期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 48, 页码 11145-11154出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3768-05.2005
关键词
glucocorticoid receptor; NMDA receptor; morphine tolerance; RU38486; protein kinase C; protein kinase A; adenylyl cyclase; cAMP response element-binding protein; CREB
资金
- NIDA NIH HHS [R01 DA08835, R01 DA008835] Funding Source: Medline
- NINDS NIH HHS [R01 NS42661, R01 NS045681, R01 NS45681, R01 NS042661] Funding Source: Medline
Spinal NMDA receptor (NMDAR), protein kinase C (PKC), and glucocorticoid receptor (GR) have all been implicated in the mechanisms of morphine tolerance; however, how these cellular elements interact after chronic morphine exposure remains unclear. Here we show that the expression of spinal NMDAR and PKC gamma after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)- dependent pathway. Chronic morphine (10 mu g, i.t.; twice daily for 6 d) induced a time- dependent upregulation of GR, the NR1 subunit of NMDAR, and PKC gamma within the rat's spinal cord dorsal horn. This NR1 and PKC gamma upregulation was significantly diminished by intrathecal coadministration of morphine with the GR antagonist RU38486 or a GR antisense oligodeoxynucleotide. Intrathecal coadministration of morphine with an adenylyl cyclase inhibitor (2', 5'-dideoxyadenosine) or a protein kinase A inhibitor (H89) also significantly attenuated morphine- induced NR1 and PKC gamma expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKC gamma. Moreover, the expression of phosphorylated CREB was upregulated within the spinal cord dorsal horn after chronic morphine, and a CREB antisense oligodeoxynucleotide coadministered intrathecally with morphine prevented the upregulation of GR, NR1, and PKC gamma. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKC gamma expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKC gamma may be an important mechanism that contributes to the development of morphine tolerance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据