This proposal is for an Independent Scientist Award (K02). This award will provide the candidate with release time to expend her research skills and enhance her ability for scientific investigations and mentoring. The candidate has demonstrated that chronic morphine use or abuse is associated with an increased incidence of many diseases, and animal studies have demonstrated that morphine can alter a number of immune parameters. Although these effects of morphine are very well established, it still remains unresolved the receptor type involved in morphine mediated effects on immune parameters. In addition it is still controversial if it is the central mu-opioid receptors or receptors present on target cells that mediates morphine's immunosuppressive effects. The objective of this proposal is to determine the contribution of these receptors in modulating the immune system and to gain insight into the intracellular mechanisms by which morphine mediates its effects. The research plan is to investigate the role of Mu-opioid receptors in morphine mediated immunosuppression by using wild type and MORKO mice. These studies will include the role of Mu receptors in the brain and its role in hypothalamic-pituitary-adrenal axis activation. Subsequently, the proposal will investigate the relative role of peripheral Mu opioid receptors in morphine mediated immunosuppression. The mechanisms by which Mu-opioid receptors modulate cytokine gene expression will also be studied. Finally, mRNA will be isolated from the immune cells of MORKO mice following chronic morphine treatment and gene families that are altered will be investigated using gene array technology. In addition collaboration with several investigators experienced with a) T-cell biology b) Opioid induced G-protein coupling c) viral infections and d) Gene array technology will contribute enormously to the overall enhancement of the quality and depth of the PI research program.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA015349-03
Application #
6801566
Study Section
Special Emphasis Panel (ZDA1-KXA-N (16))
Program Officer
Thadani, Pushpa
Project Start
2002-09-10
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$69,673
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Koodie, Lisa; Yuan, Hongyan; Pumper, Jeffery A et al. (2014) Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol 184:1073-1084
Ninkovi?, Jana; Roy, Sabita (2013) Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids 45:9-24
Meng, Jingjing; Yu, Haidong; Ma, Jing et al. (2013) Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One 8:e54040
Dutta, Raini; Krishnan, Anitha; Meng, Jingjing et al. (2012) Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae. J Neurosci 32:9917-30
Chanakira, Alice; Dutta, Raini; Charboneau, Richard et al. (2012) Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-? and VEGFR-2 expression. Am J Physiol Heart Circ Physiol 302:H1173-84
Ninkovi?, Jana; Roy, Sabita (2012) Morphine decreases bacterial phagocytosis by inhibiting actin polymerization through cAMP-, Rac-1-, and p38 MAPK-dependent mechanisms. Am J Pathol 180:1068-79
Roy, Sabita (2011) Drugs of abuse effects on immunity and microbial pathogenesis. J Neuroimmune Pharmacol 6:435-8
Roy, Sabita; Ninkovic, Jana; Banerjee, Santanu et al. (2011) Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J Neuroimmune Pharmacol 6:442-65
Wang, Jinghua; Ma, Jing; Charboneau, Rick et al. (2011) Morphine inhibits murine dendritic cell IL-23 production by modulating Toll-like receptor 2 and Nod2 signaling. J Biol Chem 286:10225-32
Das, Subhas; Kelschenbach, Jennifer; Charboneau, Richard et al. (2011) Morphine withdrawal stress modulates lipopolysaccharide-induced interleukin 12 p40 (IL-12p40) expression by activating extracellular signal-regulated kinase 1/2, which is further potentiated by glucocorticoids. J Biol Chem 286:29806-17

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