Mu Opioid Modulation of Breathing During Postnatal Development in the Rat

Abstract

Clinical administration of opioid drugs has long been associated with respiratory depression, but the mechanisms by which opioids influence breathing are not yet well understood, particularly in the neonate. Mu opioid modulation of breathing during postnatal development was investigated in the rat. Experiments were conducted in vivo on animals aged 2-3 days (P2-3), P6-8. P11-13 and Pl7-21, and adult. Respiratory frequency, tidal volume and minute volume were recorded in unanaesthetised, freely moving neonates and adults using barometric plethysmography. Blood-gas measurements were made in a separate group of anaesthetised pups. Subjects were administered the muselective opioid agonists dermorphin and fentanyl, Drugs were administered ip or sc in pups, and icv in adults, with the exception of fentanyl, which was injected sc in all age groups. Effects of the opioid drugs on resting breathing, blood-gases and hypoxic-, and hypercapnic-stimulated breathing were assessed. Dermorphin and fentanyl both caused marked respiratory depression. Mu-l- and mu-2-mediated effects of the mu agonists were distinguished using the mu-l antagonist naloxonazine (NALZ). In neonates, mu receptor activation caused a gasping-like response (markedly depressed frequency with a raised tidal volume) that was NALZ-sensitive. After blockade of mu-l receptors with NALZ, dermorphin caused a small but significant fall in tidal volume. Stimulation of mu receptors by dermorphin also caused a NALZ-insensitive inhibition of the ventilatory response to hypoxia and hypercapnia. In adults, fentanyl and dermorphin both caused a reduction of frequency and minute volume. The effects of fentanyl on adult ventilation were prevented by NALZ, whereas the effects of dermorphin were not. Thermoregulation was also affected by dermorphin and fentanyl administration in neonates and adults. Core body temperatures were recorded during respiratory experiments to allow calculation of tidal volume and minute volume. In pups, mu activation caused NALZ-sensitive hypothermia. In adults, fentanyl and dermorphin had no effect on body temperature when administered alone, but when injected in the presence of NALZ, the two drugs caused hyperthermia and hypothermia, respectively. The results of this study indicate that, in neonates, opioid-induced respiratory depression occurs via both mu-l and mu-2 receptors. Mu-l receptor activity caused gasping, whereas activation of mu-2 receptors induced a reduction in resting tidal volume and blunted responses to hypoxia and hypercapnia. In adults, fentanyl and dermorphin induced respiratory depression via mu-l and mu-2 receptors, respectively. Mu-l activation caused hypothermia in neonatal rats, but the role of mu opioid receptors in modulation of body temperature in the adult was less clear. It was concluded that administered opioid drugs act via both mu-1 and mu-2 receptors to inhibit normal as well as hypoxic and hypercapnic breathing in the neonatal rat. Reductions in the degree of opioid influence occur during neonatal development.