Effects of loperamide and other opioid-related substances on the transcriptional regulation of the rat pro-opiomelanocortin gene in AtT20 cells

Although opioid peptides are involved in the regulation of the hypothalamic -pituitary-adrenal axis, their role in pro-opiomelanocortin (POMC) gene exp ression at the pituitary level is not known. We therefore examined the effe cts of opioid receptor agonists, including recently discovered endogenous o pioid peptides, on POMC gene expression using the AtT20PL cell line, a subc lone of AtT20 in which the rat POMC 5' -promoter-luciferase fusion gene was stably incorporated. The endogenous mu-opioid receptor agonists endomorphi n 1 and 2 had no effect on either basal or corticotropin-stimulating-hormon e-induced POMC expression. This was also the case with the delta-agonist BU BUC, the kappa-agonist U50488H and the orphan receptor agonist orphanin FQ. In contrast, the synthetic mu-agonist loperamide significantly inhibited b asal and yet enhanced cAMP-induced POMC expression. The inhibitory effect o f loperamide was mimicked by the calmodulin antagonist W7 and antagonized b y the calcium channel blocker nifedipine, whereas neither the inhibitory no r the enhancing effect of loperamide was influenced by the opioid antagonis t naloxone. These results suggest that the synthetic mu-agonist loperamide has a modulatory effect on the 5' -promoter activity of the POMC gene. This effect does not seem to be mediated through the classical mu-opioid recept or but rather in part through a calcium/calmodulin-related mechanism. Copyr ight (C) 2001 S. Karger AG, Basel.