K. Fecho et al., MECHANISMS WHEREBY MACROPHAGE-DERIVED NITRIC-OXIDE IS INVOLVED IN MORPHINE-INDUCED SUPPRESSION OF SPLENIC LYMPHOCYTE-PROLIFERATION, The Journal of pharmacology and experimental therapeutics, 272(2), 1995, pp. 477-483
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.