P-glycoprotein ATPase activating effect of opioid analgesics and their P-glycoprotein-dependent antinociception in mice

Pharmacol Biochem Behav. 2006 Nov;85(3):629-36. doi: 10.1016/j.pbb.2006.10.018. Epub 2006 Nov 28.


It is well known that opioid analgesics exert central antinociceptive actions. However, in vivo and in vitro studies have shown that some opioid analgesics given systemically have limited access to the central nervous system because of the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-dependent drug efflux transporter, is one component of the BBB. In this report, we assessed the antinociceptive effect of morphine, fentanyl, and meperidine in P-gp deficient (mdr1a KO) mice, and compared these effects with those in wild type (WT) mice. The antinociceptive effects of morphine and fentanyl in mdr1a KO mice were significantly greater than those in WT mice. However, there was no clear difference in the antinociceptive effects of meperidine in the two genotypes. In addition, we determined the effect of opioid analgesics on P-gp ATPase activity, which is requisite for drug transport, using mouse brain capillary endothelial cells. In our observations, morphine and fentanyl, but not meperidine, significantly increased P-gp ATPase activity, and the drugs' concentration-response curves were bell-shaped, reaching a peak at a concentration of 1 muM. These results suggest that P-gp ATPase activity may be, at least in part, involved in the antinociceptive potencies of those opioid analgesics that are substrates for P-gp.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adenosine Triphosphatases / metabolism*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Blood-Brain Barrier
  • Brain / metabolism
  • Enzyme Activation
  • Fentanyl / pharmacology
  • Male
  • Meperidine / pharmacology
  • Mice
  • Mice, Inbred ICR
  • Morphine / pharmacokinetics
  • Morphine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Analgesics, Opioid
  • Morphine
  • Meperidine
  • Adenosine Triphosphatases
  • Fentanyl