The role of multidrug resistance-associated protein in the blood–brain barrier and opioid analgesia
Version of Record online: 2 MAY 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 67, Issue 9, pages 609–619, September 2013
How to Cite
Su, W. and Pasternak, G. W. (2013), The role of multidrug resistance-associated protein in the blood–brain barrier and opioid analgesia. Synapse, 67: 609–619. doi: 10.1002/syn.21667
- Issue online: 17 JUL 2013
- Version of Record online: 2 MAY 2013
- Accepted manuscript online: 19 MAR 2013 05:07AM EST
- Manuscript Accepted: 13 MAR 2013
- Manuscript Received: 28 DEC 2012
- National Institute on Drug Abuse of the National Institutes of Health. Grant Numbers: DA06241, DA07242, DA02615, Senior Scientist Award (DA00220)
- National Cancer Institute of the National Institutes of Health. Grant Number: CA08748
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 transporter 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 rats and 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. Synapse 67:609–619, 2013. © 2013 Wiley Periodicals, Inc.