Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro.
Human immunodeficiency virus (HIV) infection selectively targets the striatum, a region rich in opioid receptor-expressing neural cells, resulting in gliosis and neuronal losses. Opioids can be neuroprotective or can promote neurodegeneration. To determine whether opioids modify the response of neurons to human immunodeficiency virus type 1 (HIV-1) Tat protein-induced neurotoxicity, neural cell cultures from mouse striatum were initially characterized for mu and/or kappa opioid receptor immunoreactivity. These cultures were continuously treated with morphine, the opioid antagonist naloxone, and/or HIV-1 Tat (1-72) protein, a non-neurotoxic HIV-1 Tat deletion mutant (TatDelta31-61) protein, or immunoneutralized HIV-1 Tat (1-72) protein. Neuronal and astrocyte viability was examined by ethidium monoazide exclusion, and by apoptotic changes in nuclear heterochromatin using Hoechst 33342. Morphine (10nM, 100nM or 1microM) significantly increased Tat-induced (100 or 200nM) neuronal losses by about two-fold at 24h following exposure. The synergistic effects of morphine and Tat were prevented by naloxone (3microM), indicating the involvement of opioid receptors. Furthermore, morphine was not toxic when combined with mutant Tat or immunoneutralized Tat. Neuronal losses were accompanied by chromatin condensation and pyknosis. Astrocyte viability was unaffected. These findings demonstrate that acute opioid exposure can exacerbate the neurodegenerative effect of HIV-1 Tat protein in striatal neurons, and infer a means by which opioids may hasten the progression of HIV-associated dementia.
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington 40536-0298, USA.
J A
JA
Gurwell
A
A
Nath
Q
Q
Sun
J
J
Zhang
K M
KM
Martin
Y
Y
Chen
K F
KF
Hauser
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D004357:Drug Synergism; D015696:Gene Products, tat / Q000235:genetics / Q000633:toxicity*; D015497:HIV-1; D006570:Heterochromatin / Q000187:drug effects; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000633:toxicity*; D009270:Naloxone / Q000494:pharmacology; D009294:Narcotics / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D011994:Recombinant Proteins / Q000633:toxicity; D017384:Sequence Deletion; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D006570:Heterochromatin; D009294:Narcotics; D009498:Neurotoxins; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D009270:Naloxone; D009020:Morphine