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Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking
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.
Insights
Rats voluntarily consumed morphine solutions daily, developing tolerance and dependence within 18 days. Plasma morphine levels showed significant distribution and clearance patterns in this study of chronic morphine intake.
Area of Science:
- Pharmacology
- Neuroscience
- Animal Behavior
Background:
- Opioid self-administration is a key model for studying addiction.
- Understanding the development of tolerance and dependence is crucial for addiction research.
Purpose of the Study:
- To investigate the development of morphine tolerance and dependence in rats using a controlled, voluntary intake paradigm.
- To characterize plasma morphine levels and their pharmacokinetics during chronic self-administration.
Main Methods:
- Rats were provided access to 0.05% morphine solutions or water at scheduled intervals.
- Tolerance was assessed via analgesic response to morphine challenge doses.
- Dependence was evaluated by naloxone-induced withdrawal scores.
- Plasma morphine concentrations were measured using pharmacokinetic sampling.
Main Results:
- Morphine tolerance plateaued by day 18 of intake.
- Naloxone-induced withdrawal scores plateaued between days 14-18 for higher doses.
- Plasma morphine levels ranged from 167-300 ng/ml 1 hour post-access, decreasing by 50% within 6 hours.
- 90% of rats accepted morphine, with no significant health issues observed besides reduced weight gain.
Conclusions:
- Voluntary, scheduled access to morphine solutions reliably induces tolerance and dependence in rats.
- Pharmacokinetic profiles indicate consistent absorption and elimination patterns.
- This model provides a valuable tool for studying the neurobiological underpinnings of opioid use disorder.