Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor.
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 PKCgamma after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 microg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKCgamma within the rat's spinal cord dorsal horn. This NR1 and PKCgamma 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 PKCgamma expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKCgamma. 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 PKCgamma. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKCgamma expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKCgamma may be an important mechanism that contributes to the development of morphine tolerance.
Lim
Grewo
G
Pain Research Group, Division of Pain Medicine, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Wang
Shuxing
S
Zeng
Qing
Q
Sung
Backil
B
Yang
Liling
L
Mao
Jianren
J
D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004334:Drug Administration Schedule; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D006727:Hormone Antagonists; C409466:NR1 NMDA receptor; D016376:Oligonucleotides, Antisense; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D015735:Mifepristone; D009020:Morphine; D003907:Dexamethasone; C087857:protein kinase C gamma; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases