CHARACTERIZATION OF NEONATAL RAT FENTANYL TOLERANCE AND DEPENDENCE

Fentanyl and morphine are administered to human neonates and infants t o provide analgesia and sedation during painful and stressful procedur es. These opioids have often been shown to produce tolerance and depen dence during continuous intravenous infusion. In neonatal animals, mor phine produces tolerance and dependence, yet little is known about fen tanyl. This report describes the first model for studying opioid toler ance 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 mu g/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 be tween naive and saline pump-implanted animals. However, the fentanyl p ump-implanted animals were tolerant to fentanyl. The tolerance observe d was not the result of gender, developmental changes, fentanyl distri bution 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 fenta nyl 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 neonata l opioid exposure in juvenile and adult animals.