Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats

Summary

• 1. For 6-week periods in two studies, rats made tolerant to and maintained on intraperitoneal injection of morphine (200 mg/kg) once daily in the morning resided on alternate nights in one end of a 3-compartment linear maze with water for drinking and on the intervening nights in the other end-compartment with etonitazene (10 meg/ml) for drinking. On this schedule, temporal contiguity was provided between the unrelieved nocturnal “primary” morphine abstinence syndrome (including elevated frequency of “wet dog” shakes) and the specific environment of the water-end of the linear maze, while in the other end, opportunity was provided for reinforcement of etonitazene-drinking through reduction of the nocturnal “primary” morphine abstinence syndrome. Saline-injected normal rats were trained identically except that the concentration of etonitazene was 5 meg/ml. In one study, the etonitazene solution was tagged with anise-flavor while in the other study, tactile-visual cues were used. Also, other morphine-tolerant and normal rats were maintained on intraperitoneal injections of morphine (200mg/ kg) or saline respectively once each morning for 6 weeks in home cages without any training.

• 2. At the end of the 6-week periods, all injections were terminated and all rats in linear mazes were transferred to home cages. On test days at intervals of one or more weeks thereafter, the previously morphine-injected rats exhibited higher “wet dog” shake frequencies in their former “abstinence places” (linear maze or home cage) over periods of 155 and 44 days after termination of injections in the two studies, while conditions of previous housing were not systematically related to “wet dog” shake frequencies in the previously saline-injected normal rats.

• 3. In “free choice” tests (etonitazene, 5 meg/kg, versus water) conducted on the nights of the same test days, the previously morphine-injected rats (both studies) drank more of the etonitazene solution than the previously saline-injected normal rats up to 58 days after termination of injections in one study and 44 days in the other, but “trained” and “untrained” previously morphine-injected rats did not differ significantly from each other in this regard.

• 4. It is concluded that although classical conditioning of morphine-abstinence phenomena (and by inference, “craving” for the drug) is demonstrable, the pre-potent factor in disposing to relapse, at least in the rat under the experimental conditions described, is the long-term persistence of unconditioned disturbances in homeostasis following with-drawal of morphine which can provide a source of reinforcement for operant conditioning of opioid-seeking behavior during “relapse-testing” sessions even without benefit of previous “training”.