Title:Opiate Addiction Therapies and HIV-1 Tat: Interactive Effects on Glial [Ca2+]i, Oxyradical and Neuroinflammatory Chemokine Production and Correlative Neurotoxicity
Volume: 12
Issue: 6
Author(s): Sylvia Fitting, Shiping Zou, Nazira El-Hage, Masami Suzuki, Jason J. Paris, Christina J. Schier, Jose W. Rodriguez, Myosotys Rodriguez, Pamela E. Knapp and Kurt F. Hauser
Affiliation:
Keywords:
Calcium, chemokines, buprenorphine, methadone, morphine, neuro-acquired immunodeficiency syndrome
(neuroAIDS), opioid drug abuse, oxidative stress.
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 mixedglial
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, concentrationdependent,
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.