Long-Term Treatments with Morphine and Naloxone have Sex-Differentiated Effects on Luteinizing Hormone Secretion in Chronically Catheterized Fetal Pigs

Short- (one bolus injection) and long-term (repeated injections over a period of at least 7 days) effects of drugs on pituitary function in pig fetuses were studied to investigate the influence of morphine and naloxone on luteinizing hormone secretion in the chronically catheterized pig fetus between days 102 and 110 of gestation (term: 113±1 SD day). Both substances were intravenously administered in two doses: 0.1 mg and 1 mg/fetus. Repeated injections at 2-day intervals enabled us to study short- as well as long-term effects. Morphine acutely inhibited luteinizing hormone secretion both in male and female fetuses. Long-term treatment with morphine at both doses caused an inhibition of basal luteinizing hormone (levels before treatment on each day) in females (0.1 mg: r=-0.60, P<0.001; 1 mg: r=-0.45, P<0.05) while male fetuses were unaffected. Naloxone did not have any short-term effects, either in females or in males. In the long-term study, however, naloxone at 1 mg dose decreased basal luteinizing hormone levels in male fetuses (r=-0.55, P<0.01), whereas in females no effect was evident. Co-administration of 0.1 mg naloxone +0.1 mg morphine abolished the long-term inhibitory effect observed in females when 0.1 mg morphine alone was given. These results indicate that the link between opioids and the luteinizing hormone system is functional in the pig from at least 2 weeks before birth. Furthermore, there is a sex difference in the long-term effects of both morphine and naloxone. The origin of the apparently paradoxical long-term effect of naloxone in male fetuses remains unclear.