Experiential factors, such as stress, are major determinants of vulnerability to drug addiction and relapse. The behavioral controllability of the stressor is a major determinant of how exposure to a stressor impacts addictive processes. Recent evidence suggests that controllable stressors, such as escapable shock (ES), activate ventral regions of the medial prefrontal cortex (mPFCv), whereas physically identical, but uncontrollable stress (inescapable shock, IS) does not. This activation is critical to the blunting effect that control has on neurochemical and behavioral sequelae of stress. Our laboratory has previously shown that IS, but not ES, potentiates morphine-conditioned place preference (CPP). However, the role of the mPFCv in this phenomenon is unknown. The present experiments investigated the role of the mPFCv during ES and IS in determining the effects of the stressor on subsequent morphine-CPP. Intra-mPFCv microinjection of the GABA(A) agonist muscimol 1 h before ES led ES to potentiate morphine-CPP, as does IS. Conversely, the potentiation of morphine-CPP normally observed in IS rats was blocked by intra-mPFCv microinjection of the GABA(A) antagonist picrotoxin 1 h before IS. These results suggest that during stress, activation of the mPFCv prevents subsequent potentiation of morphine-CPP, whereas inactivation of the mPFCv during stress does not. Thus, activation of the mPFCv during a stress experience is both necessary and sufficient to block the impact of stress on morphine-CPP, and control over stress blunts stress-induced potentiation of morphine effects by activating the mPFCv.