Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome

Abstract

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Keywords: Hypercapnia; Hypoxia; Microglia; NAS; NOWS; Opioid.