Pharmacological characterization of supersensitivity to naltrexone in squirrel monkeys

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.