Doctor of Philosophy
Pharmacology & Toxicology
William L. Dewey
Diabetes mellitus affects millions of people. Although diabetics can lead relatively normal lives, all treatments for the disease are symptomatic and not curative. The purpose of this investigation was to determine whether the sensitivity to opiates and other selected centrally-acting drugs in animals is altered by streptozotocin (STZ)-induced diabetes. A second objective was to determine which aspect of the diabetic syndrome primarily was responsible for the altered sensitivity. Other experiments were performed in an attempt to elucidate the mechanism whereby this altered sensitivity occurred.
STZ-induced diabetes or dextrose-induced transient hyperglycemia did not have a significant effect on the duration of hexobarbital-induced anesthesia. Similarly, following 5 days treatment with phenobarbital, the duration of hexobarbital-induced anesthesia was reduced equally in both control and STZ-induced diabetic mice. STZ-induced diabetes did not alter the acute oral LD50 of nicotine.
The antinociceptive potency of morphine as determined by the tail-flick test was significantly decreased (p < 0.05) in STZ-induced diabetic mice and mice pretreated with equimolar doses of hypertonic dextrose or fructose. STZ-induced diabetic rats and spontaneously diabetic mice were also significantly less sensitive to the antinociceptive effects of morphine as quantitated by the tail-flick test. The ability of morphine to inhibit phenquuinone-induced writhing was attenuated in STZ-induced diabetic mice. Hypoglycemic mice were significantly more sensitive to morphine in the tail-flick test. Insulin reversal of dextrose-induced and STZ-induced diabetic hyperglycemia returned sensitivity to morphine-induced antinociception in the tail-flick test to control values. Pretreatment with the non-metabolizable sugar 3-0-methylglucose at a dose equimolar to the doses of dextrose and fructose had no effect on morphine potency. The antinociceptive potencies of phenazocine and levorphanol were altered similarly to that of morphine, but the potencies of methadone, propoxyphene and meperidine were not altered by changes in blood glucose levels.
The LD50 of morphine but not methadone was significantly decreased in STZ-induced diabetic mice. These results confirm the selectivity of the STZ-induced diabetes to alter the sensitivity of morphine and not methadone, and are provocative since they show that the lethal effect of morphine is altered in the opposite direction from the antinociceptive potency.
Levels of morphine in the brains of STZ-induced diabetic and insulin-treated STZ-induced diabetic mice were not significantly different from control mice. The durations of action of morphine in STZ-induced diabetic and control mice were similar, although the level of antinociception in the diabetic mice was lower at all time points.
STZ-induced diabetes in mice did not alter serum osmolarity and brain water content. Mice receiving various pretreatments (STZ-induced diabetes, STZ-induced diabetes plus insulin, dextrose, fasting or fasting plus insulin) were subjected to analyses of their serum glucose levels, serum insulin levels, and brain glucose levels. From these data only blood glucose levels correlated (inversely) with the antinociceptive potency of morphine.
The results of these experiments led to the hypothesis that the hyperglycemia was the aspect of diabetes principally responsible for selectively affecting the potency of certain opiate-like pharmacologic agents.
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