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    Chronic morphine vs. morphine withdrawal: differential effects on HIV neurotoxicity through the expression of CCL5

    Cover for Chronic morphine vs. morphine withdrawal: differential effects on HIV neurotoxicity through the expression of CCL5
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    View/Open: Campbell_georgetown_0076D_12770.pdf (2.1MB)

    Creator
    Campbell, Lee Anthony Richard
    Advisor
    Mocchetti, Italo
    Abstract
    The effect of opioids in the progression of Human Immunodeficiency Virus (HIV)-associated Neurocognitive Disorders (HAND) remains under debate. M-tropic, CCR5-receptor preferring strains of HIV are associated with primary infection, thereby initiating the damaging effects of HIV in both the periphery and the brain. Moreover, it has been established that the M-tropic HIV protein gp120BaL can cause direct neuronal apoptosis alone, which can be prevented by the chemokine CCL5, a natural ligand to CCR5. Because opioids are previously shown to modulate immune functions, including the expression of chemokines and cytokines, studying the effects of opioids on CCL5 expression and resulting gp120BaL toxicity may give insights to the pathogenesis of HAND.
     
    In this dissertation, we focus on two specific aims. We first define the effects of two morphine treatment paradigms- chronic morphine or morphine withdrawal, on the expression of CCL5, pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), and microglial number in vivo. Rats treated with chronic escalating dosages of morphine exhibited elevated CCL5 in the frontal cortex and striatum along with a decrease in pro-inflammatory cytokines and a reduction in the number of microglia. Conversely, spontaneous withdrawal from morphine reduced CCL5 levels, increased pro-inflammatory cytokines and increases microglial number. Due to these observations we hypothesize that withdrawal rather than chronic use of morphine may potentiate gp120BaL toxicity.
     
    The second aim tested this hypothesis by injecting gp120BaL into the rat striatum and treating animals with the chronic morphine or morphine withdrawal paradigm. We observed a decrease in caspase-3 and TUNEL positive cells with animals undergoing chronic morphine treatment compared to saline. Additionally, we found that morphine withdrawal significantly increased the damage caused by gp120BaL. Finally, using lentiviral technology, we were able to examine the role that CCL5 played in the protective effect of chronic morphine. We recreated protection using a lentiviral vector expressing CCL5 alone. Furthermore, we abolished the protective effect of chronic morphine using lentiviral vectors expressing CCL5 shRNA. These data shed light on the importance of the cycle of opioids use and withdrawal in the pathogenesis of HAND and suggest an important role of endogenous chemokines such as CCL5 in the disease process.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/712466
    Date Published
    2014
    Subject
    CCL5; gp120BaL; HIV neurotoxicity; Morphine; Morphine withdrawal; Pharmacology; Neurosciences; Pharmacology; Neurosciences;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    114 leaves
    Collections
    • Graduate Theses and Dissertations - Pharmacology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility