Modification of behavioral effects of morphine, meperidine and normeperidine by naloxone and by morphine tolerance.

Lever-press responding of morphine-tolerant and nontolerant squirrel monkeys was maintained under a multiple fixed-interval 5-min, fixed-interval 5-min schedule of food or electric shock presentation. Under the multiple schedule, the first response after a 5-min interval produced either food or shock depending on the prevailing stimulus. Responding maintained by either food or shock was characterized by patterns of positively accelerated responding during the 5-min interval. Morphine (0.1-1.0 mg/kg), meperidine (0.3-10.0 mg/kg) and normeperidine (1.0-17.0 mg/kg) produced dose-related decreases in rates of responding and produced small changes in the temporal pattern of responding in monkeys not tolerant to morphine. Food- and shock-maintained responding generally were affected similarly. Naloxone (0.1-3.0 mg/kg) had no effect when given alone to nontolerant monkeys. Both morphine tolerance and naloxone administration reversed the rate-decreasing effects of morphine and shifted the morphine dose-effect function to the right. Naloxone administration and morphine tolerance also reversed the rate-decreasing effects of meperidine and normeperidine, but unlike with morphine, combinations of naloxone and meperidine or normeperidine disrupted temporal patterns of responding and, at the higher doses, increased rates of responding well above control values. Drug effects in morphine-tolerant or naloxone-treated monkeys were not dependent on the event maintaining responding as comparable local rates of responding maintained by food or shock presentation were affected similarly. It was concluded that meperidine and normeperidine possess behavioral effects in common with those of morphine as well as pronounced non-morphine-like effects which are revealed by interference with the receptors upon which morphine acts.