Cross tolerance between morphine and methionine-enkephalin

Abstract

TOLERANCE and dependence are characteristic symptoms in man during prolonged use of opiates. We have pointed out¹ that for an understanding of these phenomena the interaction between endogenous enkephalin and exogenous opiates is of importance. Normally, enkephalin can be assumed to control inhibitory mechanisms determining the rate of neurotransmitter release. If, however, opiates are administered with the intent of increasing the effects of these inhibitory mechanisms, then control will pass from the endogenous enkephalin to the exogenous opiates. Since tachyphylaxis is a pharmacological characteristic of opiates, a state of tolerance will arise in which increasing amounts of opiates will be required to maintain the desired effect. As an important step in the elucidation of the mechanism of action of enkephalin, it was necessary to establish whether cross tolerance between enkephalin and opiates is found in morphine-tolerant animals. This point was tested in two morphine-sensitive models, the myenteric plexus-longitudinal muscle preparation from the guinea pig ileum^2,3 and the mouse vas deferens⁴. As natural enkephalin consists of about 75% methionine–enkephalin and 25% leucine–enkephalin⁵, the relative potencies of synthetic methionine–enkephalin and morphine were compared in preparations obtained from animals with different degrees of tolerance. Cross tolerance between morphine and methionine–enkephalin was shown to occur in the two preparations obtained from animals implanted with morphine pellets.