Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections

Abstract

Infection rate among intravenous drug users (IDU) is higher than the general public, and is the major cause of morbidity and hospitalization in the IDU population. Epidemiologic studies provide data on increased prevalence of opportunistic bacterial infections such as TB and pneumonia, and viral infections such as HIV-1 and hepatitis in the IDU population. An important component in the intravenous drug abuse population and in patients receiving medically indicated chronic opioid treatment is opioid withdrawal. Data on bacterial virulence in the context of opioid withdrawal suggest that mice undergoing withdrawal had shortened survival and increased bacterial load in response to Salmonella infection. As the body of evidence in support of opioid dependency and its immunosuppressive effects is growing, it is imperative to understand the mechanisms by which opioids exert these effects and identify the populations at risk that would benefit the most from the interventions to counteract opioid immunosuppressive effects. Thus, it is important to refine the existing animal model to closely match human conditions and to cross-validate these findings through carefully controlled human studies. Better understanding of the mechanisms will facilitate the search for new therapeutic modalities to counteract adverse effects including increased infection rates. This review will summarize the effects of morphine on innate and adaptive immunity, identify the role of the mu opioid receptor in these functions and the signal transduction activated in the process. The role of opioid withdrawal in immunosuppression and the clinical relevance of these findings will also be discussed.

Figure 1. Morphine modulates IL-2 promoter activity

Binding of Morphine to the mu-opioid receptor results in superactivation of adenylyl cyclase which is mediated by the βγ subunit of heterotrimeric G protein complex. Activation of adenylyl cyclase by the βγ subunit increases intracellular cAMP leading to activation of ICER competing out CREB from the IL-2 promoter, thereby preventing recruitment of NFAT to the CD-28 responsive element.

Figure 2. Morphine skews the lineage bias of CD4⁺ T cells towards T_H2 phenotype

Morphine leads to superactivation of adenylyl cyclase and increase in intracellular cAMP levels. cAMP activates p38 MAPK, in turn leading to CREB phosphorylation and nuclear translocation. CREB promotes activation of GATA3 and it’s binding to the consensus motifs. GATA3 activation on one hand inhibits activation of T-Bet, inhibiting IFNγ production. On the other hand it enters the positive feedback loop involving IL4 and STAT6 thereby committing itself to the T_H2 phenotype.

Figure 3. Schematic outline illustrating modulation of both innate and adaptive immunity following morphine treatment

Morphine modulates both branches of the immune system leading to inhibition of host’s defenses and impaired pathogen clearance by binding to the mu-opioid receptor. Morphine treatment inhibits innate immunity by inhibiting macrophage and neutrophil phagocytic, bactericidal, chemotactic and migratory functions. In addition morphine treatment inhibits antigen presentation by dendritic cells and reduces NK cytotoxicity. By reducing mast cell activation morphine affects gut permeability further increasing host’s risk of infection. Morphine mediated modulation of adaptive immune functions is not as well as explored. Chronic morphine treatment leads to a decrease in T_H1 cytokine production and T cell activation, and increases T_H1 cell death and T_H2 differentiation. In B cells, morphine treatment has been implicated to reduce antibody production, MHC II expression and proliferation. In summary, by inhibiting key effectors of both branches of the immune system morphine treatment inhibits pathogen clearance and enhances bacterial dissemination.