Opioids, such as heroin and morphine, have been shown to cause abnormalities in the functioning of immune cells and to render these cells more ?susceptible? to human immunodeficiency virus-1 (HIV) infection. In addition, heroin, morphine, and other intravenous opiate drugs may accelerate/amplify the neurotoxic mechanisms of HIV that lead to the development of HIV associated neurocognitive disorders (HAND), even in the presence of antiretroviral therapy. However, HIV positive opiate users undergo cycles of withdrawal, which could modify several cellular mechanisms that negatively impact synaptic repair. Few studies have addressed the neurotoxic effects of opioid withdrawal in conjunction with HIV and their mechanisms. Our preliminary data indicate that these mechanisms may include the proliferation of pro-inflammatory (e.g. M1-like) microglia. Therefore, we propose to test the hypothesis that opiate withdrawal, through proliferation of reactive microglia, augments the neurotoxic property of the HIV protein gp120. To test this hypothesis, we will examine whether morphine withdrawal accelerates neuronal degeneration observed in gp120 transgenic mice and whether methadone reverses this effect. Other experiments will determine the cellular and molecular mechanisms whereby withdrawal is neurotoxic. To this end, we will examine the hypothesis that morphine withdrawal promotes microglia proliferation by increasing colony-stimulating factor 1, a chemokine that regulates the proliferation of adult microglia. The long-term goal of this proposal is to establish whether the neurotoxic effects of HIV could be managed in opioid abusers by reducing the cycles of opioid withdrawal. These studies are of high significance since they could elucidate a novel mechanism contributing to HAND in drug abusers. A better understanding of these mechanisms may lead to the development of novel and more effective drug therapies to delay HAND.
Lay Abstract This proposal intends to test the novel hypothesis that morphine withdrawal ?cold turkey? increases neuronal degeneration in an animal model of HIV. Data from this proposal will help in a better understanding of the mechanisms used by HIV and drugs of abuse to cause the brain pathology, and in the design of new compounds that inhibit brain damage caused by the dependence to morphine.
| Bachis, Alessia; Campbell, Lee A; Jenkins, Kierra et al. (2017) Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor. Neurotox Res 32:509-517 |
| Fe Lanfranco, Maria; Loane, David J; Mocchetti, Italo et al. (2017) Combination of Fluorescent in situ Hybridization (FISH) and Immunofluorescence Imaging for Detection of Cytokine Expression in Microglia/Macrophage Cells. Bio Protoc 7: |
