Cytokine reversal of morphine-induced suppression of the antibody response.

Female C3HeB/FeJ mice implanted with a morphine pellet exhibit a decreased primary antibody response in vitro as measured by the plaque-forming cell (PFC) assay. Suppression was detected at 24 hr following pellet implantation, was maximal at 48 hr and returned to normal by 120 hr. Splenocytes from control mice cocultured with splenocytes from morphine-treated mice (3:1 ratio) did not show a significant suppression, suggesting that morphine is not inducing the production of suppressor cells and/or factors. However, cells from morphine-treated mice cocultured with control cells (3:1) had a restored response. Further coculture experiments demonstrated that addition of adherent cells, but not nonadherent cells, restored the antibody response, suggesting that the macrophages from morphine-treated mice were deficient or defective. In vitro addition of interleukin (IL)-6, IL-1 beta or interferon-gamma (0.5-50 U/ml) attenuated the suppression of the PFC response in cells from morphine-treated mice, whereas higher doses (100 U/ml) restored completely the PFC response to control levels. Addition of IL-2, IL-4 or IL-5 to cultures from morphine-treated mice had little effect. Thus, morphine appears to cause immune suppression by reducing macrophage numbers or by interfering with the production or release of specific cytokines which are needed for a normal antibody response. Collectively, these data suggest that the macrophage is a key cellular target for the suppressive effects of morphine on the antibody response.