The brain is both the source and the recipient of peptide signals. The question is: Do endogenous, blood-borne peptide molecules influence brain function? Brain regions with the tight capillaries of the blood-brain barrier (BBB) extract low but measurable amounts of labeled peptide molecules from an intracarotid bolus injection. In the rat, the extraction fractions of beta-casomorphin-5, DesGlyNH2-arginine-vasopressin, arginine-vasopressin, lysine-vasopressin, oxytocin, gonadoliberin, substance P, and beta-endorphin, studied in this laboratory, range from 0.5% (substance P) to 2.4% (arginine-vasopressin). Extraction varies little among the 15 examined brain regions. As shown for arginine-vasopressin, the extracted peptides may be bound in part to specific binding sites located on the luminal membrane of the tight endothelial cells. Transport of peptide molecules across the BBB cannot be ruled out, but it is unlikely that endogenous peptides pass the BBB in physiologically significant amounts. In contrast, in brain regions with leaky capillaries, e.g., selected circumventricular organs including the pineal gland, neurohypophysis, and choroid plexus, the peptide fraction extracted approaches that of water. Within the circumventricular organs, the peptide molecules actually reach the cellular elements of the tissue. However, no studies definitively show that peptides reach neurons in the deeper layers of the brain. On the other hand, blood-borne peptides influence the BBB permeability by altering the transport of essential substances. The effect may be mediated by specific peptide binding sites located at the luminal membrane of the endothelium. It is possible that the effect of peptides on the BBB is necessary for proper brain function.(ABSTRACT TRUNCATED AT 250 WORDS)