Document Type
Article
Publication Title
Nature Communications
ISSN
2041-1723
Volume
13
DOI
10.1038/s41467-022-31342-z
First Page
1
Last Page
15
Publication Date
6-23-2022
Abstract
Several investigations into the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly assumed to possess limited permeability across the blood-brain barrier. Unfortunately, the poor pharmacokinetic properties of current PAMORAs have resulted in misunderstandings of the role of central nervous system and gastrointestinal tract in precipitating side effects such as opioid-induced constipation. Here, we develop a drug delivery approach for restricting the passage of small molecules across the blood-brain barrier. This allows us to develop naloxone- and oxycodone-based conjugates that display superior potency, peripheral selectivity, pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. These probes allow us to demonstrate that the mu-opioid receptors in the central nervous system have a fundamental role in precipitating opioid-induced constipation. Therefore, our conjugates have immediate use as pharmacological probes and potential therapeutic agents for treating constipation and other opioid-related side effects.
Recommended Citation
Tuhin, M.,
Liang, D.,
Liu, F.,
Aldawod, H.,
Amin, T.,
Ho, J. S.,
Emara, R.,
Patel, A. D.,
Felmlee, M. A.,
Park, M. S.,
Uchizono, J. A.,
&
Alhamadsheh, M. M.
(2022).
Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects.
Nature Communications, 13, 1–15.
DOI: 10.1038/s41467-022-31342-z
https://scholarlycommons.pacific.edu/phs-facarticles/634
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This work is licensed under a Creative Commons Attribution 4.0 International License.
