Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via mu-opioid receptors in primary cultures of mouse cerebral cortical neurons.
Our previous in vivo experiment demonstrates that chronic morphine treatment up-regulates diazepam binding inhibitor (DBI) transcripts in mouse cerebral cortex, although detailed mechanisms were unclear (Katsura et al. [1998] J. Neurochem. 71:2638-2641). This study sought to elucidate the precise mechanisms of DBI mRNA up-regulation by long-term treatment with morphine using primary cultures of mouse cerebral cortical neurons. A significant increase in DBI mRNA was observed after sustained exposure to 0.3 microM morphine for 2 days, and the maximal expression occurred after 2 days of exposure, whereas transient exposure to 0.3 microM morphine for 15 min, 1 hr, and 3 hr produced no changes in the expression. Continuous exposure to DAMGO also significantly increased DBI mRNA expression, which was completely abolished by a selective antagonist of mu-opioid receptors, beta-funaltrexamine (beta-FNA). The morphine-induced increase in DBI mRNA expression and its content were completely inhibited by naloxone and beta-FNA, and the inhibitory potential of naloxonazine was about half that of beta-FNA. On the other hand, kappa- and delta-opioid receptor antagonists showed no effects on the morphine-induced increase in DBI mRNA. In addition, both a calmodulin antagonist and a CaM II kinase inhibitor significantly suppressed the morphine-induced increase in DBI mRNA. These results indicate that the increase in DBI expression is induced by continuous activation of mu-opioid receptors but not of kappa- and delta-opioid receptors and is regulated by the calcium/calmodulin-related phosphorylation system.
Shibasaki
Masahiro
M
Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan.
Katsura
Masashi
M
Torigoe
Fumiko
F
Honda
Takeshi
T
Sumimoto
Ayaka
A
Tsujimura
Atsushi
A
Ohkuma
Seitaro
S
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000493:pharmacokinetics; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D026261:Diazepam Binding Inhibitor; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D012333:RNA, Messenger; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine