Acute morphine pretreatment sensitizes rats to the response rate-decreasing effects of opioid antagonists naloxone and naltrexone. The effect appears to be mu-opioid receptor specific, as pretreatment with non-mu-selective opioid agonists results in less pronounced sensitization. In the present study, food-deprived rats were trained to respond for food reinforcement on a FI 3-min schedule (9.5 min) with multiple trials. Doses of opioid antagonists were administered cumulatively before each trial of a session following 4-h pretreatment with either vehicle or morphine (3.0 mg/kg). Morphine pretreatment sensitized rats to naltrexone, lowering its ED50 from 20 to 0.03 mg/kg. It also sensitized rats to naloxone and to diprenorphine, another pure antagonist. Morphine-induced sensitization was stereoselective among the optical isomers of the benzomorphans, cyclazocine, pentazocine, and N-allylnormetzocine. In addition, acute morphine pretreatment resulted in sensitization to the mixed agonist/antagonist nalorphine, but not to buprenorphine or nalbuphine. The results extend previous findings concerning the importance of the mu-opioid receptor in the development of sensitization to opioid antagonists.