| First Author | Thompson SJ | Year | 2000 |
| Journal | Anesthesiology | Volume | 92 |
| Issue | 5 | Pages | 1392-9 |
| PubMed ID | 10781286 | Mgi Jnum | J:62348 |
| Mgi Id | MGI:1858787 | Doi | 10.1097/00000542-200005000-00030 |
| Citation | Thompson SJ, et al. (2000) Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92(5):1392-9 |
| abstractText | 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 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. |
