THE EFFECT OF PRENATAL METHADONE EXPOSURE ON DEVELOPMENT AND NOCICEPTION DURING THE EARLY POSTNATAL-PERIOD OF THE RAT

The effects of prenatal exposure to methadone via Alzet osmotic minipump on early postnatal development and on nociceptive behavioral endpoints were assessed in Sprague-Dawley rat pups during the first three postnatal weeks. This treatment regimen appeared to produce no maternal toxicity, with dams developing and maintaining dependence upon methadone through parturition. Methadone-exposed dams exhibited a withdrawal syndrome consisting of wet-dog shakes, diarrhea, vocalizations and irritability when challenged with naloxone 24 h postpartum. Pups exhibited a similar withdrawal syndrome following naloxone challenge consisting of mouthing and licking, hyperactive response to touch and vocalizations 24 h postpartum. Although no significant difference in litter size was evident in methadone-treated litters, a 16% pup mortality rate was observed in these litters. Prenatal methadone-exposed pups exhibited a significant body weight reduction at birth that resolved by postnatal day 2 (P2) in males and P4 in females. Methadone-exposed pups exhibited significant developmental delay in the expression of the negative geotaxic response and ability to perform a vertical screen task. On P4 methadone-exposed pups exhibited enhanced analgesic response to a morphine challenge while, conversely, 21-day-old pups exhibited a significantly reduced analgesic response to this challenge. These studies indicate that this method of prenatal exposure to methadone can produce dependence in the dam and offspring without substantial mortality, induce developmental delay and alter analgesic responses to opiate challenge in exposed pups during the preweanling period.