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Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

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Abstract

Emerging evidence suggests that opioid drugs, such as morphine and heroin, can exacerbate neuroAIDS. Microglia are the principal neuroimmune effectors thought to be responsible for neuron damage in HIV-infected individuals, and evidence suggests that opioid drugs acting via μ opioid receptors in microglia aggravate the neuropathophysiological effects of HIV. Key aspects of microglial function are regulated by the P2X family of ATP activated ligand-gated ion channels. In addition, opioid-dependent microglial activation has been reported to be mediated through P2X4 signaling, which prompted us to investigate whether the cation-permeable P2X receptors contribute to the neurotoxic effects of HIV and morphine. To address this question, neuron survival, as well as other endpoints including changes in dendritic length, extracellular ATP levels, and intracellular calcium levels, were assayed in primary neuron-glia co-cultures from mouse striatum. Treatment with TNP-ATP, a non-selective P2X antagonist, prevented the neurotoxic effects of exposure to morphine and/or HIV Tat, or ATP alone, suggesting P2X receptors mediate the neurotoxic effects of these insults in striatal neurons. Although P2X7, and perhaps P2X1, receptor activation decreases neuron survival, neither P2X1, P2X3, nor P2X7 selective receptor antagonists prevented Tat and/or morphine-induced neurotoxicity. These and other experiments indicate the P2X receptor family contributes to Tat- and morphine- related neuronal injury, and provide circumstantial evidence implicating P2X4 receptors in particular. Our findings reveal that members of the P2X receptor family, especially P2X4, may be novel therapeutic targets for restricting the synaptodendritic injury and neurodegeneration that accompanies neuroAIDS and opiate abuse.

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Acknowledgments

We wish to thank Dr. Pamela E. Knapp for reviewing the manuscript. We gratefully acknowledge the support of the National Institutes of Health (NIH)-National Institute on Drug Abuse grants T32 DA007027, R01 DA018633 and K02 DA027374.

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The authors declare no competing financial interests.

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  1. Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA

    Mary E. Sorrell & Kurt F. Hauser

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  1. Mary E. Sorrell
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  2. Kurt F. Hauser
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Correspondence to Kurt F. Hauser.

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Sorrell, M.E., Hauser, K.F. Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures. J Neuroimmune Pharmacol 9, 233–244 (2014). https://doi.org/10.1007/s11481-013-9507-z

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