title: Negative relationship between morphine analgesia and P-glycoprotein expression levels in the brain.
abstract: It is known that opioid analgesics given systemically have limited distribution into the brain because of their interaction with P-glycoprotein (P-gp), an ATP-dependent efflux pump acting at the blood-brain barrier (BBB). We previously found that morphine and fentanyl showed higher analgesic potencies in P-gp-deficient mice compared with those in wild-type mice, suggesting that their analgesic effects are considerably dependent on P-gp expression. In this study, we focused on individual differences in the analgesic effectiveness of morphine, in cortical P-gp expression, and in basal P-gp ATPase activity in male ICR mice. We found that there were 3- to 10-fold differences between the magnitude of morphine analgesia (3 mg/kg, s.c.; tail-pinch method) in mice. Furthermore, there was a significant negative correlation between morphine's analgesic effects and individual P-gp expression in the cortex as estimated by western blot analysis. In addition, basal P-gp ATPase activities in isolated membrane preparations of brain capillary endothelial cells (BCECs) were negatively correlated with the magnitude of the analgesic effect of morphine. These results indicate that the individual differences in morphine analgesia may be due to some functional or quantitative differences in individual P-gp in BCECs, acting at the BBB.
authors: Department of Pharmacology, Wakayama Medical University, Kimiidera, Wakayama, Japan.
authors: Wakako
authors: W
authors: Hamabe
authors: Takehiko
authors: T
authors: Maeda
authors: Norikazu
authors: N
authors: Kiguchi
authors: Chizuko
authors: C
authors: Yamamoto
authors: Shogo
authors: S
authors: Tokuyama
authors: Shiroh
authors: S
authors: Kishioka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000199:Actins; D000701:Analgesics, Opioid; D009020:Morphine; D000251:Adenosine Triphosphatases