Characterization of neonatal rat fentanyl tolerance and dependence

Fentanyl and morphine are administered to human neonates and infants to provide analgesia and sedation during painful and stressful procedures. These opioids have often been shown to produce tolerance and dependence during continuous intravenous infusion. In neonatal animals, morphine produces tolerance and dependence, yet little is known about fentanyl. This report describes the first model for studying opioid tolerance and dependence in neonatal animals with use of osmotic minipumps. Postnatal day 6 rat pups were anesthetized and then remained naive or were surgically implanted subcutaneously with Alzet osmotic minipumps containing either saline or fentanyl (100 microg/kg/hr). Tolerance and dependence were assessed 72 hr after implantation. The ED50 values for fentanyl antinociception in the tail-flick test were not different between naive and saline pump-implanted animals. However, the fentanyl pump-implanted animals were tolerant to fentanyl. The tolerance observed was not the result of gender, developmental changes, fentanyl distribution or changes in fentanyl metabolism. These results indicate that continuous administration of fentanyl via osmotic minipump can render normal neonatal rats tolerant and physically dependent on fentanyl in 72 hr. Withdrawal precipitated by naloxone (5 mg/kg s.c.) in the fentanyl pump-implanted animals was characterized by increased spontaneous activity, micturition/defecation, wall climbing, abdominal stretching, tremors, scream on touch and spontaneous vocalization. This new model may provide a tool for studying the long-term consequences of neonatal opioid exposure in juvenile and adult animals.