Magnitude of initial effect influences development of tolerance to morphine in rats responding under a fixed-ratio schedule of food presentation

Abstract

This experiment examined whether development of tolerance to the rate-decreasing effects of morphine can be modulated by the magnitude of the initial effect of morphine. Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food delivery in daily 30 min sessions. Subjects were assigned to two groups, which did not differ in initial sensitivity to morphine, and given daily injections of morphine under dosing schedules chosen to have different initial effects. Group 1 received daily pre-session injections of 10 mg/kg morphine, which initially suppressed lever pressing completely, and post-session injections of saline. Group 2 received morphine in two injections, one pre-session and one post-session. The initial daily doses 10 mg/kg pre- and 9 mg/kg post-session) decreased rates by 30% or less. The proportion of the 10 mg/kg dose administered pre-session was increased gradually over 10 weeks. Group 2 developed greater tolerance than did group 1, as assessed by changes in the dose of morphine required to suppress response rates by > 50%. After 3 months of repeated treatment, the ED(50) of morphine increased 2.5-fold in group 2, but only 1.4-fold in group 1. When the daily dose of morphine was raised to 20 mg/kg (10 mg/kg pre- and 10 mg/kg 14 h post-session) for all subjects, the ED(50) of morphine increased 6.7-fold in group 2, but only 2.6-fold in group 1. During repeated treatment, the groups did not differ in the dose of maloxene required to suppress response rates or elicit weight loss. Following termination of morphine treatment, the ED(50) of morphine returned to original values in group 2, but was 1.8-fold lower than initial values in group 1. Thus, a pronounced [??103] decreasing effect of morphine retarded development of tolerance, perhaps by a conditioning process.