MECHANISMS WHEREBY MACROPHAGE-DERIVED NITRIC-OXIDE IS INVOLVED IN MORPHINE-INDUCED SUPPRESSION OF SPLENIC LYMPHOCYTE-PROLIFERATION

Previous research by our laboratory demonstrated that in vivo administ ration of morphine to rats suppresses concanavalin-A (Con A)-stimulate d proliferation of splenic lymphocytes in a dose-dependent, naltrexone -reversible manner. More recently, we showed that morphine-induced sup pression of Con A-stimulated proliferation of lymphocytes depends on a n increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lym phocyte proliferation in Con A-stimulated splenocyte cultures. The res ults show that the addition of hemoglobin, a scavenger of extracellula r NO, to Con A-stimulated splenocyte cultures dose-dependently attenua tes the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocy te cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5,8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and e xtracellular release of NO from macrophages in Con A-stimulated spleno cyte cultures. The results further suggest that the formation of the o xidant peroxynitrite through a reaction between NO and superoxide anio n does not contribute significantly to the suppression of lymphocyte p roliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more complet ely for the morphine-induced suppression of lymphocyte proliferation.