A comparative study of the reproductive effects of methadone and benzo[a]pyrene in the pregnant and pseudopregnant rat.

Benzo[a]pyrene (BP; 50 mg/kg) or methadone (5 mg/kg) was given subcutaneously to pregnant rats at different stages of gestation. Both BP and methadone affected the reproductive performance of pregnant rats by significantly increasing the number of resorptions and fetal wastage, and by decreasing the fetal weight. The same dosage levels of BP and methadone were also given to pseudopregnant rats (PSP) with an induced decidual cell reaction (DCR) in an attempt to distinguish whether adverse effects occur in the maternal or fetal compartment or both. Since the hormonal requirements for DCR and implantation are similar and the anatomical, histological, cytological, time sequential changes as well as appearance of the vasculature system for DCR and decidua are indistinguishable, PSP with DCR is similar to pregnancy except for the lack of a fetal compartment. BP, in this PSP model, significantly reduced the uterine wet weight and cyclic nucleotide (cAMP) and cGMP) levels whereas methadone was without a detectable effect. Our findings then suggest that BP may exert its effects adversely on both the maternal and fetal compartments, whereas methadone may act primarily in the fetal compartment.

Evidence for hormonal imbalance after methadone treatment in pregnant and pseudopregnant rats.

The effects of methadone (METH) on the plasma estriol level and hormonal target tissues' cyclic nucleotides (cAMP and cGMP) were investigated in pregnant and pseudopregnant rats. In the pregnant animals, METH (5 mg/kg/day), given once daily from Days 6 to 15 of gestation, significantly reduced the maternal body weight gain in association with an increase in the number of dams bearing resorptions (56%) and a significant reduction in fetal body weight (33%). An inhibition of the plasma estriol level by METH was observed on Day 9 of gestation. Stimulation of the sympatho-adrenal axis and hypothalamo-pituitary axis by acute METH administration was observed and correlated with a significant increase in the levels of cyclic nucleotides in the uterus and adrenal glands of pregnant rats. However, tolerance to METH effects on cyclic nucleotide levels developed by Day 15 of gestation. METH also depressed the fetal cyclic nucleotide levels on Days 12 and 15 of gestation. These findings suggest that METH had pronounced effects on hormonal secretion during pregnancy, and hormonal transport to or hormonal production by the fetuses. In contrast, METH did not exhibit any adverse effects on the hormonal and cyclic nucleotide levels of pseudopregnant rats with deciduoma formation; a model for the maternal compartment. These latter findings may reflect METH's adverse effects on the fetal compartment, and suggest the use of pseudopregnancy as a model to distinguish adverse drug effects between these compartments.

Acute and subchronic effects of methadone on the blood hormonal levels of pregnant and nonpregnant Charles River CD-1 mice.

Blood levels of ACTH, FSH, and estriol were measured throughout the estrous cycle and estriol was determined at different stages during pregnancy in Charles River CD-1 mice treated with 10 mg/kg/day of methadone or vehicle (physiological saline). Animals received one dose in a constant volume (10 ml/kg) per day subcutaneously of either methadone or saline. Blood samples of nonpregnant mice were collected 1 hour after the first dose for acute effects and 1 hour after the last dose treatment for subchronic effects. The acute administration of methadone in nonpregnant mice produced an increase in ACTH level throughout the estrous cycle whereas subchronic treatment reduced ACTH level by 51%. Acute treatment did not alter the estriol or FSH levels whereas subchronic treatment significantly lowered estriol by 17% and FSH by 79%. Methadone injected beginning on day 1 of gestation and continued through day 15 did not produce any effect on maternal body weight or food consumption but resulted in an increase in resorption sites and decrease in implantation sites. The estriol levels in control pregnant mice were 19.8, 54.8, and 109.1 ng/ml on days 1, 10, and 15 of gestation, respectively. A significant reduction of 18.8% and 35.2% in estriol was associated with methadone treatment by days 10 and 15 of gestation, respectively. Methadone, by affecting several hormonal levels in both pregnant and nonpregnant CD-1 mice, may be responsible for some of the adverse effects on reproduction encountered in this species.