Neonatal withdrawal following pre- and postnatal exposure to methadone in the rat.

Recent evidence has shown that infant rats undergo precipitated withdrawal following chronic postnatal injection of morphine. In this study we examined whether or not infants exposed to methadone prenatally via the placental blood supply and postnatally via the dam's milk would also experience precipitated withdrawal. Dam's were implanted on gestational day 14 with osmotic minipumps containing one of two concentrations of methadone to supply the opiate throughout gestation and the first postnatal week. Nontreated and pair-fed controls were used. On postnatal day 7, pups were injected with naltrexone and their locomotor activity and ultrasonic vocalizations measured. Methadone exposed pups were more active and vocalized more when injected with naltrexone than with saline. The controls did not show these behavioral changes. The milk of methadone-exposed dams apparently contains sufficient quantities of the opiate for dependence to develop. The results are consistent with other data that demonstrate that very young rat pups can experience an opiate abstinence syndrome that includes increased behavioral activation.

Prenatal administration of buprenorphine in the rat: effects on the rest-activity cycle at 22 and 30 days of age.

Three doses of buprenorphine (BUP) were administered by osmotic minipump from day 8 of gestation through parturition. In addition to 0.3, 1.0, and 3.0 mg/kg/day of BUP, a vehicle control group received sterile water via minipump and a nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. BUP produced a dose response reduction in maternal water intake and reduced maternal weight gain among the two high dose groups; resorptions and birthweight were unaffected. BUP increased perinatal mortality in the two high dose groups compared with the vehicle controls and produced inconsistent effects on postnatal growth. To examine the effects of BUP on the rest-activity cycle of the offspring, groups of 3 littermates from each of the treated and control groups were tested for an 8 h observation period on electronic activity monitors at 22 and 30 days of age. Unlike previous effects described for prenatally administered methadone, a disruption in the rest-activity cycle was not observed for any of the BUP treated groups.

Prenatal administration of buprenorphine using the osmotic minipump: a preliminary study of maternal and offspring toxicity and growth in the rat.

Buprenorphine, an opioid with mixed agonist-antagonist properties, is gaining new attention as an effective pharmacotherapy for opioid and possibly cocaine abuse. With a view to its consideration for use with pregnant clients and because so little is know of its potential developmental toxicity, we have carried out this preliminary study. Three doses of buprenorphine (BUP) were administered by osmotic minipump from day 8 of gestation through parturition. In addition to 0.3, 1.0, and 3.0 mg/kg/day of BUP, a vehicle control group received sterile water via minipump and a nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. BUP produced a dose response reduction in maternal water intake but had no effect on maternal weight gain, the frequency of resorptions, or birthweight. BUP had no effect on perinatal mortality and produced inconsistent effects on postnatal growth. The unique chemical and pharmacological properties of this compound, especially its bell-shaped or asymptotic dose response effects, are discussed with respect to the development of an adequate animal model to evaluate neurobehavioral effects and assess its safety for use during pregnancy.

Prenatal administration of methadone in the rat: acoustic startle amplitude and the rest-activity cycle at 30 days of age.

Two doses of methadone were administered by osmotic minipump from Day 8 of gestation through parturition, a dosing technique previously shown to produce physical dependence in the dams. A pair-fed control group received sterile water via minipump and was allowed to eat and drink only the amount consumed by the high-dose group on the same gestation days. A nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. The effects of methadone on maternal and offspring toxicity replicated our previous findings. At 29-31 days of age each treated and control animal was tested either for changes in acoustic startle amplitude or the rest-activity cycle. Methadone treated offspring were no different from the controls on either measure. These findings support the hypothesis derived from our earlier research that prenatal exposure to methadone produces a prolonged but transitory opioid abstinence. This is evidenced by increased startle amplitude and a disturbed rest-activity cycle that peaks at approximately 3 weeks of age. We demonstrate that these effects are no longer evident at 4 weeks of age. Together, these findings define a state of hyperexcitability in the young rat that resolves by 1 month of age. This transitory state parallels clinical descriptions of human infants undergoing opiate abstinence.