INVIVO TRANSPORT OF A DYNORPHIN-LIKE ANALGESIC PEPTIDE, E-2078, THROUGH THE BLOOD-BRAIN-BARRIER - AN APPLICATION OF BRAIN MICRODIALYSIS

In vivo transport through the blood-brain barrier (BBB) has been demonstrated for a dynorphin-like analgesic peptide, CH3-[I-125]Tyr-Gly-Gly-Phe-Leu-Arg-CH3Arg-D-Leu-NHC2H5 ([I-125]E-2078). A remarkable time-dependent increase in the distribution volume of [I-125]E-2078 in the brain parenchyma separated from blood vessels and capillaries was observed during a brain perfusion. The distribution volume of [I-125]E-2078 in the brain parenchyma after 20 min of perfusion was 2.18 +/- 0.09-mu-l/g brain (mean +/- SE) and was significantly greater than the distribution volume of [H-3]inulin (0.994 +/- 0.138-mu-l/g brain), providing in vivo evidence for the penetration of [I-125]E-2078 into the brain parenchyma. Brain microdialysis was carried out to collect directly the brain interstitial fluid (ISF) during the brain perfusion of [I-125]E-2078. No metabolite of [I-125]E-2078 in the brain ISF was found by high-performance liquid chromatographic analysis of the brain dialysate. The concentrations of [I-125]E-2078 and [C-14]sucrose in the brain ISF were estimated based on an in vitro evaluation of dialysis clearance. The concentration ratio of [I-125]E-2078 between the brain ISF and the brain perfusate was determined to be 2.92 x 10(-1) +/- 0.50 x 10(-1) and was approximately 100 times higher than that of [C-14]sucrose (2.71 x 10(-3) +/- 1.43 x 10(-3)), demonstrating transport of [I-125]E-2078 through the BBB in vivo. On the other hand, no remarkable difference in the cerebrospinal fluid (CSF)-to-perfusate concentration ratios of [I-125]E-2078 and [C-14]sucrose was observed, indicating little contribution of the blood-CSF barrier (BCSF barrier) transport to the penetration of [I-125]E-2078 into the brain.