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Activation of P2X4 Receptors on Glia is Necessary for Opioid or HIV‐1 Associated Neurodegeneration
Author(s) -
Sorrell Mary Ellen,
Zou Shipping,
Knapp Pamela,
Hauser Kurt
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb513
Subject(s) - neurotoxicity , microglia , purinergic receptor , pharmacology , opioid , receptor , neurodegeneration , medicine , opioid receptor , immunology , inflammation , toxicity , disease
Individuals who abuse μ opioid receptor agonists are at an increased incidence of HIV‐1‐associated neurocognitive disorders (HAND) with more severe symptoms. Microglia play a major role in HIV neuropathogenesis by harboring the infection and producing inflammatory molecules that lead to neuronal injury/death. Extracellular purines also increase microglial activation and neuronal injury. Morphine reportedly increases microglial motility through P2X4 signaling. To test whether HIV‐1 and opioid‐induced neurotoxicity are mediated via purinergic signaling, cocultures of primary neurons and mixed glia were treated with HIV‐1 Tat, morphine, and/or TNP‐ATP, a non‐selective P2X antagonist. Individual neurons were tracked and neuron survival vs. time was assessed. Tat and morphine neurotoxicity was preventable by treatment with TNP‐ATP. Next we investigated neuronal injury by measuring dendritic pruning and excessive increases in intracellular Ca2+ concentration ([Ca2+]i). In both assays, TNP‐ATP blocked Tat/morphine‐induced injury. To investigate P2X receptor involvement, selective antagonists against the P2X1, P2X3, and P2X7 receptor subtypes were screened. These subtypes were not involved in Tat + morphine neurotoxicity. Lastly, cells from P2X4 null mice were used and confirmed that P2X4 receptors on glia are necessary for opiate/Tat neurotoxicity. Support: NIH DA018633 , DA028741 , DA007027.