Effect of N-Allyl Normorphine on Excretion of G-14-Labeled Morphine in Mice

Abstract

The use of X-allyl normorphine in the treatment of respiratory depression resulting from overdosage of morphine or one of its synthetic substitutes (1,2) has been indicated by the many favorable responses which have been obtained both experimentally and clinically. The practical application of this antagonism, however, precedes any reasonable explanation of the mechanism involved in the spectacular recoveries reported in the literature. The experiments reported here indicate that N-Allyl normorphine is capable of producing at least two secondary effects in intact, morphinized animals, in addition to central stimulation. These results were obtained in the course of studies on the excretion of C-14-labeled, biosynthesized (3) morphine, utilizing small amounts of the drug; the quantity of alkaloid was not sufficient to cause central depression of remarkable degree.

Morphine has been shown to produce an antidiuretic response in experimental animals (4); the mouse shares this property of the alkaloid. This finding and other data suggested that a partial explanation of N-Allyl normorphine's action might rest in an increased ability to excrete morphine, free or conjugated, by activation of renal or other mechanisms, thereby decreasing the time that the drug could exert its effects.

Methods. Eight mice weighing 20 g each were injected intraperitoneally with 0.070 mg of C-14-labeled morphine base, each dose equivalent to 2100 counts (the specific activity of the compound isolated from Papaver somniferum was 30000 counts per mg per minute). Four of the animals were then injected intraperitoneally with 500 y of N-allyl normorphine (“Nalline”, Merck). The Straub reaction appeared in each animal approximately 2 minutes after injection of the C-14 morphine.

The urine was collected hourly in glass metabolism cages and suitable aliquots of each sample were plated on copper discs and counted in open window, gas-flow counters; results are expressed as counts recovered per hour.