Human neuroblastoma SH-SY5Y and small-cell lung carcinoma U1690 cells of neuroendocrine origin were exposed to morphine for 1 h, 3 h or 5 days. These treatments did not alter activities of AP-1, NF-kappa B and YY1 transcription factors in SH-SY5Y cells or NF-kappa B and YY1 in U1690 cells. Five-day morphine treatment, however, caused a twofold increase in the activity of a sequence-non-specific, spermidine-activated DNA-binding factor in U1690 cells. The morphine effect was prevented by the antagonist naloxone. The DNA-binding factor bound preferentially to double-stranded DNA ends. This fact and data on subunit composition, molecular masses of subunits, and supershift/inhibition by specific antibodies in a band shift assay, show the spermidine-activated factor to be identical with the Ku protein, the DNA-binding subunit of DNA-dependent protein kinase. The effect observed may be one of the mechanisms through which opioids influence gene regulation.