J Neuroimmune Pharmacol (2011) 6:442–465 DOI 10.1007/s11481-011-9292-5 INVITED REVIEW Opioid Drug Abuse and Modulation of Immune Function: Consequences in the Susceptibility to Opportunistic Infections Sabita Roy & Jana Ninkovic & Santanu Banerjee & Richard Gene Charboneau & Subhas Das & Raini Dutta & Varvara A. Kirchner & Lisa Koodie & Jing Ma & Jingjing Meng & Roderick A. Barke Received: 26 May 2011 /Accepted: 27 June 2011 /Published online: 26 July 2011 # Springer Science+Business Media, LLC 2011 Abstract Infection rate among intravenous drug users opioid withdrawal. Data on bacterial virulence in the (IDU) is higher than the general public, and is the major context of opioid withdrawal suggest that mice undergoing cause of morbidity and hospitalization in the IDU popula- withdrawal had shortened survival and increased bacterial tion. Epidemiologic studies provide data on increased load in response to Salmonella infection. As the body of prevalence of opportunistic bacterial infections such as TB evidence in support of opioid dependency and its immuno- and pneumonia, and viral infections such as HIV-1 and suppressive effects is growing, it is imperative to under- hepatitis in the IDU population. An important component in stand the mechanisms by which opioids exert these effects the intravenous drug abuse population and in patients and identify the populations at risk that would benefit the receiving medically indicated chronic opioid treatment is most from the interventions to counteract opioid immuno- suppressive effects. Thus, it is important to refine the : : : : : existing animal model to closely match human conditions S. Roy J. Ninkovic S. Banerjee S. Das R. Dutta and to cross-validate these findings through carefully V. A. Kirchner : J. Ma : R. A. Barke Department of Surgery, University of Minnesota, controlled human studies. Better understanding of the Minneapolis, MN 55455, USA mechanisms will facilitate the search for new therapeutic : modalities to counteract adverse effects including increased S. Roy J. Meng infection rates. This review will summarize the effects of Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA morphine on innate and adaptive immunity, identify the role : of the mu opioid receptor in these functions and the signal R. G. Charboneau R. A. Barke transduction activated in the process. The role of opioid Department of Surgery, Veterans Affairs Medical Center, withdrawal in immunosuppression and the clinical rele- Minneapolis, MN 55417, USA vance of these findings will also be discussed. L. Koodie School of Dentistry, University of Minnesota, Keywords Opioid drug abuse . Morphine . Immune Minneapolis, MN 55455, USA function . Opportunistic infections S. Roy (*) Division of Infection, Inflammation and Vascular Biology, University of Minnesota, Introduction MMC 195, 420 Delaware Street SE, Minneapolis, MN 55455, USA e-mail: [email protected] The status of the immune system generally dictates the outcome following microbial infection in an organism. S. Roy Invasion of a host by pathogenic infectious agents initiates Department of Surgery and Pharmacology, a sequence of immune responses through interactions University of Minnesota, 11-204 Moos Tower, MMC 195, 420 Delaware Street SE, between a diverse array of pathogen-borne virulence factors Minneapolis, MN 55455, USA and the immune surveillance mechanisms of the host. In J Neuroimmune Pharmacol (2011) 6:442–465 443 human infections, the integrity of the host immune system and only partially dependent on sympathetic activation and an appropriate host response is crucial for pathogen (Peterson et al. 1987;Bryantetal.1991; Casellas et al. clearance. Primary immune deficiencies predispose to 1991; Perez-Castrillon et al. 1992). With the discovery of different infections, depending on the nature of the opioid receptors on leukocytes, research focus has shifted underlying immune defect. An inappropriate immune to direct effects of opioids on immune cells and will response may not only result in lack of protection, but therefore be the topic of discussion of this review. even contribute to disease severity. Chronic opioid use and In this section, we summarize seminal studies and abuse has been documented to severely compromise the current literature investigating how morphine directly immune system and thereby, increase the risk of opportu- inhibits the innate immune system by modulating macro- nistic infection (Roy and Loh 1996; Roy et al. 2006; phage, neutrophil, dendritic, mast and natural killer cell Friedman and Eisenstein 2004; Dinda et al. 2005). This is function. supported by epidemiological studies showing increased prevalence of opportunistic infections such as tuberculosis, Macrophage HIV infection and pneumonia in opioid