BACKGROUND There are reports that opioid preconditioning induces opioid-receptor-dependent neuroprotection against cerebral ischemia. This experiment was performed to test whether pretreatment with fentanyl, a synthetic primary mu-opioid receptor agonist, would affect the regional cerebral blood flow (rCBF) in focal cerebral ischemia in rats. METHODS Twenty-four hours before permanent and unilateral middle cerebral artery (MCA) occlusion, rats were pretreated with normal saline, 200 microg/kg of fentanyl i.p. or 500 microg/kg of fentanyl i.p. The rats were anesthetized with isoflurane and were mechanically ventilated to cannulate the vessels and to occlude MCA. One hour after MCA occlusion, the rCBF was measured using (14)C-iodoantipyrine. RESULTS The cortical rCBF decreased 1 h after MCA occlusion in all the experimental groups. In the ischemic cortex, the rCBF of the rats treated with 500 microg/kg of fentanyl was significantly greater (+80%, p < 0.05) than that of the control animals. The rCBF of the ischemic cortex of the rats treated with fentanyl 200 microg/kg seemed higher than in the control animals, but the difference was not statistically significant. The rCBF was similar in the nonischemic brain regions such as the contralateral cortex or pons among the experimental groups. CONCLUSIONS Our data demonstrated that pretreatment with fentanyl improved the rCBF in the focal ischemic area without change in rCBF in the nonischemic cortex. Our data suggest that fentanyl could be effective in improving the rCBF in the focal ischemic area when used as a preconditioning agent and that improvement of rCBF could be one of the contributing factors of neuroprotection by opioid preconditioning.