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Chronic prenatal methadone exposure alters central opioid mu-receptor affinity in both fetal and maternal brain
N A Darmani1, S H Schnoll, U Pandey
1Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
The effects of chronic prenatal methadone exposure (6.3-9.0 mg/kg/day) via osmotic minipumps to pregnant dams on fetal and maternal brain opioid mu-receptors were assessed on gestation day 20 and day 7 postnatally. By using the 3H-DAMGO binding assay, it was shown that chronic methadone treatment (gestation days 7-20) did not affect mu-receptor capacity in both fetal and maternal brains during gestation day 20, nor when tested 7 days after delivery. However, this chronic exposure decreased mu-receptor affinity in both fetal and maternal brain homogenates when determined on day 20 of pregnancy. Scatchard analysis of binding data in both tissues indicated that the methadone-induced increase in KD returned to control values when tested 7 days after delivery. The change in mu-receptor affinity was not due to competition between 3H-DAMGO and residual methadone. Extensive washing of the brain homogenates failed to alter the affinity of the receptor but decreased the concentration of the residual methadone. This decrease in receptor affinity was also observed in extensively washed brain tissue from female adult rats treated acutely with methadone (9.0 mg/kg, IP) or when brain homogenates were exposed to methadone (50 ng/ml) in vitro. Thus, these data suggest that methadone alters mu-receptor affinity by some unknown mechanism.
The effects of chronic prenatal methadone exposure (6.3-9.0 mg/kg/day) via osmotic minipumps to pregnant dams on fetal and maternal brain opioid mu-receptors were assessed on gestation day 20 and day 7 postnatally. By using the 3H-DAMGO binding assay, it was shown that chronic methadone treatment (gestation days 7-20) did not affect mu-receptor capacity in both fetal and maternal brains during gestation day 20, nor when tested 7 days after delivery. However, this chronic exposure decreased mu-receptor affinity in both fetal and maternal brain homogenates when determined on day 20 of pregnancy. Scatchard analysis of binding data in both tissues indicated that the methadone-induced increase in KD returned to control values when tested 7 days after delivery. The change in mu-receptor affinity was not due to competition between 3H-DAMGO and residual methadone. Extensive washing of the brain homogenates failed to alter the affinity of the receptor but decreased the concentration of the residual methadone. This decrease in receptor affinity was also observed in extensively washed brain tissue from female adult rats treated acutely with methadone (9.0 mg/kg, IP) or when brain homogenates were exposed to methadone (50 ng/ml) in vitro. Thus, these data suggest that methadone alters mu-receptor affinity by some unknown mechanism.