We investigated opiate-amphetamine interactions within the nucleus accumbens in responding for conditioned reward. Separate groups of animals received 4-day intra-accumbens treatment with either saline, morphine (0.5 microgram/0.5 microliter), [D-Ala2 NMe-Phe4 Gly-ol5]-Enkephalin (DAMGO; 1.0 micrograms/0.5 microliter), or [D-Pen2,5]-Enkephalin (DPEN; 2.0 micrograms/0.5 microliter). One two subsequent test days, these rats were given a challenge of d-amphetamine (2.0 and 10.0 micrograms/0.5 microliter) and responding for conditioned reward was measured. In the conditioned reinforcement (CR) procedure, food-deprived animals were trained in an initial phase to associate a food reward (primary reinforcement) with a compound stimulus (light/click). In the next phase, a lever was introduced and responding on the lever produced the compound stimulus alone (secondary reinforcement). Previous evidence shows that psychostimulants but not opiates markedly potentiate responding for conditioned reward. In the present design, animals previously treated with either morphine or DAMGO (preferential mu agonists) showed potentiated lever responding following amphetamine challenges, relative to either DPEN- or saline-treated animals. These findings show that prior exposure of nucleus accumbens neurons to mu-selective opiates induces sensitization to the effects of amphetamine. The results are discussed in terms of opioid effects on dopamine transmission and second messenger systems.