Work

Spinal dehydroepiandrosterone sulfate induces convulsion-like behavior via NMDA receptor-mediated Ca2+ influx and sigma-1 receptor-mediated intracellular Ca2+ release

Year: 2026

Type: article

Abstract: Dehydroepiandrosterone sulfate (DHEAS) is a neurosteroid that modulates spinal nociception and hyperalgesia. However, the immediate impact of an acute increase in spinal DHEAS remains poorly understood. Here, we report that intrathecal (i.t.) administration of DHEAS (0.3–10 nmol) dose-dependently induces an abrupt, transient convulsion-like behavior lasting approximately 5 min in mice, whereas its unconjugated form DHEA exhibits no such effect. This behavior was significantly attenuated by pre-treatment with either the NMDA receptor antagonist MK-801 or the sigma-1 receptor (Sig-1R) antagonist BD1047, and almost completely abolished by their co-administration. Although the L-type Ca 2+ channel blocker nifedipine had no effect on DHEAS-induced behavior, ruling out voltage-gated Ca 2+ influx, combination experiments with specific Ca 2+ modulators revealed distinct underlying mechanisms. The inhibitory effect of the extracellular Ca 2+ chelator EGTA was synergistically potentiated when combined with BD1047, but showed no additive effect with MK-801. Conversely, depletion of intracellular Ca 2+ stores with thapsigargin produced robust synergistic inhibition with MK-801, but not with BD1047. Taken together, our findings demonstrate that an acute increase in spinal DHEAS triggers transient convulsion-like behavior via dual-source Ca 2+ signaling (extracellular influx via NMDA receptors and intracellular release via Sig-1Rs), highlighting calcium source-dependent mechanisms underlying neurosteroid-induced spinal hyperexcitability.

Source: Molecular Brain

DOI: 10.1186/s13041-026-01350-x