Spinal Cord Stimulation Alleviates Neuropathic Pain Involves Regulation of the Ca²⁺/CaN/NFAT4 Pathway in Spinal...

Spinal cord stimulation (SCS) represents an established neuromodulatory intervention for refractory neuropathic pain (NP), yet the cellular mechanisms underlying its anti-inflammatory effects remain incompletely defined. The activation of astrocytes, especially polarization into the A1-like phenotype, is crucial for the persistence of central sensitization. This study aimed to investigate whether the analgesic effects of SCS are associated with modulation of astrocyte activation and calcium ions (Ca²⁺) / calcineurin (CaN) / nuclear factors of activated T cells 4 (NFAT4) pathway signaling in the spinal dorsal horn. In a rat model of chronic constriction injury (CCI), the present study found that SCS significantly ameliorated mechanical allodynia and reduced spinal levels of proinflammatory cytokines. Furthermore, SCS suppressed spinal dorsal horn astrocyte activation and attenuated their polarization toward the A1-like phenotype. In association with these changes, SCS reduced CCI-induced spinal Ca²⁺ elevation, downregulated CaN and NFAT4 expression, and decreased NFAT4 nuclear translocation. In vitro experiments further demonstrated that inhibition of CaN or NFAT4 similarly attenuated astrocyte activation, A1-like polarization, and proinflammatory cytokine release. The findings suggest that the analgesic effect of SCS in NP is associated with suppression of Ca²⁺/CaN/NFAT4 pathway signaling and attenuation of neurotoxic A1-like astrocyte polarization and neuroinflammation. This study supports the involvement of an astrocyte-related Ca²⁺/CaN/NFAT4 signaling axis in the biological effects of SCS and provides a potential therapeutic target for improving neuromodulation-based pain management. Graphical Abstract. Spinal cord stimulation alleviates neuropathic pain and is associated with reduced Ca²⁺/CaN/NFAT4 pathway signaling, astrocyte activation, and A1-like polarization in the spinal dorsal horn. Spinal cord stimulation reverses the activation of the Ca²⁺/CaN/NFAT4 signaling pathway in spinal dorsal horn caused by peripheral nerve injury, thereby inhibiting NFAT4 nuclear translocation. This suppresses A1-like astrocyte polarization and proinflammatory cytokine release, alleviating neuropathic pain.