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

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‐γ synthesis and splenic‐ and lymph node‐lymphocyte proliferation and activation of macrophage TNF‐α and IL‐1β 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‐γ synthesis and activation of macrophage‐cytokine synthesis is CORT‐independent and only partially dependent on sympathetic activation.