Opiates have been used extensively in the treatment of pain but with the severe side effect of addiction, which is believed to be related to opiates' direct (primary) or indirect (secondary) neurotoxicity. In this study, the effects of opioids on cell growth and apoptosis have been examined in human neuroblastoma cell line SK-N-SH. Etorphine, a wide-spectrum and potent agonist of opioid receptors, was found to significantly inhibit cell growth and to induce apoptosis. The inhibitory and apoptotic activities of etorphine followed a dose- and time-dependent manner. The more specific agonists of opioid receptors such as morphine, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAGO), [D-Pen2, D-Pen5]-enkephalin (DPDPE), dynorphin A and nociceptin/orphanin FQ did not show similar toxic activities under the same conditions. In addition, the effects of etorphine could not be blocked by the opioid receptor antagonist naloxone, suggesting that the effects of etorphine might not be mediated by a classical opioid receptor. However, pretreatment of SK-N-SH cells with pertussis toxin (PTX) blocked the inhibition of cell growth and apoptosis induced by etorphine, indicating the involvement of PTX-sensitive G proteins in the processes. It was also shown that etorphine-induced apoptosis was prevented by actinomycin D (AD) and interleukin-1beta converting enzyme inhibitor I. Interestingly, etorphine was similarly potent to inhibit growth of pheochromocytoma (PC12) cells but less effective in SH-SY5Y neuroblastoma cells and C6 glioma cells. We propose that inhibition of cell growth and induction of apoptosis may be one mechanism of opioid neurotoxicity.