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Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via mu-opioid receptors in primary cultures of mouse cerebral cortical neurons.

Shibasaki M, Katsura M, Torigoe F, Honda T, Sumimoto A, Tsujimura A, Ohkuma S

Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan.

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.

Published 20 September 2007 in J Neurosci Res, 85(13): 2971-80.
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