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(Journal of Leukocyte Biology. 2002;71:782-790.)
© 2002 by Society for Leukocyte Biology

The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the µ-opioid receptor

Jinghua Wang*, Richard Charboneau{dagger}, Sudha Balasubramanian*, Roderick A. Barke{dagger}, Horace H. Loh* and Sabita Roy*,{dagger}

* Department of Pharmacology, University of Minnesota, Minneapolis; and
{dagger} Department of Surgery, Veterans Affairs Medical Center, Minneapolis, Minnesota, and North Memorial Medical Center, Robbinsdale, Minnesota

Correspondence: Dr. Sabita Roy, Veterans Affairs Medical Center, Research RT 151, Room 3N 107, One Veterans Drive, Minneapolis, MN 55417. E-mail: royxx002{at}tc.umn.edu.

Wild-type and µ-opioid receptor knockout (MORKO) mice were used to investigate the role of corticosterone (CORT) and the µ-opioid receptor (MOR) in chronic morphine-mediated immunosuppression. We found that although plasma CORT concentrations in CORT infusion (10 mg/kg/day) and morphine-pellet implantation (75 mg) mice were similar (400–450 ng/ml), chronic morphine treatment resulted in a significantly higher (two- to threefold) inhibition of thymic, splenic, and lymph node cellularity; inhibition of thymic-lymphocyte proliferation; inhibition of IL-2 synthesis; and activation of macrophage nitric oxide (NO) production when compared with CORT infusion. In addition, results show that the inhibition of IFN-{gamma} synthesis and splenic- and lymph node-lymphocyte proliferation and activation of macrophage TNF-{alpha} and IL-1ß synthesis occurred only with chronic morphine treatment but not with CORT infusion. These morphine effects were abolished in MORKO mice. The role of the sympathetic nervous system on morphine-mediated effects was investigated by using the ganglionic blocker chlorisondamine. Our results show that chlorisondamine was able to only partially reverse morphine’s inhibitory effects. The results clearly show that morphine-induced immunosuppression is mediated by the MOR and that although some functions are amplified in the presence of CORT or sympathetic activation, the inhibition of IFN-{gamma} synthesis and activation of macrophage-cytokine synthesis is CORT-independent and only partially dependent on sympathetic activation.

Key Words: glucocorticoids • sympathetic nervous system • hypothalamic pituitary adrenal axis • neuroimmunomodulation




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