Morphine dependence and diabetes. II. Alterations of normorphine potency in the guinea-pig ileum and mouse vas deferens and of ileal morphine dependence by changes in glucose concentration.

The effects of glucose in vitro at concentrations of 100, 200 and 400 mg/dl on responses of the guinea-pig ileum and mouse vas deferens to opiates were studied. Responses of the electrically stimulated ileum to normorphine were significantly reduced (IC50 values: 26.3 +/- 4.3, 40.5 +/- 3.7 and 71.8 +/- 16.6 nM) as the glucose concentration increased, whereas the potency of normorphine was not affected by equimolar substitutions of glucose with the nonmetabolizable sugar 3-O-methylglucose. The potency of naloxone to induce withdrawal contractions of ilea incubated in Ringer's solution for 3 or 4.5 hr with 1 microM morphine was also significantly decreased as the concentration of glucose in the incubations increased, indicating a reduction of acute dependence development by high glucose. The potency of normorphine was also reduced by increasing concentrations of glucose in electrically stimulated vasa deferentia from nondiabetic (db/m+, m+/m+) C57BL/KsJ mice (IC50 values: 0.53 +/- 0.01, 0.77 +/- 0.01 and 1.84 +/- 0.03 nM), but not in vasa deferentia from their diabetic (db/db) littermates. These results support our hypothesis that the decreased sensitivity to morphine and decreased development of physical dependence on morphine in in vivo models of diabetes reported previously by our laboratory is due primarily to the hyperglycemia associated with diabetes.