Contextual Influences on Naltrexone Sensitization During Daily Morphine Exposure

Naltrexone-precipitated withdrawal in animals that receive morphine daily can include decreases in operant responding. However, naltrexone also can decrease operant responding in untreated animals, depending on prior naltrexone exposure and reinforcer contingencies. The present study was conducted to further evaluate changes in the behavioral effects of naltrexone consequent to morphine exposure and changes in behavioral context. Tolerance to the effects of both μ- (morphine, heroin, buprenorphine, methadone) and κ-opioid (U50,488) agonists during daily chronic morphine also was evaluated. Squirrel monkeys (n = 4) responded under a multiple schedule consisting of 4 18-minute cycles, each comprising a 10-minute timeout period followed by 3-minutes during which fixed-ratio responding was maintained by food presentation, a 2-minute timeout period, and 3-minutes during which fixed-ratio responding was maintained by stimulus-shock termination (SST). Control response rates were comparable under both schedule conditions. All drugs decreased food-maintained responding and, albeit requiring 0.5-1 log unit higher doses, morphine, heroin, methadone, and U50,488 also decreased SST-maintained responding. Daily morphine (3.2 mg/kg/day) produced tolerance to the rate-decreasing effects of μ-opioid agonists in the absence of sensitization to naltrexone's rate-decreasing effects. Doubling the daily dose of morphine and eliminating components of SST-maintained responding resulted in a 1.5-log unit leftward shift of the naltrexone dose-effect function. Full sensitization to naltrexone's ability to decrease food-maintained responding (3-log unit leftward shift) emerged after reintroducing SST-maintained performance into daily sessions. These results indicate that naltrexone's effects on operant responding during morphine maintenance can be influenced by behavioral context as well as the level of dependence. SIGNIFICANCE STATEMENT: Repeated administration of high naltrexone doses in nonopioid dependent individuals may result in behaviorally disruptive effects of low doses (naltrexone supersensitivity). Low doses of naltrexone also have disruptive effects during opioid dependence. These studies show that the expression of naltrexone effects during opioid dependence is a product of both pharmacological and behavioral factors.