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Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs


Many peptides and transmitters found within the brain also have peripheral sites of action. We now demonstrate that the brain releases functionally active neurotransmitters/neuromodulators directly from the brain into the blood through a saturable P-glycoprotein (Pgp) transport system. Downregulating Pgp1 expression with antisense reduced the brain-to-blood transport of morphine, β-endorphin and other opioids. Lowering Pgp expression significantly enhanced systemic morphine analgesia and prevented tolerance, but diminished the analgesic activity of centrally administered morphine, implying that supraspinal analgesia resulted from a combination of central and peripheral mechanisms activated by morphine transported from the brain to the blood. Similarly, mice with a disruption of the Mdr1a gene were more sensitive to systemic morphine and less sensitive to morphine given centrally. This ability of the Pgp transport system to pump functionally active compounds from the brain to periphery defines a potentially important mechanism for the central nervous system to modulate peripheral systems.

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Figure 1: Efflux of radiolabeled compounds from the brain.
Figure 2: Competition of the efflux of the radiolabeled compounds from the brain.
Figure 3: Identification of Pgp in rat brain.
Figure 4: Downregulation of peptide secretion from the brain by Pgp antisense treatment and verapamil.
Figure 5: Effect of Pgp antisense on systemic and central morphine analgesia and tolerance.
Figure 6: Morphine analgesia in an Mdr1a−/− mouse.


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This work was supported, in part, by research grants (DA02615 and DA07242) and a Senior Scientist Award (DA00220) to G. W. P. and a training grant (T32DA07274) to M. K. and W. S. from the National Institute on Drug Abuse, and a core grant from the National Cancer Institute (CA08748) to M.S.K.C.C.

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Correspondence to Gavril W. Pasternak.

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King, M., Su, W., Chang, A. et al. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci 4, 268–274 (2001).

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