al. Esketamine attenuates bone cancer pain by suppressing MAPK signaling and glial activation in the spinal dorsal horn of rats. Sci Rep (2026). https://doi.org/10.1038/s41598-026-38137-y

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  • Received: 02 September 2025

  • Accepted: 29 January 2026

  • Published: 02 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-38137-y

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Keywords

  • Bone cancer pain
  • Spinal dorsal horn
  • Esketamine
  • Glial activation
  • MAPK
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