Downregulation of spinal glutamate transporter EAAC1 followingnerve injury is regulated by central glucocorticoid receptors in rats

Abstract

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 μg=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 κB (NF-κB) within the ipsilateral spinal cord dorsal horn, which also was attenuated by either RU38486 (4>2=0.5 μg=vehicle) or a GR antisense oligonucleotide. The immunohistochemical data indicated a pattern of colocalization between GR and EAAC1 as well as GR and NF-κB within the spinal cord dorsal horn. Since, NF-κB 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-κB 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.