EXCRETION OF COMBINED MORPHINE IN THE TOLERANT ANDNON-TOLERANT DOG

That there may be some differences in the handling of morphine by the tolerant and non-tolerant animals which might explain tolerance has long been intimated. Recently Gross and Thompson (1) have demonstrated the presence of a combined form of morphine in the urine of dogs after morphine administration and found further that there are distinct differences in amounts of this “combined ” morphine in the tolerant and non-tolerant animals, the non-tolerant dog excreting approximately twice as much of the combined form as the tolerant dog. It has been previously established by Pierce and Plant (2) that there is no marked difference in the excretion of free morphine, since both the tolerant and non-tolerant dog excrete approximately 10 to 20 per cent of a given dose as free morphine. Oberst (3) has established the presence of “bound ” morphine in the urine of human addicts. By his method the amount of “bound ” morphine was three to thirty-six times the quantity of free morphine. The fact that the non-tolerant dog excretes a much larger proportion of a given dose of morphine in a combined form as compared to the amount ex-creted by the tolerant dog indicates at least a partial difference in the handling of morphine as tolerance is established, but this difference is insufficient to explain the question of tolerance. It was therefore thought important to study further the properties of this combined fraction. While these studies do not shed any more light on the question of tolerance, we have established a further difference in the metabolism of morphine in the tolerant and non-tolerant dog. METHODS Both tolerant and non-tolerant dogs were employed. The tolerant animals were on a constant 20 mgm./kgm./day morphine sulfate dosage for two to three years, while the non-tolerant dogs were given the same dosage for not over two days. Diet and water intake were controlled before and during the experimental periods. For greater detail concerning care and handling of the animals see Plant and Pierce (4). The method of analysis has been described by Gross and Thompson (1)