Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
J Pain. 2013 Nov;14(11):1485-91. doi: 10.1016/j.jpain.2013.07.007. Epub 2013 Sep 7.
The present study examined whether the histone deacetylase inhibitor valproate prevents downregulation of glutamate transporters in the primary cultured astrocytes and in the spinal cord after L5-L6 spinal nerve ligation (SNL) and whether this action of valproate on spinal glutamate transporters prevents spinal glutamate dysregulation and development of hypersensitivity after SNL. In cultured astrocytes, valproate prevented downregulation of glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter in a concentration-dependent manner. Repeated oral administration of valproate reduced the development of hypersensitivity and prevented the downregulation of spinal GLT-1 and glutamate-aspartate transporter expression in rats after SNL, but did not affect mechanical nociception and expression of those transporters in normal rats. Valproate's effects on hypersensitivity and spinal GLT-1 expression in SNL rats were blocked by intrathecal administration of the selective GLT-1 blocker dihydrokainic acid or the GLT-1 selective small interfering RNA (siRNA). Extracellular glutamate concentration in the spinal cord, measured by microdialysis, was increased in animals with SNL or after GLT-1 selective siRNA treatment, and valproate prevented the SNL-induced glutamate increase. These results suggest that valproate reduces the development of chronic pain after nerve injury in part by preventing downregulation of glutamate transporters, especially GLT-1, to maintain normal extracellular glutamate concentrations in the spinal cord.
This study demonstrates that valproate prevents the downregulation of glutamate transporters in the spinal cord, which contributes in part to the development of chronic pain after nerve injury. Given clinical availability and established safety profiles, perioperative use of valproate should be tested to prevent chronic pain after surgery.
本研究旨在探讨组蛋白去乙酰化酶抑制剂丙戊酸是否能防止 L5-L6 脊神经结扎后原代培养星形胶质细胞和脊髓中谷氨酸转运体的下调，以及丙戊酸对脊髓谷氨酸转运体的这种作用是否能防止脊髓谷氨酸失调和脊神经结扎后敏感性的发展。在培养的星形胶质细胞中，丙戊酸以浓度依赖性方式防止谷氨酸转运体-1(GLT-1)和谷氨酸-天冬氨酸转运体的下调。重复口服丙戊酸可减少敏感性的发展，并防止脊神经结扎后大鼠脊髓 GLT-1 和谷氨酸-天冬氨酸转运体表达的下调，但不影响正常大鼠的机械性痛觉和这些转运体的表达。鞘内给予选择性 GLT-1 阻断剂二氢酮酸或 GLT-1 选择性小干扰 RNA(siRNA)可阻断丙戊酸对脊神经结扎大鼠敏感性和脊髓 GLT-1 表达的影响。通过微透析测量脊髓细胞外谷氨酸浓度，在脊神经结扎或 GLT-1 选择性 siRNA 处理后增加，丙戊酸可防止 SNL 诱导的谷氨酸增加。这些结果表明，丙戊酸通过防止谷氨酸转运体，特别是 GLT-1 的下调，来维持脊髓细胞外谷氨酸浓度的正常，从而部分减少神经损伤后慢性疼痛的发展。
本研究表明，丙戊酸可防止脊髓中谷氨酸转运体的下调，这在一定程度上有助于神经损伤后慢性疼痛的发展。鉴于临床可用性和既定的安全性概况，应测试围手术期使用丙戊酸以防止手术后慢性疼痛。
