Long‐term Cardiorespiratory Anomalies in Rat Offspring Following Prenatal Morphine Exposure

Abstract

The incidence of opioid‐related pregnancies is a growing public health concern. Although not all infants born from opioid using mothers require hospitalization, many exhibit a variety of withdrawal symptoms (Neonatal Opioid Withdrawal Syndrome, NOWS) often requiring weeks of neonatal intensive care. There are longer‐term effects of prenatal opioid use including altered CNS function comprising cognitive impairments, neurobehavioral abnormalities and increased risk of Sudden Infant Death Syndrome (SIDS). In fact, abnormal cardiorespiratory regulation in infants born following prenatal opioid exposure includes reduced vagal tone, tachypnea, delayed arousal, and altered ventilatory responses to hypoxia and hypercapnia. In the present study, we used a rat model to characterize long‐term (postnatal (P) 10 days of age) cardiorespiratory responses of the offspring following in utero morphine exposure. Pregnant dams received twice daily (morning and evening) subcutaneous injections of various doses of morphine (1, 5 or 10mg/kg) during the 3rd week of pregnancy to mimic 3rd trimester maternal opioid use. Following birth, rat pups (and the nursing dam) were left untreated and whole‐body plethysmography was used to assess the acute hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses at P10 days of age. Heart rate was also assessed in rats fitted with a custom‐made jacket with built‐in ECG electrodes. Generally, the postnatal effects of morphine were dose‐dependent: 1) increasing doses of in utero morphine exposure caused a progressive attenuation of the HCVR in 10 day old rats; 2) there was a high rate of neonatal (within 24hrs of birth) mortality in the highest (10mg/kg) prenatal dose; 3) however, the rats who survived exhibited both an attenuated HVR and HCVR; and 4) rats also exhibited resting tachycardia and tachypnea (at 5–10 mg/kg) compared to in utero saline treated rats. These data demonstrate a long‐term (10 days) effect of prenatal morphine exposure on resting cardiorespiratory function, including impairments in ventilatory defense responses to acute hypoxia and hypercapnia. These cardiorespiratory anomalies could offer a window of insight into the pathophysiology of the increased risk of SIDS seen in infants born from mothers of substance use.