Chronic in utero buprenorphine exposure causes prolonged respiratory effects in the guinea pig neonate

Abstract

Our laboratory studies the effects of in utero opioid exposure on the neonate. In this work we test the effects of chronic in utero exposure to buprenorphine on the neonate. Buprenorphine is a promising candidate for treatment of opioid addiction during pregnancy and it has been suggested to decrease the neonatal abstinence syndrome in human infants. In our guinea pig model, we focused not only on the respiratory effects of in utero exposure on the neonate, but also studied withdrawal signs in the neonate, a major concern of all opioid treatment during pregnancy. Pregnant guinea pigs were treated with daily subcutaneous injections of 0.1mg/kg buprenorphine during the second half of gestation. We measured weight, locomotor activity and respiratory function in pups of ages 3 to 14 days. Respiratory response was recorded using a two-chamber plethysmograph, while pups were breathing either room air or 5% CO(2). Our results show that chronic in utero exposure to buprenorphine induces respiratory effects up to day 14 after birth, while earlier studies have shown that effects of either in utero methadone or morphine only persist in the first week after birth in the guinea pig model. These data provide important information for clinical trials of buprenorphine treatment suggesting that duration and severity of respiratory effects of in utero buprenorphine exposure should be monitored.

Figure 1

Respiratory effects of in utero buprenorphine treatment (gray bars) were compared to vehicle (black bars) during room air (RA) breathing (left) and during 5% CO₂ challenge (right). Major respiratory parameters, inspiratory minute ventilation (V_I) (A, B), breathing frequency (f_R) (C, D), tidal volume (V_T) (E, F), and inspiratory effort (V_T/T_I) (G, H) are shown. Several differences exist between buprenorphine and saline exposed pups. Differences are greatest in the youngest animals and during CO₂ challenge. Vertical bars represent standard error (S.E.). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. vehicle; ^a p < 0.05 vs. 7-day same treatment; ^b p < 0.05 vs. 10-day same treatment; ^c p < 0.05 vs. 14-day same treatment.

Figure 2

Delta response for buprenorphine (gray bars) and vehicle (black bars) treated pups was calculated as the percent change from RA breathing to CO₂ challenge compared to the mean for all litters of the same age and treatment group during RA breathing. ΔV_I (A), Δf_R (B), ΔV_T (C), and ΔV_T/T_I (D) are graphed. The delta response is vastly decreased for all parameters in the youngest animals, while it is increased in older animals (ΔV_T, and ΔV_T/T_I). Vertical bars represent standard error (S.E.). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. vehicle; ^a p < 0.05 vs. 7-day same treatment; ^b p < 0.05 vs. 10-day same treatment; ^c p < 0.05 vs. 14-day same treatment.

Figure 3

Effects on oxygen metabolism of in utero buprenorphine treatment (gray bars) were compared to vehicle (black bars). Oxygen consumption VO₂ (A), CO₂ production VCO₂ (B), V_I/VO₂ (C), and V_I/VCO₂ (D) are graphed for all test days. Differences between treatment groups are greatest in 3 day old pups, indicating withdrawal related hyperventilation in buprenorphine exposed pups. Vertical bars represent standard error (S.E). ** p < 0.01, *** p < 0.001 vs. vehicle; ^a p < 0.05 vs. 7-day same treatment; ^b p < 0.05 vs. 10-day same treatment; ^c p < 0.05 vs. 14-day same treatment.