DEVELOPMENT AND MAINTENANCE OF MORPHINE-TOLERANCE AND DEPENDENCE IN RAT BY SCHEDULED ACCESS TO MORPHINE DRINKING SOLUTIONS

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  • 1 January 1978
    • journal article
    • research article
    • Vol. 205  (3) , 536-546
Abstract
Rats were housed in 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-min 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 4 respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg per 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 h 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 decreased to 50% of the levels detected at 1 h after the access period. Of the rats, 90% 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.