Modulation of metabolic effects of morphine-6-glucuronide by morphine-3-glucuronide

Abstract

Modification of pharmacological effects of morphine by its glucuronides has been recently reported. Morphine-6-glucuronide (M6G) is a more potent opioid agonist than morphine, whereas morphine-3-glucuronide (M3G) has no opioid effects and has been suggested to be an antagonist of morphine's antinociceptive and respiratory depressive effects. This study addressed the metabolic effects of direct central nervous system administration of M3G and its interaction with the hyperglycemic effects of M6G. Hormonal and whole body glucose metabolic effects of M3G, M6G, and M3G + M6G ICV administration were studied in conscious unrestrained chronically catheterized rats. Whole body glucose kinetics were assessed with a primed constant intravenous infusion of 3[ 3H]glucose in rats injected intracerebroventricularly (ICV) with H 2O (5 μl), M3G (1 μg), M6G (1 μg), or M3G (1 μg) + M6G (1 μg). A significant rise in plasma glucose level was observed after ICV injection of M6G (28%), and M3G + M6G (41 %), but not after M3G as compared to time-matched H 2O control. Early increases in the rate of glucose appearance (Ra) and whole body glucose utilization (Rd) were observed (58% and 48%, respectively) 30 min after M3G + M6G administration, whereas the increases after M6G injection were progressive and reached values 47% higher than basal 180 min after injection. M3G administration enhanced the M6G induced increase in plasma glucose level (+21%), Ra (+29%), Rd (+26%), and plasma lactate level (+21%). Though no significant hormonal change was observed in H 2O, M3G, and M6G injected animals, the combination of M3G + M6G resulted in a significant increase in circulating catecholamine levels with no alterations in plasma corticosterone, insulin, and glucagon. These results indicate that M3G at a dose that does not produce hyperglycemia enhanced the hyperglycemic effects of M6G through accelerated release of catecholamines. These findings suggest that the glucuronidated metabolites of morphine influence each other's biological effects.