Background: Opioids are widely used in pain management, acting via opioid receptors and/or Toll-like receptors (TLR) present at the central nervous system (CNS). At the blood-brain barrier (BBB), several influx and efflux transporters, 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), are responsible for the transport of xenobiotics from the brain into the bloodstream or vice versa.

Objective: ABC transporters export several clinically employed opioids, altering their neuropharmacokinetics and CNS effects. In this review, we explore the interactions between opioids and ABC transporters, and decipher the molecular mechanisms by which opioids can modify their expression at the BBB.

Results: P-gp is largely implicated in the brain-to-blood efflux of opioids, namely morphine and oxycodone. Long-term exposure to morphine and oxycodone has proven to up-regulate the expression of ABC transporters, such as P-gp, BCRP and MRPs, at the BBB, which may lead to increased tolerance to the antinociceptive effects of such drugs. Recent studies uncover two mechanisms by which morphine may up-regulate P-gp and BCRP at the BBB: 1) via a glutamate, NMDA-receptor and COX-2 signaling cascade, and 2) via TLR4 activation, subsequent development of neuroinflammation, and activation of NF-kB, presumably via glial cells.

Conclusion: The BBB-opioid interaction can culminate in bilateral consequences, since ABC transporters condition the brain disposition of opioids, while opioids also affect the expression of ABC transporters at the BBB, which may result in increased CNS drug pharmacoresistance.