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 neuro-pharmacokinetics and CNS effects. In this review, we explore the interactions between opioidsand 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 ex-posure 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 uncov-er 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 neuro-inflammation, and activation of NF-κB, 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.

Subchronic morphine treatment induces P‐glycoprotein (P‐gp) up‐regulation at the blood–brain barrier. This study investigates the rate and extent to which P‐gp and breast cancer‐resistance protein (Bcrp) increase at the rat blood–brain barrier following subchronic morphine treatment. Rats were given increasing doses of morphine (10–40 mg/kg) or saline i.p. twice daily for 5 days. The brain cortex large vessels and microvessels were then mechanical isolated 6, 9, 12, 24, and 36 h after the last injection. The gene and protein expression of P‐gp and Bcrp in morphine‐treated and control rats were compared by qRT‐PCR and western blotting. The levels of Mdr1a and Bcrp mRNAs were not significantly modified 6 h post morphine, but the Mdr1a mRNA increased 1.4‐fold and Bcrp mRNA 2.4‐fold at 24 h. P‐gp and Bcrp protein expression in brain microvessels was unchanged 6 h post morphine and increased 1.5‐fold at 24 h. This effect was more pronounced in large vessels than in microvessels. However, extracellular morphine concentrations of 0.01–10 μM did not modify the expressions of the MDR1 and BCRP genes in hCMEC/D3 human endothelial brain cells in vitro. MK‐801 (NMDA antagonist) and meloxicam (cyclo‐oxygenase‐2 inhibitor) given after morphine treatment completely blocked P‐gp and Bcrp up‐regulation. Interestingly, misoprostol and iloprost, two well‐known agonists of prostaglandin E2 receptors induced both MDR1 and BCRP mRNA levels in hCMEC/D3. Thus, morphine does not directly stimulate P‐gp and Bcrp expression by the brain endothelium, but glutamate released during morphine withdrawal may do so by activating the NMDA/cyclo‐oxygenase‐2 cascade.