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The Journal of Neuroscience, January 12, 2005, 25(2):488-495; doi:10.1523/JNEUROSCI.4127-04.2005

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Behavioral/Systems/Cognitive
Central Glucocorticoid Receptors Modulate the Expression and Function of Spinal NMDA Receptors after Peripheral Nerve Injury

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

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

Central glucocorticoid receptors (GRs) and NMDA receptors (NMDARs) have been shown to play a significant role in the mechanisms of neuropathic pain after peripheral nerve injury; however, how central GRs and NMDARs interact in this process remains unknown. Here we show that the expression and function of spinal NMDARs after peripheral nerve injury were modulated by central GRs. Chronic constriction nerve injury (CCI) in rats induced a time-dependent upregulation of NR1 and NR2 subunits of the NMDAR within the spinal cord dorsal horn ipsilateral to CCI. The upregulation of NMDARs was significantly diminished by intrathecal administration (twice daily for postoperative days 1-6) of either the GR antagonist RU38486 or an antisense oligonucleotide against GRs. Moreover, this CCI-induced expression of NMDARs was significantly attenuated in rats receiving intrathecal treatment with an interleukin-6 (IL-6) antiserum and in mice with protein kinase C (PKC) knock-out. Because IL-6 and PKC mediated the upregulation of central GRs after CCI as demonstrated previously, the results suggest that IL-6 and PKC served as cellular mediators contributing to the GR-mediated expression of NMDARs after CCI. Functionally, nociceptive behaviors induced by NMDAR activation and CCI were reversed by a single intrathecal administration of the GR antagonist RU38486. Conversely, a single intrathecal injection with the noncompetitive NMDAR antagonist MK-801 reversed neuropathic pain behaviors exacerbated by the GR agonist dexamethasone in CCI rats. These data suggest that interactions between central GRs and NMDARs through genomic and nongenomic regulation may be an important mechanism critical to neuropathic pain behaviors in rats.

Key words: glucocorticoid receptor; NMDA receptor; neuropathic pain; nerve injury; RU38486; interleukin; protein kinase C

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Received Oct 5, 2004; revised November 10, 2004; accepted November 22, 2004.

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