Morphine-6-beta-D-glucuronide respiratory pharmacodynamics in the neonatal guinea pig

Morphine-6-beta-D-glucuronide (M6G) is a metabolite of morphine with opioid activity in adults. No data are available, however, on the developmental pharmacology of M6G including investigation of the respiratory effects of M6G in the neonate. A randomized, placebo-controlled study comparing the time-action, dose-response and potency of the respiratory effects of M6G to morphine was done using a nonanesthetized neonatal guinea pig model and a noninvasive computerized plethysmograph technique. Respiration was measured while the neonate breathed room air followed by 5% CO2 in air. M6G (0.5-5.0 mg/kg) and morphine (1.5-15 mg/kg) administered subcutaneously decreased ventilation in 3-, 7- and 14-day-old neonatal guinea pigs given a 5% CO2 challenge. During CO2 inhalation, time-to-peak action for M6G occurred 21 min later than for morphine. At maximal ventilatory depression on day 3, a dose of 1.5 mg/kg morphine or M6G decreased minute ventilation while breathing 5% CO2 by 30% compared to placebo. Ventilation also decreased as a function of age in both placebo and drug-treated animals. The percent respiratory depression relative to placebo remained constant for a given dose of morphine as the neonate aged, but not for M6G, which increased in potency. M6G was equipotent to morphine on day 3 after birth, but was 8-fold more potent by day 7. This increase in potency persisted through day 14. The increased potency of M6G that accompanies aging may be caused by either a change in M6G disposition or a change in opioid receptors during development of the neonatal guinea pig.