Wang Shuxing, Lim Grewo, Yang Liling, Sung Backil, Mao Jianren
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, WACC 324, 15 Parkman Street, Boston, MA 02114, USA.
Pain. 2006 Jan;120(1-2):78-85. doi: 10.1016/j.pain.2005.10.015. Epub 2005 Dec 19.
Previous studies have shown that glucocorticoid receptors (GR) were upregulated, whereas glutamate transporters were downregulated, within the spinal cord dorsal horn after peripheral nerve injury. However, the relationship between the expression of spinal GR and glutamate transporter after nerve injury remains unknown. In the present study, we examined the hypothesis that central GR would regulate the expression of spinal glutamate transporter EAAC1 following chronic constriction nerve injury (CCI) in rats. CCI induced a significant downregulation of EAAC1 expression primarily within the ipsilateral spinal cord dorsal horn when examined on postoperative day 7 using both Western blot and immunohistochemistry. The downregulation of EAAC1 was significantly diminished after either the GR antagonist RU38486 (4 > 2 = 0.5 microg = vehicle) or a GR antisense oligonucleotide was administered intrathecally twice daily for postoperative day 1-6. Moreover, CCI induced a significant downregulation of nuclear factor kappaB (NF-kappaB) within the ipsilateral spinal cord dorsal horn, which also was attenuated by either RU38486 (4 > 2 = 0.5 microg = vehicle) or a GR antisense oligonucleotide. The immunohistochemical data indicated a pattern of colocalization between GR and EAAC1 as well as GR and NF-kappaB within the spinal cord dorsal horn. Since, NF-kappaB has been shown to regulate the expression of those cellular elements linked to inflammation and tissue injury and its activity can be negatively regulated by GR activation, these results suggest that spinal GR through NF-kappaB may play a significant role in the regulation of EAAC1 expression after peripheral nerve injury, a cellular pathway that may contribute to the development of neuropathic pain behaviors in rats.
先前的研究表明，外周神经损伤后脊髓背角内糖皮质激素受体（GR）上调，而谷氨酸转运体下调。然而，神经损伤后脊髓GR表达与谷氨酸转运体之间的关系仍不清楚。在本研究中，我们检验了以下假设：在大鼠慢性压迫性神经损伤（CCI）后，中枢GR会调节脊髓谷氨酸转运体EAAC1的表达。在术后第7天使用蛋白质印迹法和免疫组织化学法检测发现，CCI主要在同侧脊髓背角诱导了EAAC1表达的显著下调。在术后第1 - 6天每天两次鞘内注射GR拮抗剂RU38486（4 > 2 = 0.5微克 = 溶剂）或GR反义寡核苷酸后，EAAC1的下调显著减轻。此外，CCI在同侧脊髓背角诱导了核因子κB（NF - κB）的显著下调，这也被RU38486（4 > 2 = 0.5微克 = 溶剂）或GR反义寡核苷酸所减弱。免疫组织化学数据表明脊髓背角内GR与EAAC1以及GR与NF - κB之间存在共定位模式。由于NF - κB已被证明可调节与炎症和组织损伤相关的细胞成分的表达，并且其活性可被GR激活负向调节，这些结果表明脊髓GR可能通过NF - κB在外周神经损伤后EAAC1表达的调节中发挥重要作用——这一细胞途径可能导致大鼠神经性疼痛行为的发展。
