P-glycoprotein, a transmembrane protein, was first identified in tumor cells, but is also present at the luminal borders of other normal tissues, including intestinal and bronchial epithelium, and renal tubules, where it acts to either secrete xenobiotics or to prevent their absorption. P-glycoprotein has also been identified in mouse, rat, bovine, and human brain capillary endothelium, and believed to be a vital component of the blood–brain barrier.
The team of Thompson et al. used P-glycoprotein knockout mice and wild-type mice to determine whether P-glycoprotein limits opioid-induced analgesia in vivo . After baseline assessment of thermal analgesia using the animals’ response to the standard hotplate test, each mouse received subcutaneous injections of morphine, morphine-6-glucuronide (M-6-G), methadone, fentanyl, and meperidine. Morphine was studied at doses of 1, 5, 10, and 20 mg/kg in the wild-type mice and 1, 3, and 5 mg/kg in the knockout mice; M-6-G at doses of 1, 3, and 5 mg/kg in both groups of animals; methadone at 5 mg/kg; fentanyl at 50 μg/kg; and meperidine at 50 mg/kg. Hot plate tests were repeated and each animal’s latency to hind paw licking behavior was recorded. The effect of cyclosporine (100 mg/kg), a P-glycoprotein inhibitor, on morphine analgesia in both types of mice was also assessed in separate experiments.
Morphine induced greater analgesia in knockout mice than in wild-type mice; morphine brain concentrations were also greater in knockout mice. The authors also verified greater analgesia in knockout mice with methadone and fentanyl, but not with meperidine or M-6-G. Pretreatment with cyclosporine significantly increased analgesia in wild-type mice but had no effect in knockout mice. Results suggest that, at least in mice, P-glycoprotein limits morphine entry into the brain.