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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-38137-y.