title: Saturable brain-to-blood transport of endomorphins.
abstract: Opiate-modulating tetrapeptides such as tyrosine-melanocyte-stimulating hormone-release inhibiting factor-1 (Tyr-MIF-1; Tyr-Pro-Leu-Gly-NH2) and Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) are saturably transported from brain to blood. We examined whether two recently described endogenous opiate tetrapeptides with similar structures, the mu-specific endomorphins, also are transported across the blood-brain barrier (BBB). We found that the efflux rates of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) were each self-inhibited by an excess of the respective endomorphin, thereby defining saturable transport. Cross-inhibition of the transport of each endomorphin by the other indicated shared transport. By contrast, no inhibition of the efflux of either endomorphin resulted from coadministration of Tyr-MIF-1, indicating that peptide transport system-1 (PTS-1) was not involved. Tyr-W-MIF-1, which is partially transported by PTS-1, significantly (P<0.01) decreased the transport of endomorphin-1 and tended (P=0.051) to decrease the transport of endomorphin-2, consistent with its role as both an opiate and antiopiate. Although involved in modulation of pain, coinjection of calcitonin gene-related peptide or constriction of the sciatic nerve did not appear to inhibit endomorphin efflux. Thus, the results demonstrate the existence of a new efflux system across the BBB which saturably transports endomorphins from brain to blood.
authors.affiliation: VA Medical Center and Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kastin
authors.forename: M B
authors.initials: MB
authors.lastname: Fasold
authors.forename: R R
authors.initials: RR
authors.lastname: Smith
authors.forename: K A
authors.initials: KA
authors.lastname: Horner
authors.forename: J E
authors.initials: JE
authors.lastname: Zadina
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008026:Ligation; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000378:metabolism* / Q000493:pharmacokinetics; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology / Q000601:surgery
chemical_list: D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D026901:Membrane Transport Proteins; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C077532:tyrosyl-prolyl-tryptophyl-glycinamide; C105294:endomorphin 2; C036930:tyrosyl-prolyl-leucyl-glycinamide; D009075:MSH Release-Inhibiting Hormone; C043912:peptide permease; D015740:Calcitonin Gene-Related Peptide