Modulation of breathing by mu(1) and mu(2) 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 ad ults using barometric plethysmography. Subjects were administered the highl y selective mu opioid agonists dermorphin and fentanyl. Fentanyl, which rea dily crosses the blood-brain barrier, was included to ensure that developme ntal changes in blood-brain barrier restrictions did not mask some of the d ermorphin effects in older neonates. Drugs were administered subcutaneously in neonates and adults, although dermorphin was given by intracerebroventr icular route only in adults. In neonates, mu agonist administration caused a gasping-like pattern of breathing, characterized by a marked fall in freq uency and a smaller increase in tidal volume. The gasping response was prev ented by pre-treatment with the long-acting mu (1) antagonist naloxonazine (NALZ). In the presence of NALZ, mu agonists elicited only a small, but sig nificant, reduction in tidal volume. Both dermorphin and fentanyl showed mo re potent activity in younger pups than in older pups, possibly in the case of dermorphin because of developmental maturation of blood-brain barrier f unction. In adults, fentanyl and dermorphin both caused a reduction in freq uency and minute volume. The response of adults to fentanyl, but not dermor phin, was prevented by NALZ. These results suggest that both mu (1) and mu (2) receptors contribute to opioid-induced respiratory depression during ne onatal and adult life. (C) 2001 Elsevier Science BN. All rights reserved.