Fentanyl citrate analgesia attenuates the excess nitrogen excretion in the urine and glucose production induced by trauma. On the other hand, intracerebroventricular injection of morphine stimulates excretion of stress hormones, such as catecholamines and corticosterone. Furthermore, morphine levels in the brain are increased during fasting and sepsis. The aims of this study were to determine whether intracerebroventricular injection of tumor necrosis factor- (TNF-) elevates morphine levels in the rat brain and whether prophylactic administration of fentanyl blocks metabolic responses induced by intracerebroventricular injection of TNF- because of a reduction of morphine levels in the brain. Morphine levels in the brain were increased from 648 to 1,134 fmol/g at 30 min after intracerebroventricular injection of TNF- (P < 0.05 vs. control). This increase was associated with an increase in stress hormones (corticosterone: 416.1 ± 69.1 ng/ml, P < 0.05 vs. control; epinephrine: 3,778.3 ± 681.3 pg/ml, P < 0.01 vs. control) and an enhancement of proteolysis (254.2 ± 45.7 µmol Leu · kg¹ · h¹, P < 0.01 vs. control) and glucose production (7.5 ± 0.7 mg · kg¹ · min¹, P < 0.05 vs. control). Fentanyl reduced morphine levels in the brain to 624 fmol/g (not significant vs. control), resulting in a reduction of stress hormone levels in the plasma and blunted metabolic responses. In conclusion, prophylactic administration of fentanyl prevented an increase in morphine levels in the brain induced by intracerebroventricular injection of TNF-, leading to a reduction in stress hormone levels and subsequent metabolic responses.