Enhancing effect of morphine on ambulatory activity produced by repeated administration in mice

Abstract

Characteristics of changes in ambulatory activity after repeated administration of morphine, 5, 10 or 20 mg/kg s.c., were investigated in male mice of dd strain. The drug was administered 10 times at intervals of 1, 3-4 or 7 days, and the ambulatory activity of each mouse was measured by a tilting-type round activity cage with a 25 cm diameter for 180 min after each administration. Morphine, 5-20 mg/kg induced a dose-dependent increase in the ambulatory activity, and this effect attained to a peak at 60-90 min and persisted for 120-180 min after the administration. An augmentation of sensitivity (a reverse tolerance) to the ambulation-increasing effect of morphine was induced by the repeated administration of 10 and 20 mg/kg morphine, regardless of the intervals. The reverse tolerance achieved the maximum on the 5-6th administration day, and almost the same level of sensitivity was maintained until the 10th administration day. There was no significant difference in the activity counts at the peak time among the groups of mice varing the administration intervals. However, the persistence of increased ambulatory activity tended to be longer in the group of mice given morphine at intervals of 7 days than in the group given it at intervals of 1 day. The reverse tolerance, once produced, attenuated 2 months after the cessation of the repeated administration. However, the ambulatory activity counts did not return to those on the 1st administration day. In contrast, development of reverse tolerance to the ambulation-increasing effect of morphine could not be observed when mice were put into a glass jar, in which the ambulation was completely restricted, for 180 min after each administration. The factors involved in the production of reverse tolerance to morphine are discussed.