Abstract
A growing body of evidence supports an important role of the transcription factor cAMP responsive element binding protein (CREB) in mediating opioid-induced changes in the cAMP pathway. Regulation of CREB and subsequent changes in gene expression may underlie some long-term cellular adaptations associated with the administration of opioid drugs. The effect of morphine on the level of the transcription factor CREB, as well as CREB phosphorylation, was investigated in NG108-15 cells. Morphine and the δ-opioid receptor agonist [ d-Pen 2,5]enkephalin (DPDPE) produced a dose-dependent increase in CREB phosphorylation. The effect was reversed by naloxone and naltrindole, respectively. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), the protein kinase inhibitor staurosporine, as well as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), an inhibitor of protein kinase C and cAMP-dependent protein kinase, but not N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-8), an inhibitor of cAMP- and cGMP-dependent protein kinase, blocked the opioid-induced CREB phosphorylation. The obtained results suggest that in the cells studied opioids affect, via the δ-opioid receptor, stimulatory intracellular mediator systems involving Ca 2+/calmodulin and the protein kinase C pathway.
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