The catastrophic effects of opioids use on public health and the economy are documented clearly in numerous studies. Repeated morphine administration can lead to either a decrease (tolerance) or an increase (sensitization) in its behavioral and rewarding effects. Morphine-induced sensitization is a major problem and plays an important role in abuse of the opioid drugs. Studies reported that morphine may exert its effects by the release of nitric oxide (NO). NO is a potent neuromodulator, which is produced by nitric oxide synthase (NOS). However, the exact role of NO in the opioid-induced sensitization is unknown. In this study, we reviewed the role of NO on opioid-induced sensitization in 2 important, rewarding regions of the brain: nucleus accumbens and ventral tegmentum. In addition, we focused on the contribution of NO on opioid-induced sensitization in the limbic system.