ETORPHINE INHIBITS CELL-GROWTH AND INDUCES APOPTOSIS IN SK-N-SH CELLS- INVOLVEMENT OF PERTUSSIS-TOXIN-SENSITIVE G-PROTEINS

Opiates have been used extensively in the treatment of pain but with t he severe side effect of addiction, which is believed to be related to opiates' direct (primary) or indirect (secondary) neurotoxicity. In t his study, the effects of opioids on cell growth and apoptosis have be en examined in human neuroblastoma cell line SK-N-SH. Etorphine, a wid e-spectrum and potent agonist of opioid receptors, was found to signif icantly inhibit cell growth and to induce apoptosis. The inhibitory an d apoptotic activities of etorphine followed a dose-and time-dependent manner. The more specific agonists of opioid receptors such as morphi ne, [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAGO), [D-Pen(2), D -Pen(5)]-enkephalin (DPDPE), dynorphin A and nociceptin/orphanin FQ di d not show similar toxic activities under the same conditions. In addi tion, the effects of etorphine could not be blocked by the opioid rece ptor antagonist naloxone, suggesting that the effects of etorphine mig ht not be mediated by a classical opioid receptor. However, pretreatme nt of SK-N-SH cells with pertussis toxin (PTX) blocked the inhibition of cell growth and apoptosis induced by etorphine, indicating the invo lvement of PTX-sensitive G proteins in the processes. It was also show n that etorphine-induced apoptosis was prevented by actinomycin D (AD) and interleukin-1 beta 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 g lioma cells. We propose that inhibition of cell growth and induction o f apoptosis may be one mechanism of opioid neurotoxicity. (C) 1997 Els evier Science Ireland Ltd.