Differential regulation of prohormone convertase 1/3, prohormone convertase 2 and phosphorylated cyclic-AMP-response element binding protein by short-term and long-term morphine treatment: implications for understanding the "switch" to opiate addiction.

摘要: Drug addiction is a state of altered brain reward and self-regulation mediated by both neurotransmitter hormonal systems. Although an organism's internal system attempts to maintain homeostasis when challenged exogenous opiates other drugs abuse, it eventually fails, resulting in the transition from drug use abuse. We propose that attempted maintenance achieved, part, through alterations levels processing enzymes control ratio active hormone pro-hormone. Two pro-hormone convertases, PC1/3 PC2 are believed be responsible for activation many neurohormones expression these dependent on presence cyclic-AMP response element (CRE) their promoters. Therefore, we studied effects short-term (24-h) long-term (7-day) morphine treatment hypothalamic phosphorylated cyclic-AMP-response binding protein (P-CREB). While exposure down-regulated, up-regulated P-CREB, rat hypothalamus as determined Western blot analysis. Quantitative immunofluorescence studies confirmed regulatory actions paraventricular dorsomedial nucleus hypothalamus. Specific radioimmunoassays demonstrated increase following led increased TRH biosynthesis evidence TRH/5.4 kDa C-terminal proTRH-derived peptide ratios median eminence. Promoter activity experiments somatomammotrope GH3 cells containing mu-opioid receptor CRE(s) promoter required morphine-induced regulation PC2. Our data suggest prohormone may lead multiple bioactive hormones compensatory mechanism whereby organism tries restore its homeostatic milieu. The down-regulation PC1/3, P-CREB up-regulation signal mediating switch