Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein

Anesthesiology. 2000 May;92(5):1392-9. doi: 10.1097/00000542-200005000-00030.


Background: P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids.

Methods: Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined.

Results: Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice.

Conclusions: These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Analgesia*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Area Under Curve
  • Brain / drug effects*
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Fentanyl / pharmacology
  • Injections, Subcutaneous
  • Male
  • Meperidine / pharmacology
  • Mice
  • Mice, Knockout
  • Morphine / metabolism
  • Morphine / pharmacology


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