Ontogeny of respiratory sensitivity and tolerance to the mu-opioid agonist fentanyl in rat

Whereas developmental changes in analgesic sensitivity and tolerance to the mu-opioid agonist fentanyl have been reported, knowledge of respiratory responses to that drug is lacking. Using 7- and 14-day-old (P7, P14) and adult conscious rats, we first established, using whole body plethysmography, the fentanyl dose that decreased minute ventilation by 50% (ED50) at each age. ED50 increased with postnatal age (40, 60 and 120 μg/kg sc, respectively), indicating a high sensitivity to fentanyl in the youngest rats that decreased with maturation. In separate rat groups of the 3 ages, we injected each ED50 dose, once a day, for several consecutive days, until tolerance was established. Tolerance was defined as a reduction in respiratory depression from 50% to 75% of baseline. All age groups reached tolerance in minute ventilation, respiratory frequency, tidal volume and instantaneous flow (equivalent to respiratory drive). The P14 rat pups attained tolerance more rapidly (at 2.6 days) than did either the younger (5.1 days) or the adult rats (4.4 days). These results indicate that respiratory sensitivity and tolerance to fentanyl in rat vary in a distinct manner during maturation.