title: Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at μ-opioid receptor-expressing glia.
abstract: Individuals infected with human immunodeficiency virus-1 who abuse opiates can have a higher incidence of virus-associated neuropathology. Human immunodeficiency virus does not infect neurons, but viral proteins such as transactivator of transcription and glycoprotein 120, originating from infected glia, are neurotoxic. Moreover, functional changes in glial cells that enhance inflammation and reduce trophic support are increasingly implicated in human immunodeficiency virus neuropathology. In previous studies, co-exposure with morphine enhanced transactivator of transcription neurotoxicity towards cultured striatal neurons. Since those cultures contained µ-opioid receptor-expressing astroglia and microglia, and since glia are the principal site of infection in the central nervous system, we hypothesized that morphine synergy might be glially mediated. A 60 hour, repeated measures paradigm and multiple co-culture models were used to investigate the cellular basis for opiate-enhanced human immunodeficiency virus neurotoxicity. Morphine co-exposure significantly enhanced transactivator of transcription-induced neuron death when glia were present. Synergistic effects of morphine on transactivator of transcription neurotoxicity were greatest with neuron-glia contact, but also occurred to a lesser extent with glial conditioned medium. Importantly, synergy was lost if glia, but not neurons, lacked µ-opioid receptors, indicating that opiate interactions with human immunodeficiency virus converge at the level of µ-opioid receptor-expressing glia. Morphine enhanced transactivator of transcription-induced inflammatory effectors released by glia, elevating reactive oxygen species, increasing 3-nitrotyrosine production by microglia, and reducing the ability of glia to buffer glutamate. But neuron survival was reduced even more with glial contact than with exposure to conditioned medium, suggesting that noxious elements associated with cell contact augment the toxicity due to soluble factors. Similar morphine-transactivator of transcription synergy was also observed in studies with the clade C sequence of HIV-1 transactivator of transcription, which did not cause neuron death unless morphine was present. Several paradoxical observations related to opiate effects were noted when µ-opioid receptors were specifically ablated from either glia or neurons. This suggests that µ-opioid receptor loss in isolated cell types can fundamentally distort cell-to-cell signalling, revealing opponent processes that may exist in individual cell types. Our findings show the critical role of glia in orchestrating neurotoxic interactions of morphine and transactivator of transcription, and support the emerging concept that combined exposure to opiates and human immunodeficiency virus drives enhanced pathology within the central nervous system.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.forename: Yun-Kyung
authors.initials: YK
authors.lastname: Hahn
authors.forename: Sandra P
authors.initials: SP
authors.lastname: Welch
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D017450:Receptors, Opioid, mu; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine
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