addicts (Georges et al. 1999;Nathetal.2002; Quaglio et al. 2002). Macrophages are one of the first lines of innate immune Confounding variables such as sharing of unsterilized, defense against invading pathogens. They play an essen- contaminated needles, nutritional status, environment tial role in pathogen clearance through their phagocytic, influences, history of drug use and genetic variability can chemotactic and bactericidal actions. Therefore, any contribute to the frequency of infections in these patients, defects in macrophage function can be detrimental for however, epidemiological studies suggest that the immune the host. Macrophages have been at the center of many modulating effects of morphine abuse to be a major factor studies examining morphine mediated immune suppres- in disease prevalence (Georges et al. 1999;Nathetal. sion and the significant role they play as the key factors in 2002; Quaglio et al. 2002). Furthermore, in animal studies the innate immune system. Opioid inhibition of the innate where these variables can be controlled, morphine treat- immune system has been observed at several levels. ment (used as a surrogate for heroin which is rapidly Morphine treatment has been implicated in the inhibition converted to morphine following first pass metabolism) of cytokine secretion, leukocyte recruitment and bacterial results in significant immune detriment with increased clearance. By decreasing the proliferative capacity of susceptibility to opportunistic infections (Roy and Loh 1996; macrophage progenitor cells and lymphocytes, morphine Roy et al. 2006). Defense against microbes is mediated by treatment reduces the number of macrophages that are the early reactions of innate immunity and the later response available to respond to infection (Roy et al. 2006) thereby of adaptive immunity. Chronic morphine abuse has been compromising the host’s ability to fight off invading shown to affect both arms of immune defense (Vallejo et al. pathogens. Furthermore, morphine treatment has been also 2004). This review will summarize the effects of chronic and shown to directly inhibit macrophages’ ability to ingest acute morphine on innate and adaptive immunity, identify the opsonized pathogens (Casellas et al. 1991; Szabo et al. role of the mu opioid receptor and the signal transduction 1993; Tomei and Renaud 1997). activated in the process. The role of opioid withdrawal in Initial opioid induced immunosuppression studies inves- immunosupression and the clinical relevance of these tigated the role of endogenous opioids such as leucine (leu) findings will also be discussed. or methionine (met) enkephalin. It was observed that in vitro administration of endogenous opioid peptides such as leu- and met-enkephalin resulted in inhibition of phagocy- Morphine modulation of innate immune function tosis by murine macrophages of opsonized sheep red blood cells (Casellas et al. 1991). When the field expanded to Studies supporting a direct role for opioids on immune examine the role of exogenous opioids in this process, system modulation emerged with the discovery of opioid findings showed that morphine treatment also led to receptors on immune cells. The concept of direct and indirect inhibition of macrophage function. Murine peritoneal morphine action was first introduced through work with macrophages undergoing morphine treatment exhibited morphine dependent rodents. Extensive body of literature suppression of phagocytosis, respiratory burst activity now supports that morphine-induced immunosuppression is (Menzebach et al. 2004) while in human monocytes mediated primarily by the mu opioid receptor (MOR), morphine has been implicated to inhibit and chemotaxis although some functions are amplified following sympathetic (Perez-Castrillon et al. 1992). By preventing bacterial activation or in the presence of corticosterone (CORT). The internalization morphine leads to inadequate bacterial inhibition of IFN-gamma synthesis and activation of clearance. Furthermore, through inhibition of respiratory macrophage-cytokine synthesis is CORT-independent burst activity, morphine attenuates bacterial killing which 444 J Neuroimmune Pharmacol (2011) 6:442–465 together with diminished phagocytosis leads to increased et al., which examined respiratory burst activity in response to bacteremia and bacterial escape from latency in mice phorbol myristate acetate (PMA) (Peterson et al. 1987; (Bhaskaran et al. 2001; Wang et al. 2005; Lugo-Chinchilla Peterson et al. 1989). et al. 2006). Human studies and rodent models of drug Along with inhibition of bacterial clearance (Grimm et abuse indicate that morphine impairs the host’s ability to al. 1998a), morphine treatment leads to inhibition of eradicate infection by inhibiting