Opiate-induced Analgesia Is Increased
and Prolonged in Mice Lacking P-glycoprotein

by
Thompson SJ, Koszdin K, M DV, Bernards CM
Departments of Comparative Medicine and Anesthesiology,
University of Washington,
Seattle, Washington.
Anesthesiology 2000 May; 92(5):1392-1399


ABSTRACT

TBACKGROUND: 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 mdrknockout 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.
Pain
LAAM
Arousal
Morphine
Tramadol
Nociceptin
Methadone
Endomorphins
Novelty and pain
Receptor regulation
Discounting rewards
Fentanyl and ketamine
Opioids, mood and cognition


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