Effects of met-enkephalin on cell proliferation in different models of adrenocortical-cell growth.
Met-enkephalin (met-Enk) is an opioid peptide that acts via three main subtypes of receptors referred to as mu (mu)-, delta (delta)- and zeta (zeta)-receptor. While the first two receptor subtypes mediate the classic opioid effects of met-Enk, zeta-receptors are reported to be involved in the non-opioid actions of the peptide, i.e. the inhibitory effect on the cell growth. Despite the fact that met-Enk is known to regulate the function of the hypothalamic-pituitary-adrenal axis acting on both its central and peripheral branches, none is known on the effects of met-Enk on adrenal growth. Hence, we have investigated the effects of met-Enk and its receptor agonists and antagonists on cell proliferation in three different models of rat adrenal growth: i) immature adrenal cortex, ii) regenerating adrenal cortex and iii) primary cultures of adrenocortical cells. In in vivo experiments, rats were given subcutaneous injections of 1 nmol/100 g of the peptides 28, 16 and 4 h before the sacrifice, and proliferative activity was assessed by counting the number of metaphase-arrested cells (after vincristine administration). In in vitro studies, cultured adrenocortical cells were exposed for 48 h to the peptides at a concentration of 10(-6) M, and proliferative activity was measured by the EZ4U method. The blockade of mu- and delta-receptors raised proliferative activity in immature adrenals and decreased it in regenerating glands, and the effects were reversed by mu- and delta-receptor agonists. Naltrexone-induced blockade of all met-Enk receptor subtypes decreased proliferative activity in immature adrenal and raised it in regenerating glands. The exposure to either mu- or delta-receptor agonists and antagonists evoked doubtful or no effects on the proliferative activity of cultured adrenocortical cells. In contrast, met-Enk exerted a marked antiproliferogenic effect that was reversed by naltrexone. Taken together, these findings allow us to draw the following conclusions: i) mu- and delta-receptor activation inhibits the growth of immature adrenals, stimulates adrenal regeneration, and does not affect proliferation of cultured adrenocortical cells; ii) zeta-receptors mediate the growth inhibitory effect of met-Enk on both regenerating adrenals and cultured adrenocortical cells, but unexpectedly their activation stimulates the growth of immature gland; and iii) the effects of mu- and delta-receptor activation in in vivo experiments are probably mediated by extra-adrenal indirect mechanisms.
Malendowicz
Ludwik K
LK
Department of Histology and Embryology, School of Medicine, Poznan PL-60781, Poland.
Rebuffat
Piera
P
Tortorella
Cinzia
C
Nussdorfer
Gastone G
GG
Ziolkowska
Agnieszka
A
Hochol
Anna
A
D000302:Adrenal Cortex / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004744:Enkephalin, Methionine / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology; D012038:Regeneration; D014750:Vincristine / Q000494:pharmacology
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D004744:Enkephalin, Methionine; D014750:Vincristine; D009271:Naltrexone