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

Abstract

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.

Keywords: ABC transporters; Blood-brain barrier; P-glycoprotein; TLR4; neuroinflammation; opioids.

Fig. (1)

Hypothetical regulation of P-gp and Bcrp expressions at the BBB following subchronic exposure to morphine, and presumably implicated signaling pathways. a) Implicated factors of signaling cascades activated during morphine-induced neuroinflammation or morphine withdrawal-provoked glutamate overshoot. b) Schematic representation of the implicated signaling pathways and BBB cellular environment that conduct to the regulation of P-gp and Bcrp expressions at the BBB following a subchronic exposure to morphine. Brain inflammation occurs in several conditions such as stroke, multiple sclerosis, Alzheimer’s and Parkinson’s diseases, and during morphine chronic exposure [17, 158]. Morphine activates TLR4 receptors with subsequent release of pro-inflammatory cytokines [17], such as TNF-α, which influences P-gp and Bcrp expressions at the BBB via a signaling pathway involving TNF-α receptor 1 (TNF-R1), endothelin-converting enzyme (ECE), endothelin-1 (ET-1), endothelin A and B receptors (ETA/B), nitric oxide synthase (NOS), protein kinase C (PKC), and nuclear factor-κB (NF-κB), as previously described [37, 158, 184]. During either morphine withdrawal or in the epileptic brain, high glutamate levels are found in the brain extracellular fluid [170-172, 194], which induce overexpression of P-gp and Bcrp at the BBB in endothelial cells by an NMDA receptor and COX-2-dependent mechanism [162, 174, 175, 179, 195].