Current Neuropharmacology

T.E. Salt
University College London
Institute of Ophthalmology
London EC1V 9EL


Opioids and the Blood-Brain Barrier: A Dynamic Interaction with Consequences on Drug Disposition in Brain

(E-pub Ahead of Print)

Author(s): Catarina Chaves, Fernando Remião, Salvatore Cisternino, Xavier Declèves.


Opioids are widely used in pain management whose effects are due to binding to classical opioid receptors and/or Toll-like receptors (TLR) present at the central nervous system (CNS). At the blood-brain barrier (BBB), several influx and/or efflux transporters are expressed, such as the ATP-binding cassette (ABC) P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRP, ABCC) transporters, and solute carrier transporters (SLC), and are responsible for the transport of many xenobiotics from the brain into the bloodstream or vice versa. ABC transporters participate in the export of several clinically employed opioids, altering their neuropharmacokinetics and their CNS effects. Opioids have also proven to be able to alter the expression of ABC transporters, and to promote inflammation by TLR-dependent pathway in glial cells. Given that P-gp, BCRP and MRPs can be up-regulated at the BBB in both morphine and oxycodone tolerant rats, chronic exposure to these opioids may contribute to the development of tolerance to the antinociceptive effects of these drugs. Even though the mechanisms are still not fully understood, recent studies uncover two of the mechanisms by which morphine may up-regulate the expression of P-gp and BCRP at the BBB: a first one involves glutamate release, NMDA-receptor and COX-2 activation, while the second occurs through TLR4 activation and subsequent development of neuroinflammation and activation of NF-κB. The aim of this review is to summarize interactions of opioids mainly with ABC transporters deciphering molecular mechanisms by which opioids can modify their expression at the BBB.

Keywords: Blood-brain barrier, Opioids, ABC transporters, P-glycoprotein, neuroinflammation, TLR4

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Article Details

Year: 2017
(E-pub Ahead of Print)
DOI: 10.2174/1570159X15666170504095823
Price: $95