The effect of fentanyl on the transfer of small hydrophilic molecules across the blood-brain barrier was studied in rats by measuring the blood-brain transfer coefficient (Ki) and the regional cerebral blood flow (rCBF) and by calculating the capillary permeability-surface area product. In the control group (n = 14), after a femoral artery and vein were catheterized under isoflurane anesthesia, the rats were allowed to remain awake for 1.5 h before measuring Ki (n = 8) using intravenous 14C-alpha-aminoisobutyric acid or rCBF (n = 6) using 14C-iodoantipyrine. In the fentanyl groups, rats were injected with 25 micrograms/kg (low (n = 6) or 100 micrograms/kg (high dose) of fentanyl (n = 14), followed by a continuous infusion at a rate of 50 or 200 micrograms.kg-1.h-1, respectively. Their lungs were mechanically ventilated. The Ki (low dose, n = 6; high dose, n = 8) and rCBF (high dose, n = 6) were measured 1 h after fentanyl infusion. The Ki was lower in 9 of 13 brain regions in the low-dose fentanyl group and in 7 of 13 brain regions in the high-dose fentanyl group than in the control animals. The average value of Ki in all the brain regions was 8.6 +/- 4.6 microL.g-1.min-1 in the control group, 5.2 +/- 2.9 microL.g-1.min-1 in the low-dose fentanyl group, and 5.7 +/- 2.9 microL.g-1.min-1 in the high-dose fentanyl group. High-dose fentanyl did not significantly affect rCBF in any brain region studied. The value of the regional permeability-surface area product was similar to the corresponding regional Ki in the groups studied. In conclusion, fentanyl decreased the transfer of small hydrophilic molecules across the blood-brain barrier, as demonstrated by a decreased Ki and permeability-surface area product, without significant changes in rCBF.