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 administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an 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 lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte 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 extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation.
Fecho
K
K
Department of Psychology, University of North Carolina at Chapel Hill.
Maslonek
K A
KA
Dykstra
L A
LA
Lysle
D T
DT
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D006454:Hemoglobins / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology; D013482:Superoxide Dismutase / Q000494:pharmacology
D000634:Aminoquinolines; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D009020:Morphine; C041715:6-anilino-5,8-quinolinedione; D013482:Superoxide Dismutase; D006152:Cyclic GMP; D008751:Methylene Blue