Opiate binding and effect in ileum preparations from normal and morphine pretreated guinea-pigs.

1 Dose-response curves for normorphine in the absence and presence of naloxone have been obtained from myenteric plexus-longitudinal muscle strip preparations from normal and morphine pretreated guinea-pigs. In addition, the high affinity stereospecific binding of [3H]-etorphine has been measured in homogenates of the same tissue. 2 Higher concentrations of normorphine were required to produce 50% inhibition of the electrically stimulated contractions of strip preparations from morphine pretreated animals. There was also an increase in the slope of linearized dose-response curves in opiate-tolerant preparations. Maximum opiate effect was unchanged, and responses to exogenous acetylcholine were not affected by the pretreatment. 3 There was a slight increase in the apparent equilibrium constant for naloxone after morphine pretreatment. 4 Tolerance to opiate effect was not accompanied by a change in the affinity or number of stereospecific binding sites for [3H]-etorphine. Hill plots of [3H]-etorphine binding in both control and morphine pretreated preparations gave slopes close to unity. 5 Most of these results can be explained by the assumption that in tolerant preparations, a certain fractional opiate receptor occupation threshold must be exceeded before opiate effects become apparent. It is suggested that the tissue adapts toward a threshold equivalent to the mean receptor occupancy attained during the period of opiate drug pretreatment.