title: Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites.
abstract: HIV-1 enters the CNS soon after initial systemic infection; within the CNS parenchyma infected and/or activated perivascular macrophages, microglia and astrocytes release viral and cellular toxins that drive secondary toxicity in neurons and other cell types. Our previous work has largely modeled HIV-neuropathology using the individual viral proteins Tat or gp120, with murine striatal neurons as targets. To model disease processes more closely, the current study uses supernatant from HIV-1-infected cells. Supernatant from HIV-1SF162-infected differentiated-U937 cells (HIV+sup) was collected and p24 level was measured by ELISA to assess the infection. Injection drug abuse is a significant risk factor for HIV-infection, and opiate drug abusers show increased HIV-neuropathology, even with anti-retroviral treatments. We therefore assessed HIV+sup effects on neuronal survival and neurite growth/pruning with or without concurrent exposure to morphine, an opiate that preferentially acts through µ-opioid receptors. Effects of HIV+sup ± morphine were assessed on neuronal populations, and also by time-lapse imaging of individual cells. HIV+sup caused dose-dependent toxicity over a range of p24 levels (10-500 pg/ml). Significant interactions occurred with morphine at lower p24 levels (10 and 25 pg/ml), and GSK3β was implicated as a point of convergence. In the presence of glia, selective neurotoxic measures were significantly enhanced and interactions with morphine were also augmented, perhaps related to a decreased level of BDNF. Importantly, the arrest of neurite growth that occurred with exposure to HIV+sup was reversible unless neurons were continuously exposed to morphine. Thus, while reducing HIV-infection levels may be protective, ongoing exposure to opiates may limit recovery. Opiate interactions observed in this HIV-infective environment were similar, though not entirely concordant, with Tat/gp120 interactions reported previously, suggesting unique interactions with virions or other viral or cellular proteins released by infected and/or activated cells.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Ruturaj R
authors.initials: RR
authors.lastname: Masvekar
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects; D019562:Viral Load / Q000187:drug effects
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D009020:Morphine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3