Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue

Abstract

To avoid the confounding effect of metabolic degradation, the stable mu-opioid peptide agonist [D-Arg2,Lys4]-dermorphin analogue (DALDA) was used to quantitate blood-brain barrier (BBB) permeability by intravenous injection and internal carotid artery perfusion techniques. With intravenous injection, the BBB permeability-surface area products for [3H]DALDA (0.84 +/- 0.13 microliters.min-1.g-1) and [14C]sucrose (0.39 +/- 0.05 microliters.min-1.g-1) correlated with the lipid solubility of the two molecules: the 1-octanol-Ringer partition coefficient for DALDA was approximately 2 log orders greater than that for sucrose. The brain delivery of [3H]DALDA at 30 min after intravenous administration was 0.019 +/- 0.002% of the injected dose per gram, and analgesia was induced with a 5-mg/kg dose administered systemically. In contrast to the result after intravenous injection, the BBB permeability-surface area product for DALDA estimated with the internal carotid artery perfusion technique was manyfold greater. This was due to nonspecific absorption of the peptide into the cerebral microvasculature, which precluded use of the capillary depletion technique to study transcytosis through the BBB after internal carotid artery perfusion. The present studies show that the brain delivery of a metabolically stable peptide, such as DALDA, is comparable to that for sucrose, correlates with lipid solubility, and is mediated by a nonsaturable mechanism, probably free diffusion.

Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo.

“…high and approximated that for sucrose, 10.8 ± 0.4 ml/ (min-kg) (22), suggesting the bio-PNA was removed principally by glomerular filtration and renal clearance. This was confirmed in two ways.…”

Anti-inflammatory properties of the μ opioid receptor support its use in the treatment of colon inflammation

“…However, since MOR is also expressed on various cells in peripheral tissues (11,(78)(79)(80), it may be speculated that there is a modulation of inflammation by peripheral MOR. In our study, the two selective MOR agonists, DALDA and DAMGO, and the MOR antagonist NM were selected for their inability to cross the blood-brain barrier (52)(53)(54). We therefore conclude that the protective effects of MOR during colon inflammation are probably mediated by peripheral and not central mechanisms.…”

“…Animals were sacrificed 2 days or 4 days after TNBS administration (41). The antiinflammatory effects of MOR agonists in Balb/c mice were evaluated by administration of different dosages of DALDA (10 -3 to 1 mg/kg/d) and DAMGO (10 -3 to 0.5 mg/kg/d), which selectively activate peripheral MOR and lack the ability to cross the blood-brain barrier ( Figure 1) (52,53). These compounds were administered once daily by subcutaneous injection, starting either 4 days before (preventive mode) or 30 minutes after (treatment mode) colitis induction.…”

Novel 2′,6′-Dimethyl-l-Tyrosine-Containing Pyrazinone Opioid Mimetic μ-Agonists with Potent Antinociceptive Activity in Mice

“…Although 1 was 65 to 71 times more potent than morphine after i.c.v. administration, it did not show the same degree of antinociception after peripheral injection, which may be explained by diverse factors, such as lipophilicity, molecular weight, metabolic and protease stabilities, and transport mechanisms, which might limit transit of 1 through membrane barriers (Banks and Kastin, 1990;Smith et al, 1992;Ermisch et al, 1993;Samii et al, 1994).…”