In this pilot study, we used functional magnetic resonance imaging (fMRI) to study the effects of morphine in 8 healthy, opioid-naïve volunteers. Intravenous small-dose morphine (4 mg/70 kg) or saline was administered to volunteers undergoing a fMRI scan. Infusion of morphine, but not saline, elicited mild euphoria without aversive symptoms and resulted in positive signal changes in reward structures including the nucleus accumbens, sublenticular extended amygdala, orbitofrontal cortex, and hippocampus. The positive signal in the accumbens was opposite to the signal previously reported for noxious stimuli. Morphine produces a decreased signal in cortical areas in a similar manner to sedative-hypnotic drugs such as propofol or midazolam. Activation in endogenous analgesic regions was observed in the periaqueductal gray, the anterior cingulate gyrus (decreased signal), and hypothalamus (increased signals). The pattern of activation in reward circuitry was similar to that reported for euphoric drugs of abuse, providing a model to evaluate the initial effects of morphine on the central nervous system components of the circuitry involved in addiction. The segregation of fMRI response that was observed in cortical versus subcortical regions suggests a dissociation of reward from sensory-motor and cognitive functions. Activation patterns were opposite to those previously observed for the mu antagonist, naloxone.