title: Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.
abstract: Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca²⁺]i, ROS, H₂O₂, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca²⁺]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca²⁺]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca²⁺]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Schier
authors.forename: José W
authors.initials: JW
authors.lastname: Rodríguez
authors.forename: Myosotys
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D002047:Buprenorphine / Q000378:metabolism / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D008691:Methadone / Q000378:metabolism / Q000633:toxicity; D009020:Morphine / Q000378:metabolism / Q000633:toxicity; D009292:Narcotic Antagonists / Q000378:metabolism / Q000633:toxicity*; D009294:Narcotics / Q000378:metabolism / Q000633:toxicity; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D018925:Chemokines; D009292:Narcotic Antagonists; D009294:Narcotics; D017382:Reactive Oxygen Species; D054322:tat Gene Products, Human Immunodeficiency Virus; D002047:Buprenorphine; D009020:Morphine; D002118:Calcium; D008691:Methadone