A common notion is that essentially all addictive drugs, including opioids, activate dopaminergic pathways in the brain reward system, and the inappropriate use of such drugs induces drug dependence. However, an opioid reward response is reportedly still observed in several models of dopamine depletion, including in animals that are treated with dopamine blockers, animals that are subjected to dopaminergic neuron lesions, and dopamine-deficient mice. The intracranial self-stimulation response is enhanced by stimulants but reduced by morphine. These findings suggest that dopaminergic neurotransmission may not always be required for opioid reward responses. Previous findings also indicate the possibility that dopamine-independent opioid reward may be observed in opioid-naive states but not in opioid-dependent states. Therefore, a history of opioid use should be considered when evaluating the dopamine dependency of opioid reward.