Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a recently isolated peptide that belongs to a larger family that includes Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2). Despite similarities in structure, Tyr-MIF-1 and MIF-1 can act differently in behavioral, blood-brain barrier (BBB) transport, and receptor binding systems. Tyr-W-MIF-1, like Tyr-MIF-1, has both opiate and antiopiate activity, but may be more opiate-like than Tyr-MIF-1. Tyr-MIF-1, but not MIF-1, is transported from brain to blood by peptide transport system (PTS)-1. PTS-1 transports mainly Tyr-MIF-1 and methionine enkephalin, but does not transport amino acids, peptide fragments of Tyr-MIF-1, D-Tyr-MIF-1, or unrelated peptides and proteins. We tested whether Tyr-W-MIF-1 also was transported across the BBB and, if so, whether PTS-1 was involved. 125I-Tyr-W-MIF-1 had a half-time disappearance from the brain of 22.4 min. This is faster than the efflux occurring with non-saturable reabsorption of the cerebrospinal fluid and, therefore, is consistent with saturable transport, but it is slower than the efflux rate of Tyr-MIF-1, suggesting a less robust transport than for Tyr-MIF-1 Self-inhibition with excess unlabeled Tyr-W-MIF-1 confirmed a saturable component, with a dose of 4.2 nmol producing 50% inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)