Respiratory effects of chronic in utero methadone or morphine exposure in the neonatal guinea pig

Abstract

This study uses a neonatal guinea pig model to compare the effects of in utero methadone or morphine exposure upon breathing control. We hypothesize that in utero methadone exposure will result in similar respiratory disturbances to those seen in morphine exposed neonates, but that the onset will be slower and the duration longer, due to methadone's longer elimination half-life. Pregnant Dunkin-Hartley guinea pigs received once-daily injections of methadone, morphine, or vehicle (saline) during the last half of gestation and pups were studied 3, 7, or 14 days after birth. In utero methadone or morphine exposure resulted in decreased birth weight compared to vehicle, and pups experienced a withdrawal syndrome which included increased locomotor activity and respiratory disturbances but no change in rectal temperature. Both opioid exposures increased inspiratory minute ventilation during CO(2) challenge at 3 days after birth, but only in morphine exposed pups was this withdrawal effect still present on day 7. Surprisingly, only morphine exposure increased inspiratory minute ventilation during room air breathing. We conclude that in utero methadone exposure is not equivalent to in utero morphine exposure. With respect to neonatal respiratory control, methadone-induced changes in respiration are only apparent during hypercapnia.

Fig. 1

Total activity of in utero drug exposed neonatal guinea pigs. Activity is the total count of photo-beam breaks recorded in a 15 minute period. Methadone (striped bars) or morphine (gray bars) exposed pups showed signs of withdrawal related hyperactivity on day 3; by day 7 and 14 counts were not different from control (black bars). Values are average of 6 pups per treatment. Vertical bars represent standard error (S.E). ** p<0.01, *** p<0.001 vs. vehicle; ^ p<0.05 vs. morphine; ^a p<0.05 vs. 7-day same treatment; ^b p<0.05 vs. 14-day same treatment.

Fig. 2

Respiratory effects of in utero methadone (striped bars) or morphine (gray bars) exposures compared to vehicle (black bars) during room air (RA) breathing (left column) and during 5% CO₂ challenge (middle column). CO₂ challenge induced delta response is shown as percent of baseline (RA breathing) (right column). Three major respiratory parameters, inspiratory volume (V_I) (A–C), tidal volume (V_T) (D–F) and breathing frequency (f_R) (G–I) are shown. Several differences exist between methadone and morphine exposed pups. Vertical bars represent standard error (S.E). * p<0.05, ** p<0.01, *** p<0.001 vs. vehicle; ^^^ p<0.001 vs. morphine; ^a p<0.05 vs. 7-day same treatment; ^b p<0.05 vs. 14-day same treatment.