Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2) are endogenous peptides that can exert opiate-related actions on the CNS after peripheral administration. We found that Tyr-MIF-1 radioactively labeled at the tyrosine was transported across the blood-brain barrier (BBB) in the direction of brain to blood by a saturable system. Transport occurred equally well when the tetrapeptide was labeled with 125I or when it was labeled with 3H. [3H]MIF-1 and [3H]morphine were not transported out of the CNS but were retained by the brain after intracerebroventricular injection. Both [3H]MIF-1 and [3H]morphine entered the brain after i.v. injection, with [3H]MIF-1 crossing the BBB by a mechanism that was partially saturable. The entry rate and accumulation of radioactivity by the brain was 50-100 times greater after the i.v. injection of [3H]MIF-1 than after [3H]morphine. The results show that Tyr-MIF-1 labeled with either 3H or 125I can serve equally well for the measurement of transport across the BBB, that MIF-1 has relatively substantial and rapid access from the blood to the CNS by directly crossing the BBB, and that the BBB can differentially regulate the exchange of related substances between the CNS and blood.