Interoceptive conditioning through repeated suppression of morphine-abstinence

Abstract

The reinforcing properties of etonitazene, both conditioned and unconditioned, were measured in rats that had received saline only by continuous intravenous infusion (“saline” group) and in two groups of rats that had been physically dependent on morphine to equal degrees (and presumably had developed equal degrees of tolerance to morphine): one by once daily passive intravenous injection of morphine (“injection” group) and the other by passive continuous intravenous morphine infusion at the same daily doses for approximately the same number of days (“infusion” group). Prior to passive saline and morphine administration, all rats were trained to press right and left-sided levers for water reinforcement from 1600 to 0800 hrs to a not more than 60–40 split, and these and other measures (“baselines”) were repeated after recovery from the early (acute) morphine-abstinence syndromes. Then etonitazene, 5 μg/ml, was substituted for water on the nonpreferred side and all measures were repeated from 1600 to 0800 hrs once every two weeks for 20 weeks (10 “relapse” tests). It was postulated that the daily cycles of morphine-abstinence and suppression of abstinence in the injection group only would generate latent interoceptively conditioned reinforcing properties of morphine because of conditioning of suppression of abstinence to the concomitant internal sensorial effects of morphine, which would persist after morphine withdrawal and be transferred to the internal effects of another opioid, etonitazene. It was found that across the first nine relapse tests, the injection group consumed significantly more etonitazene than the infusion group, while there were no significant differences in water consumption. Also, the number of response-contingent etonitazene drinking tube presentations in the first 30 min period of lever availability in the first relapse test (when the unconditioned reinforcing effects and other pharmacological actions of etonitazene were minimal) was significantly greater for the injection group than for either the infusion or saline group, whereas there were no significant differences among the three groups in response-contingent water tube presentations. These findings support the interoceptive conditioning hypothesis.