Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Neurosci Lett. 2011 Sep 8;502(1):52-5. doi: 10.1016/j.neulet.2011.07.023. Epub 2011 Jul 23.
Valproate produces analgesia in animals and humans, however, its mechanisms of action are yet unknown. The present study examined effects of repeated administration of valproate on behavioral hypersensitivity and expression of glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in the spinal dorsal horn in rats after L5-L6 spinal nerve ligation (SNL). SNL significantly reduced mechanical withdrawal threshold and expression of GLT-1 and GLAST in the spinal dorsal horn. Repeated oral administration of valproate reduced hypersensitivity, restored down-regulated expression of GLT-1 and GLAST in the spinal dorsal horn, and enhanced analgesia from the glutamate transporter activator riluzole. This analgesia from valproate was blocked by the selective GLT-1 blocker dihydrokainic acid (DHK). These data suggest that valproate restores down-regulated expression of glutamate transporters in the spinal cord to presumably reduce glutamate signaling and to reduce hypersensitivity after nerve injury, and that combination of valproate with riluzole produces enhanced analgesia which relies on the spinal glutamate transporters.
丙戊酸在动物和人类中产生镇痛作用，但其作用机制尚不清楚。本研究在大鼠 L5-L6 脊神经结扎后，观察了丙戊酸重复给药对行为性过敏和脊髓背角谷氨酸转运体-1（GLT-1）和谷氨酸-天冬氨酸转运体（GLAST）表达的影响。L5-L6 脊神经结扎显著降低了机械性缩足阈值和脊髓背角 GLT-1 和 GLAST 的表达。丙戊酸的重复口服给药降低了过敏反应，恢复了脊髓背角下调的 GLT-1 和 GLAST 的表达，并增强了谷氨酸转运体激活剂利鲁唑的镇痛作用。丙戊酸的这种镇痛作用被选择性 GLT-1 阻断剂二氢酮酸（DHK）阻断。这些数据表明，丙戊酸恢复了脊髓中谷氨酸转运体的下调表达，可能减少了谷氨酸信号传递，并减轻了神经损伤后的过敏反应，而丙戊酸与利鲁唑的联合使用产生了增强的镇痛作用，这依赖于脊髓中的谷氨酸转运体。
