The effects of intraventricular morphine and the metabolically stable enkephalin analogs, D-ala2-leu- and D-ala2-met-enkephalinamide, were compared on food-reinforced operant responding in nondependent, morphine-dependent and postdependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for 10 min every 6 hr for at least 8 weeks before testing. In nondependent animals, the lowest dose of the three drugs increased responding, whereas higher doses, i.e., 0.3 to 3.9 micrograms of morphine and 0.1 to 30 micrograms of the two enkephalins, produced graded decreases in responding. On a molar basis, morphine was 2 to 3 times more potent than the enkephalins in decreasing response rate. Naloxone (0.1 and 1.0 mg/kg) competitively antagonized the rate-decreasing effect of all three compounds. However, chronic morphine treatment produced varying changes in the effects of morphine and the enkephalins. Morphine-dependent rats were tolerant to the rate-decreasing action of morphine, whereas the rate-decreasing effect of D-ala2-met-enkephalinamide was unchanged and that of D-ala2-leu-enkephalinamide was enhanced. Protracted changes in the rate-decreasing effect of morphine, but not the enkephalins, were evident in postdependent animals that were tested 5 weeks after withdrawal from morphine. Thus, the effects of morphine and the enkephalins on operant responding are differentially altered as a result of chronic morphine treatment. These results could reflect an allosteric interaction between the neuronal binding sites for morphine and the enkephalins.