Effects of the opioid antagonist naloxone on human natural killer cell activity in vitro

Studies from several groups have shown that exogenous opiates as well as endogenous opioids may have direct or indirect effects on natural killer cell (NK) activity. Both enhanced and reduced NK activity have been reported in different in vivo and in vitro studies. The present study was performed to determine the effects of the opioid antagonist, naloxone, on human NK activity in vitro. Human peripheral blood mononuclear cells (PBMC) from 10 healthy normal subjects, as well as from 7 otherwise healthy methadone-maintained former heroin addicts, were used. These PBMC were incubated with a wide-concentration range (1 x 10(-12) to 1 x 10(-3) M) of (-)naloxone, the active enantiomer, and in parallel assays with (+)naloxone, the inactive enantiomer, prior to and during the NK activity assay. A significant reduction of NK activity by each enantiomer of naloxone was found only at very high concentrations, 1 x 10(-3) M (P < 0.01) and above. These concentrations are much higher than plasma levels of naloxone reached in humans during any therapeutic or research use of this opioid antagonist. This effect is probably due to an action at some site other than on classical opioid receptors. No effect was found at concentrations of naloxone below 1 x 10(-3) M. Thus, the data showed no naloxone-induced effects at concentrations of (-)naloxone which are sufficient to displace endogenous opioids from all types of classical opioid receptors, suggesting that the endogenous opioids that remained intact and bound to PBMC in vitro do not have any measurable modulatory effect on NK cell cytotoxicity activity.