Preproenkephalin gene expression and [Met5]-enkephalin levels in the developing rat heart

[Met5]-enkephalin, encoded by the preproenkephalin (PPE) gene, serves as a growth factor (opioid growth factor, OGF) during cardiac development in addition to its role as a neuroregulator. This study examined the ontogeny and relationship of gene and peptide expression in the mammalian heart during late embryonic, preweaning, and postweaning periods. Values for PPE mRNA of hearts in rats from embryonic day 16 (E16) to postnatal day 1 were 33 to 50% of levels found in adults. Adult values for the mature heart were comparable to those in the caudate, an area of the rat brain rich in PPE mRNA. Message gradually decreased during the first postnatal week to 10% of adult values and remained so until weaning. PPE mRNA on days 35 and 50 were three- and sevenfold, respectively, higher than at 21 days, and in adults was more than 50% greater than at day 50. Message for PPE in neonatal heart was regulated rapidly and in a sustained fashion by excess opioid agonist (OGF) or blockade of opioid-receptor interaction. [Met5]-enkephalin levels increased sevenfold between E18 and E20, and another 1.6-fold until birth. Having reached a zenith in the neonate, values for enkephalin-like peptide decreased gradually through the 2nd postnatal week, and were extremely low in adulthood. Indeed, a 43-fold difference in peptide levels was detected between neonatal and adult rat heart. These data provide evidence for the expression of a tightly regulated and distinct growth factor (OGF) during the crucial periods of cell proliferation and differentiation in the mammalian heart, and reveal that the source of OGF is autocrine and/or paracrine.