EFFECTS OF HYDERGINE (CCK # 179) ON THE MODIFICATION OF TOLERANCE TO MORPHINE AND l-ISOMETHADONE HYPERGLYCEMIA IN RABBITS

¹ Departments of Pharmacology, University of Oregon Medical School and University of Oregon Dental School, Portland, Oregon

1. The initial injection of morphine sulfate (15 mgm./kgm.) and l-isomethadone hydrochloride (5 mgm./kgm.) produced a measurable hyperglycemia in rabbits.

2. When morphine and l-isomethadone hydrochloride were administered daily to rabbits over a prolonged period in increasing doses, or at the same dose level for a few successive weeks, the initial hyperglycemic response diminished or disappeared indicating developing or established tolerance.

3. When such drugs were injected in doses higher than those to which tolerance was established, hyperglycemia was again produced, indicating that the mechanism producing adrenergic hyperglycemia was still responsive to the increased stress.

4. Hydergine (0.1 mgm./kgm.) administered daily to rabbits produced insignificant variations in their blood glucose levels similar to those found after application of a non-specific stress such as injection of normal saline or handling of the animals.

5. Variations in the fasting blood glucose values from week to week or during withdrawal were more marked or minimal dependent upon the more gradual or rapid increments of the dose levels of the analgesics used. The dose of l-isomethadone could not be increased rapidly or beyond 7 mgm./kgm. due to its respiratory depressive and convulsive effects.

6. Daily administration of Hydergine previous to morphine or l-isomethadone injection blocked the rise of blood glucose resulting from injection of these analgesics in the early stage.

7. Hydergine seemed to delay the onset of development of hyperglycemic tolerance to l-isomethadone; however, it failed to abolish the development of hyperglycemic tolerance to both morphine and l-isomethadone.