DISTRIBUTION AND FATE OF MORPHINE IN NON-TOLERANT AND TOLERANT DOGS AND RATS

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor

The distribution of free and "bound" morphine in dogs and rats is selective for certain tissues and fluids. "Bound" morphine is found in gall bladder bile in concentrations many fold greater than those observed in tissues and other fluids. Spleen, pancreas, thyroid and adrenal contain primarily free morphine, whereas lung, liver and kidney contain both free and "bound" morphine. Brain, cerebrospinal fluid and fat contain very little morphine in any form. Since morphine acts primarily on the central nervous system, and is presumed to be there in some concentration, nervous tissue must be highly sensitive to morphine.

In dog blood equilibrated in vivo, the distribution of free morphine is primarily extracellular, and "bound" morphine almost exclusively extracellular. Slight differences exist in the distribution of free and "bound" morphine between non-tolerant and tolerant animals, particularly if there is a short interval (as ninety minutes) between the administration of drug and sacrifice. Such differences are not of such magnitude that they cannot be explained on the basis of quantitative differences in the vascular responses of tolerant as compared with non-tolerant animals resulting in altered mobilization from the site of administration and differences in the vascular supply to the several tissues.

More than 35 per cent of morphine administered by subcutaneous injection is excreted as the "bound" form in the bile of both non-tolerant and tolerant dogs. Approximately 80 per cent of the subcutaneously administered morphine can be recovered in the urine and gall bladder bile of non-tolerant dogs sacrificed four hours (or twelve hours) after injection. The removal of all bile through a common duct fistula reduces the fecal morphine to such small amounts as to escape detection. Whereas "bound" morphine of intestinal origin (biliary) constitutes only a partial source of urinary morphine during the first 24 hours after subcutaneous injection, probably all of the urinary "bound" morphine excreted after 24 hours originates from this source. Biliary morphine is the principal source of fecal morphine, the total quantity of the latter varying with the rate of passage of intestinal contents, and the fecal bulk. The influence of these factors on the intestinal absorption of biliary morphine is the most logical explanation for the greater quantity of fecal morphine in tolerant dogs.

One "bound" form of morphine in dog urine and bile has been identified to be the phenolic substituted morphine mono-glucuronide. This conjugate is one of the principal metabolites of morphine in this animal species. However, there is present in dog urine a considerable amount of a "bound" morphine with characteristics different from the metabolite noted above, although it is a glucuronide. The suggestion is made that this is a di-conjugated product, a glucuronide of the alcoholic group and ethereal sulfate of the phenolic group of morphine.

It is the conclusion of the author that to date no acceptable evidence has been presented here, or elsewhere, to support the view that altered distribution or fate of morphine is associated with, or responsible for, tolerance development or physical dependence.

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