The role of multidrug resistance-associated protein in the blood-brain barrier and opioid analgesia

Abstract

The blood brain barrier protects the brain from circulating compounds and drugs. The ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) is involved with the barrier, both preventing the influx of agent from the blood into the brain and facilitating the efflux of compounds from the brain into the blood, raising the possibility of a similar role for other transporters. Multidrug resistance associated protein (MRP), a 190 kDa protein similar to Pgp is also ABC transport that has been implicated in the blood brain barrier. The current study explores its role in opioid action. Immunohistochemically, it is localized in the choroid plexus in ratsand can be selectively downregulated by antisense treatment at both the level of mRNA, as shown by RT-PCR, and protein, as demonstrated immunohistochemically. Behaviorally, downregulation of MRP significantly enhances the analgesic potency of systemic morphine in MRP knockout mice and in antisense-treated rats by lowering the blood brain barrier. Following intracerebroventricular administration, a number of compounds, including some opioids, are rapidly secreted from the brain into the blood where they contribute to the overall analgesic effects by activating peripheral systems. MRP plays a role in this efflux. Downregulating MRP expression leads to a corresponding decrease in the transport and a diminished analgesic response from opioids administered intracerebroventricularly. Thus, the transporter protein MRP plays a role in maintaining the blood-brain barrier and modulates the activity of opioids.

Mu Opioids and Their Receptors: Evolution of a Concept

“…This was confirmed with studies showing that removing Pgp in a knockout model or downregulating it through antisense approaches prevents the development of morphine tolerance (Lötsch et al, 2000;Zong and Pollack, 2000;King et al, 2001a). Similar findings have been reported with a second ATP transporter, multidrug-resistant protein (Su and Pasternak, 2013).…”

“…These findings were replicated, showing no difference in the spinal and supraspinal morphine ED 50 values despite over a 2-fold shift in the systemic ED 50 value (Kolesnikov et al, 1996b). The later study went one step further and shows a dramatic 19-fold shift in the analgesic activity of peripheral morphine in these same animals, raising the possibility of an important peripheral component of morphine analgesia and tolerance (King et al, 2001a;Su and Pasternak, 2013).…”

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

“…MRP1 also plays a part in the efficacy (and toxicity) of drugs used to treat nonmalignant diseases and transports various antibiotics, opiates, antiviral agents, citalopram, and statins (4,(13)(14)(15). Knock-out Abcc1 Ϫ/Ϫ mouse studies have established that MRP1/Mrp1 can be an important determinant of drug disposition because of its presence in cells at the interface between many tissues and the systemic circulation (i.e.…”

Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs

“…A number of cellular factors have been implicated, including desensitization and trafficking (19)(20)(21). Even dispositional factors influence tolerance (22)(23)(24)(25)(26). Chronic morphine up-regulates the expression of P-glycoprotein and multidrug resistant-associated protein, which are ATP transporters involved in maintaining the blood-brain barrier that impedes morphine entry into the brain.…”