Opioid antagonist (naltrexone) stimulation of cell proliferation in human and animal neuroblastoma and human fibrosarcoma cells in culture

Endogenous opioids play a role in carcinogenic events by serving as inhibitory growth factors that alter cell proliferative events by interaction with opioid receptors. The present study addresses the question of whether endogenous opioid systems function tonically in tissue culture. Using S20Y neuroblastoma, a cell line that produces a growth-related opioid peptide (i.e. [Met⁵]enkephalin) and contains the zeta receptor known to be associated with growth, the effects of opioid receptor blockade by naltrexone, a potent opioid antagonist, was examined. Drug concentrations of 10^-4 to 10^-8 M naltrexone stimulated cell proliferation, with 32-86% more cells found in the naltrexone groups than control from 12 to 48 h after initiating drug exposure; drug concentrations of 10^-9 to 10^-13 M had no effect on growth. Evaluation of labeling and mitotic indices revealed that both DNA synthesis and mitosis were increased by naltrexone, as were the number of cells with process lengths greater than 40 μm. Naltrexone (10^-6 M) also stimulated the growth of N115 murine neuroblastoma, SK-N-MC human neuroblastoma, and HT-1080 human fibrosarcoma. These results indicate that endogenous opioids function in vitro to regulate growth by inhibitory mechanisms, and do so actively. This autocrine mechanism in tissue culture also occurs in other animal neuroblastoma cell lines, as well as for human neuroblastoma and fibrosarcoma cell lines.