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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Liang Cheng,
  • Dongjie Wang,
  • Zhiqiang Zhang,
  • Yu Zhang,
  • Yunyun Tang,
  • Kuibin Bao,
  • Bin Guo,
  • Kaijing Zhang,
  • Yu Chen,
  • Hui Ren,
  • Chengfei Xu,
  • Huadong Ni

摘要

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.