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.