TOLERANCE AND CROSS-TOLERANCE TO MORPHINE-LIKE STIMULUS EFFECTS OF MU-OPIOIDS IN RATS

The purpose of these experiments was to examine the relationship of ag onist relative efficacy to the pattern of tolerance and cross-toleranc e to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fix ed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus e ffects and decreases in response rates. Repeated treatment with 20 mg/ kg per day morphine increased the ED50 for stimulus control by fentany l, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repe ated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatm ent doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated tre atment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulu s control by fentanyl or morphine by approximately two-fold. Compariso ns among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rat her repeated morphine and fentanyl treatments produced comparable tole rance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggeste d that magnitude of tolerance may vary inversely with relative efficac y of the agonist tested for morphine-like stimulus effects. During tre atment with morphine or fentanyl, greater tolerance was observed to th e morphine-like stimulus effects of the lower efficacy agonist relativ e to the higher efficacy agonist.