Chronic naltrexone supersensitizes the reinforcing and locomotor-activating effects of morphine.

Rats were implanted for 10 days with a slow-release naltrexone pellet and then the pellet was removed. Sham-control animals were treated similarly, except no pellet was implanted. One day after pellet removal or sham treatment, animals were assessed for morphine-induced conditioned place preference (CPP) or locomotor activity. CPP was evident in sham animals following two conditioning trials using 5 mg/kg subcutaneous morphine (Experiment 1) and following one conditioning trial using 8 mg/kg intravenous morphine (Experiment 2). Animals conditioned while implanted with a naltrexone pellet showed no morphine-induced CPP. More important, one day after pellet removal, naltrexone-pretreated animals given one conditioning trial with 5 mg/kg intravenous morphine displayed a greater preference for morphine-associated cues relative to sham animals given morphine (Experiment 3 and 4). This single IV morphine dose was insufficient to produce CPP in sham animals, suggesting that naltrexone-induced supersensitization may only be evident at a morphine dose below the reinforcing threshold in control animals. Further, chronic naltrexone potentiated the locomotor-activating effect of 2 mg/kg subcutaneous morphine but not of either 1 or 5 mg/kg morphine (Experiment 5). Behavioral supersensitization assessed by morphine-induced locomotor activation was transient, as it was evident one day, but not either three or 10 days following pellet removal (Experiment 6). These results confirm the functional significance of opiate receptor up-regulation following chronic opioid blockade.