In the present study, interactions between lead exposure with nitric oxide precursor (L-arginine) or nitric oxide synthase (NOS) inhibitor (L-NAME) on naloxone-induced jumping and diarrhea in morphine-dependent mice were examined. Chronic lead acetate (0.05%) exposure altered naloxone-induced jumping and diarrhea in mice. Jumping was decreased after 7 days and was unchanged 14 and 28 days after lead exposure. Diarrhea was only increased 28 days after lead exposure, which shows a difference between two signs of withdrawal syndrome. Since jumping is the most important sign, the animals were exposed to lead for 7 days in the rest of experiments. In a set of experiments, the nitric oxide agents (L-arginine) or L-NG-nitro arginine methyl ester (L-NAME) were used before naloxone injection to test their effects on the expression of jumping. The low dose of L-arginine, a precursor of nitric oxide (20 mg/kg) decreased jumping, but increased diarrhea. Higher dose of L-arginine (80 mg/kg) increased jumping, while decreased diarrhea. L-NAME decreased both jumping and diarrhea. On the other hand, L-arginine in combination with lead reversed lead-induced attenuation of naloxone-induced jumping, while decreased diarrhea. L-NANE in combination with lead decreased diarrhea, while did not alter jumping. In the second set of experiments, nitric oxide drugs were injected during development of morphine dependency. Data showed that jumping was increased or decreased by low or higher dose of L-arginine respectively. Diarrhea was also increased by the drug. L-NAME decreased both jumping and diarrhea in the development of morphine dependency. Both L-arginine and L-NAME in combination with lead decreased lead-induced jumping and diarrhea. It is concluded that nitric oxide may modulate morphine withdrawal signs and lead-induced attenuation of jumping.