A correlation between chronic morphine use and immunosuppression has been well established in the recent past. However, the detailed mechanisms by which morphine affects the immune system is not yet characterized. Recent studies have shown that morphine treatment affects all the three major components of the immune system; T-lymphocytes, B-lymphocytes and macrophages. The effects ranged from changes in the weight of primary lymphoid organs, alterations in the ratio of T-cell subpopulations and responsiveness to cytokines. Since, T-lymphocytes play a central role in immune response and modulate the function of other immunocompetent cells, it is important to investigate the mechanism of morphine action on T-cells. The activation of thymocytes/T-cells is regulated by the coordinate production of cytokines and expression of cytokine receptors. The major focus of this project is to determine the mechanisms by which morphine inhibits IL-1 induced thymocyte and T-lymphocytes proliferation. This proposal is based on the hypothesis that chronic morphine treatment blocks the proliferative signaling pathways in thymocytes and T-lymphocytes by either 1) inhibiting the expression of cytokine genes or 2) by down regulating cytokine receptors or 30 by inhibiting signal transduction pathway of cytokine receptors. Investigations will be carried out to determine the direct and indirect mechanism by which morphine inhibits IL-2 synthesis in thymocytes and T-lymphocytes. Transcriptional regulation of IL-2 synthesis and IL-2 receptor mediated signal transduction will be investigated. These studies would help to understand the relationship between morphine induced immunosuppression and the prevalence of HIV infection in the drug abuse population. Since morphine is currently administered chronically to patients suffering from cancer and other intractable pain, the proposed investigation would be useful in preventing generalized immunosuppression while retaining the analgesic properties of opioids. It is therefore clinically important to study the mechanism of morphine-induced immunosuppression.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (SRCD (04))
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University of Minnesota Twin Cities
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Roy, S; Charboneau, R G; Barke, R A (1999) Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model. J Neuroimmunol 95:107-14
Roy, S; Cain, K J; Charboneau, R G et al. (1998) Morphine accelerates the progression of sepsis in an experimental sepsis model. Adv Exp Med Biol 437:21-31
Sharp, B M; Roy, S; Bidlack, J M (1998) Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol 83:45-56
Carson, L F; Roy, S; Cain, K et al. (1998) The central response to ovarian carcinoma simulates the response to sepsis. J Surg Res 75:97-102
Roy, S; Cain, K J; Chapin, R B et al. (1998) Morphine modulates NF kappa B activation in macrophages. Biochem Biophys Res Commun 245:392-6
Roy, S; Chapin, R B; Cain, K J et al. (1997) Morphine inhibits transcriptional activation of IL-2 in mouse thymocytes. Cell Immunol 179:1-9
Roy, S; Sedqi, M; Ramakrishnan, S et al. (1996) Differential effects of opioids on the proliferation of a macrophage cell line, Bac 1.2F5. Cell Immunol 169:271-7
Roy, S; Charboneau, R; Cain, K J et al. (1995) The possible role of a central nervous system dopaminergic mechanism in hepatic c-fos protein expression following peritoneal sepsis. Arch Surg 130:1209-15;discussion 1215-6
Chapin, R B; Roy, S; Charboneau, R et al. (1995) Regulation of the transcription factor C/EBP alpha following peritoneal sepsis. J Surg Res 59:460-7
Barke, R A; Roy, S; Chapin, R B et al. (1994) The role of programmed cell death (apoptosis) in thymic involution following sepsis. Arch Surg 129:1256-61;discussion 1261-2