N-Ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12), a nitric oxide donor, 3-morpholinosydnonimine (SIN-1), a generator of peroxynitrite (ONOO −), and peroxynitrite induced cell death accompanied by DNA fragmentation in human neuroblastoma SH-SY5Y cell cultures. Morphine prevented the cell death induced by SIN-1 or peroxynitrite, but not that induced by NOC12. The protective effect of morphine was concentration-dependent (10–100 μM), but was not antagonized by naloxone. The selective ligands for opioid receptor subtypes, d-Ala 2, N-Me-Phe 4, Gly-ol 5enkephalin (DAMGO, μ-opioid receptor agonist), d-Pen 2,5enkephalin (DPDPE, δ-opioid receptor agonist) and trans-(±)-3,4-dichloro- N-methyl- N-(2-1-pyrrolidinyl-cyclohexyl)benzeneacetamide (U-50488, κ-opioid receptor agonist) even at the concentration of 100 μM did not prevent the cell death induced by SIN-1. From measurement of the absorbance spectrum of peroxynitrite, the decomposition of peroxynitrite in 0.25 M potassium phosphate buffer (pH 7.4) was very rapid and complete within seconds. However, the absorbance was very stable in the presence of morphine. In addition, morphine inhibited peroxynitrite-induced nitration of tyrosine in a concentration-dependent manner. These results indicate that morphine rapidly reacts with peroxynitrite. The present study showed that morphine prevented peroxynitrite-induced cell death through its direct scavenging action, suggesting that morphine can protect cells against damage caused by peroxynitrite.