Premium
The Role of Blood Brain Barrier Transport in the Enhanced Analgesia of Glycopeptide Opioids
Author(s) -
Egleton Richard Daniel,
Hawkins Brian T,
Bilsky Edward J,
Yeomans Larissa,
Dhanasekaran Muthu,
Polt Robin L
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a240-a
Subject(s) - glycopeptide , chemistry , blood–brain barrier , pharmacology , analgesic , opioid , penetration (warfare) , glycosylation , perfusion , peptide , opioid peptide , permeability (electromagnetism) , pharmacokinetics , in vivo , membrane , biochemistry , medicine , receptor , central nervous system , biology , antibiotics , microbiology and biotechnology , operations research , engineering
The blood brain barrier (BBB) limits the delivery of peptides to the CNS. Several methods have been developed to improve the distribution of peptides to the brain, including glycosylation. Previously we have reported that glycosylation improves the analgesic profiles of several different opioid peptides compared to their non‐glycosylated parents. In this study we investigate the role that BBB penetration plays in the analgesic profile of a family of glycosylated opioid peptides based on Leu‐enkephalin (Tyr‐DThr‐Gly‐Phe‐Leu‐Ser), with the sugar moiety attached to the Ser6. The i.c.v. and i.v. A50 values were calculated from dose‐response curves in a 55°C tail‐flick assay for each glycopeptide. Mouse in situ perfusion studies were used to measure BBB penetration of I125 glycopeptides. When administered i.v. all glycopeptides had improved analgesic profiles compared to the parent. In situ perfusion studies showed that the BBB permeability of the peptides correlated with their i.v. analgesic profile. Preliminary studies indicate that the improved penetration is due to an increased affinity to a saturable mechanism rather than a change in passive membrane permeability. These studies show that the improved BBB transport plays a significant role in the enhanced analgesia seen with glycopeptides. The improved BBB transport is due in part to a saturable transport mechanism rather than an increased passive permeability. Supported by ONR (N00014‐02‐1‐0471).