Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity

Abstract

Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB. We will also examine how expression and trafficking of ABC transporters can be modified by pain and/or opioid pharmacotherapy, a novel mechanism that can promote opioid-associated adverse drug events and development of addiction and tolerance.

Effects of Drugs of Abuse on the Blood-Brain Barrier: A Brief Overview

“…Opioids are widely-used analgesics that bind with opioid and/or toll-like receptors (TLR) in the CNS ( Chaves et al, 2017 ; Yang et al, 2018 ). Transcellular solute and xenobiotic transport across the BBB is selectively controlled by the local influx and efflux transporters, including ATP-binding cassette (ABC), P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (ABCG2), multidrug resistance-associated proteins (ABCC) transporters, and solute carrier transporters ( Abbott et al, 2010 ; Chaves et al, 2017 ).…”

Potential Pharmacokinetic Drug‐Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain

“…These authors suggested pharmacodynamic interactions between opioids and cannabinoids. However, as opioid delivery to the brain is influenced by ATP-binding cassette transporters [ 49 – 51 ], a pharmacokinetic interaction should not be neglected.…”

“…Neither codeine nor tramadol is Pgp substrates [ 51 , 57 ]. The polymorphic CYP2D6 regulates the O-demethylation of codeine and tramadol to more potent metabolites: morphine and O-desmethyl-tramadol, respectively.…”

Blood–brain barrier: mechanisms governing permeability and interaction with peripherally acting μ-opioid receptor antagonists

“…43 Morphine is able to diffuse through the EC membrane, and it also reaches the brain via active transport; however, it is subject to efflux via MRP and P-gp. [44][45][46][47][48][49] In contrast, codeine is not a substrate for MRP or P-gp and easily diffuses across the BBB. [48][49][50] Table 1 presents a summary of the permeability profiles for morphine, codeine and other currently marketed opioid receptor agonists and antagonists.…”

“… 44–49 In contrast, codeine is not a substrate for MRP or P-gp and easily diffuses across the BBB. 48–50 Table 1 presents a summary of the permeability profiles for morphine, codeine and other currently marketed opioid receptor agonists and antagonists.…”