Transport of opioids from the brain to the periphery by P-glycoprotein and multidrug resistance associated protein: Evidence for peripheral actions of centrally-administered agents

The brain can influence the physiology of a wide range of bodily functions through the autonomic and peripheral nervous systems. Hormonal activity of the pituitary provides another mechanism through which the central nervous system can modulate the activity of peripheral organs. Many peptides and transmitters found within the brain also have peripheral sites of actions. The brain microvessel endothelial cells that form the blood brain barrier have an important role in controlling the composition of the extracellular fluid environment of the brain. The blood brain barrier restricts the passive diffusion of many drugs into the brain.; P-glycoprotein (Pgp), a member of the ATP Binding Cassette (ABC) transporter superfamily, is located in the brain capillary endothelial cell membranes and has been thought to function as a component of the blood-brain barrier. While the peripheral nervous system provides important pathways for communication, we have demonstrated that the brain releases functionally active neurotransmitters/neuromodulators directly into the blood through a saturable Pgp transport system. Utilizing antisense technology, Pgp1 expression was decreased and resulted in reduced efflux of the compounds from the brain to the circulation while probes targeting Pgp2 and Pgp3 and mismatch controls were ineffective. The decreased Pgp expression in the brain capillary endothelial cells also significantly enhanced the analgesic potency of morphine given systemically and prevented tolerance with repeated dosing. The analgesic actions of intracerebroventicular administered morphine and other opioids were dependent upon the peripheral activity of the drug pumped from the brain into the periphery by Pgp. Downregulation of Pgp diminished the activity of centrally administered drugs. The mdr1 a knockout mice displayed a similar enhanced activity of system morphine administration and a decreased potency of morphine given centrally.; Multidrug resistance associated protein (MRP), a 190 kDa protein, has long been known to cause intrinsic multidrug resistance. This protein, similar to Pgp, is categorized in the ATP-binding cassette (ABC) superfamily of transporter proteins. Several reports indicate that MRP confers a pattern of drug resistance similar to Pgp. In vitro studies have shown that MRP and Pgp efflux the same anti-tumor agents with different affinities. An antisense oligodeoxynucleotide targeting MRP was utilized to modulate the expression of MRP in the brain. Immunohistochemical and RT-PCR studies demonstrated a dramatic decrease in expression of MRP protein and mRNA, respectively, in the choroid plexus of animals treated with antisense targeting MRP compared to saline and mismatch controls. Following i.c.v. administration of 125I-opiates, blood levels of these compounds decreased from 60% to 80% in antisense treated animals compared to control animals. The decrease in MRP expression in the brain also significantly enhanced the analgesic potency of systemic morphine but conversely, diminished the activity of centrally administered morphine. MRP1 knockout mice displayed similar results.; This study identified two transporters, Pgp and MRP, able to transport endogenous substances from the brain into the blood. Thus, the Pgp and MRP transport systems may provide a general important mechanism of communication between the CNS and the periphery. This may help explain the physiological interactions between the mind and body.