Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions

Abstract

Rats were housed on a cabinet designed to control their access to water or morphine solutions. They were trained to drink all of their fluid as morphine solutions or tap water during 5-minute access periods scheduled at 2 A.M., 8 A.M., 2 P.M. and 8 P.M. On this schedule, the morphine drinking rats consumed an average of 29, 27, 21 and 23% of their total daily fluid during the four respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg/day of morphine. Separate groups of rats were tested for morphine tolerance and dependence at 4-day intervals. Tolerance to the analgesic effect of challenge doses of morphine (3, 6 and 9 mg/kg) was first detected after 10 days of morphine drinking and reached a plateau after 18 days. Withdrawal scores for rats injected with 0.3 or 3 mg/kg of naloxone reached a plateau between 14 and 18 days of morphine drinking, whereas the scores of rats given 0.03 mg/kg were still increasing after 26 days of drinking. Plasma levels of morphine ranged between 167 and 300 ng/ml in blood samples collected 1 hour after each access period on the 18th day of morphine drinking. Six hours after the 8 A.M. access period, the levels of morphine in the plasma had decreased to 50% of the levels detected at 1 hour after the access period. Ninety percent of the rats accepted the morphine solutions and drank regularly for the 26 days the solutions were offered. They remained healthy throughout this period and, except for the fact that they gained 11% less body weight over the 26 days, they were visibly indistinguishable from the water drinking control rats.