Chronic exposure to the opioid growth factor, [Met5]-enkephalin, during pregnancy: maternal and preweaning effects

The opioid peptide, [Met(5)]-enkephalin (termed opioid growth factor, OGF), is an autocrine growth factor that serves as a constitutively active inhibitory agent. OGF crosses the placenta and depresses DNA synthesis in the fetus. The role of OGF in pregnancy and parturition, and the influence exerted on prenatal and neonatal features of the offspring, were studied in rats. Females received daily injections of 10 mg/kg OGF throughout gestation; all offspring were cross-fostered to lactating noninjected dams at birth. No effects on the length of gestation, course of pregnancy, behavior of the pregnant dam, maternal weight gain, or food and water intake throughout gestation were recorded in OGF-treated mothers. Moreover, nociceptive response in these females was not altered by chronic OGF exposure, and no signs of physical dependence or withdrawal could be observed following a challenge by the opioid antagonist naloxone. Litter size and the number of live births per litter of OGF-treated mothers were reduced by 25% from control subjects and a fourfold increase in stillborns was noted for mothers receiving OGF compared to control levels. Histopathologic analysis confirmed the stillborns to have died in utero. OGF-exposed neonates were normal in body weight and crown-to-rump length, but these pups were observed to be lethargic and cyanotic, and had subnormal weights of many organs. Body weights of 10-, 15-, and 21-day-old OGF-exposed rats were reduced 11-27% from control levels. Wet and dry organ weights of the rats maternally subjected to OGF were decreased from control values in six of the eight organs evaluated at 10 days. At weaning, some organs were subnormal in weight. These data lead us to hypothesize that a native opioid peptide-OGF-is integral to certain aspects of maternal, neonatal, and postnatal well-being, and that disruptions in this opioid peptide have serious repercussions on the course of pregnancy and fetal outcome.