Voltage-activated calcium channels play an important role in excitability of sensory nociceptive neurons in acute and chronic pain models. We have previously shown that low-voltage-activated calcium channels, or T-type channels (T-channels), increase excitability of sensory neurons after surgical incision in rats. We have also found that endogenous 5β-reduced neuroactive steroid epipregnanolone [(3β,5β)-3-hydroxypregnan-20-one] blocked isolated T-currents in dorsal root ganglion (DRG) cells in vitro, and reduced nociceptive behavior in vivo, after local intraplantar application into the foot pads of heathy rats and mice. Here, we investigated if epipregnanolone exerts an antinociceptive effect after intrathecal (i.t.) application in healthy rats, as well as an antihyperalgesic effect in a postsurgical pain model. We also studied if this endogenous neurosteroid blocks currents originating from high voltage-activated (HVA) calcium channels in rat sensory neurons. In in vivo studies, we found that epipregnanolone alleviated thermal and mechanical nociception in healthy rats after i.t. administration without affecting their sensory-motor abilities. Furthermore, epipregnanolone effectively reduced mechanical hyperalgesia after i.t application in rats after surgery. In subsequent in vitro studies, we found that epipregnanolone blocked isolated HVA currents in nociceptive sensory neurons with an IC₅₀ of 3.3 μM in a G-protein-dependent fashion. We conclude that neurosteroids that have combined inhibitory effects on T-type and HVA calcium currents may be suitable for development of novel pain therapies during the perioperative period.

电压激活的钙离子通道在急性和慢性疼痛模型中对感觉伤害感受神经元的兴奋性起重要作用。先前我们已经表明，在大鼠手术切口后，低压激活的钙通道或T型通道（T通道）会增加感觉神经元的兴奋性。我们还发现内源性5β减少的神经活性类固醇epipregnanolone [（3β，5β）-3-hydroxypregnan-20-one]在体外阻断了背根神经节（DRG）细胞中分离的T电流，并降低了体内的伤害感受，在健康大鼠和小鼠的足垫中局部足底施用后。在这里，我们调查了在健康大鼠的鞘内（it）施用后，eprepregnanolone是否发挥抗伤害作用，以及在术后疼痛模型中是否具有抗痛觉过敏作用。我们还研究了这种内源性神经甾体是否阻断了源自大鼠感觉神经元中高压激活（HVA）钙通道的电流。在体内研究中，我们发现表孕烯醇酮给药后可减轻健康大鼠的热和机械伤害感受，而不会影响它们的感觉运动能力。此外，表孕烯醇酮在手术后应用于大鼠后可有效减少机械性痛觉过敏。在随后的体外通过研究，我们发现Epipregnanolone以G蛋白依赖性方式阻断了伤害性感觉神经元中的孤立HVA电流，IC ₅₀为3.3μM 。我们得出的结论是，对T型和HVA钙电流具有联合抑制作用的神经固醇可能适合围手术期开发新的疼痛疗法。