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The Journal of Neuroscience, November 30, 2005, 25(48):11145-11154; doi:10.1523/JNEUROSCI.3768-05.2005

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Cellular/Molecular
Expression of Spinal NMDA Receptor and PKC after Chronic Morphine Is Regulated by Spinal Glucocorticoid Receptor

Grewo Lim, Shuxing Wang, Qing Zeng, Backil Sung, Liling Yang, and Jianren Mao

Pain Research Group, Division of Pain Medicine, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

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 after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 µg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKC within the rat's spinal cord dorsal horn. This NR1 and PKC 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 expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKC. 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. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKC expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKC may be an important mechanism that contributes to the development of morphine tolerance.

Key words: glucocorticoid receptor; NMDA receptor; morphine tolerance; RU38486; protein kinase C; protein kinase A; adenylyl cyclase; cAMP response element-binding protein; CREB

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Received May 20, 2005; revised October 18, 2005; accepted October 19, 2005.

This article has been cited by other articles:

				D. Owen and S. G. Matthews Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs J. Physiol., January 1, 2007; 578(1): 249 - 257. [Abstract] [Full Text] [PDF]

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