| This project evaluated the role of altered opioid metabolism and pharmacodynamics in sickle cell transgenic mice as possible mechanisms for the high analgesic dose requirement in sickle cell anemia (SCA).; In vitro studies with hepatic microsomes showed that drug metabolism is altered in sickle cell transgenic mice. The cyp2d22-catalyzed conversion of codeine to morphine and ugt2-catalyzed conversion of morphine to M3G were increased in sickle microsomes, whereas ugt1a1 activity was inhibited.; Bilirubin is the endogenous substrate of ugt1a1, and is suspected to alter enzyme activity at a transcriptional level. Bilirubin levels are higher than normal in SCA, and whether bilirubin was the cause for altered metabolism was tested. Studies revealed that sickle cell transgenic mice had higher plasma bilirubin levels, mimicking the human condition. Liver microsomes from bilirubin-treated mice showed an increased conversion of codeine to morphine, and a decreased glucuronidation of estradiol. However, bilirubin treatment had no effect on the glucuronidation of morphine in vitro. Rats were employed to study the effect of bilirubin on in vivo morphine pharmacokinetics, but these data are preliminary and inconclusive.; The hypothesis that analgesics may show altered pharmacodynamics in SCA was tested in sickle cell transgenic mice. Morphine pharmacokinetics seemed unaltered in sickle mice. However, baseline responses of these mice to various nociception tests were significantly different than controls. Sickle mice were more sensitive to noxious stimuli in the radiant light tail and paw flick tests. They also showed lower latencies in the rotorod stress test. These studies indicated that sickle mice might be more sensitive to certain pain stimuli. The pharmacodynamics of morphine at 3 mg/kg and 10 mg/kg doses were different between sickle and control groups of mice, with sickle mice showing greater antinociception post-dose. These studies, however, were preliminary, and need to be repeated with more animals before appropriate conclusions can be drawn. |
