Modulation of breathing by mu1 and mu2 opioid receptor stimulation in neonatal and adult rats.

Opioid modulation of breathing during postnatal development through to the adult was investigated in the rat. Respiratory frequency, tidal volume and minute volume were recorded in unanesthetized, unrestrained rat pups and adults using barometric plethysmography. Subjects were administered the highly selective mu opioid agonists dermorphin and fentanyl. Fentanyl, which readily crosses the blood-brain barrier, was included to ensure that developmental changes in blood-brain barrier restrictions did not mask some of the dermorphin effects in older neonates. Drugs were administered subcutaneously in neonates and adults, although dermorphin was given by intracerebroventricular route only in adults. In neonates, mu agonist administration caused a gasping-like pattern of breathing, characterized by a marked fall in frequency and a smaller increase in tidal volume. The gasping response was prevented by pre-treatment with the long-acting mu1 antagonist naloxonazine (NALZ). In the presence of NALZ, mu agonists elicited only a small, but significant, reduction in tidal volume. Both dermorphin and fentanyl showed more potent activity in younger pups than in older pups, possibly in the case of dermorphin because of developmental maturation of blood-brain barrier function. In adults, fentanyl and dermorphin both caused a reduction in frequency and minute volume. The response of adults to fentanyl, but not dermorphin, was prevented by NALZ. These results suggest that both mu1 and mu2 receptors contribute to opioid-induced respiratory depression during neonatal and adult life.