Martínez Rodríguez, Antón LeandroBrea Floriani, José ManuelDomínguez Medina, EduardoVarela Liste, María JoséCimadevila Fondevila, MartaAllegue Toscano, CatarinaCruz Guerrero, RaquelMonroy, XavierMerlos, ManuelBurgueño, JavierCarracedo Álvarez, ÁngelLoza García, María Isabel2026-01-132026-01-132021-06-29Antón L. Martínez, José Brea, Eduardo Domínguez, María J. Varela, Marta Cimadevila, Catarina Allegue, Raquel Cruz, Xavier Monroy, Manuel Merlos, Javier Burgueño, Ángel Carracedo, and María I. Loza ACS Chemical Neuroscience 2021 12 (14), 2619-2628 DOI: 10.1021/acschemneuro.1c001291948-7193https://hdl.handle.net/10347/45062Neuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we described and validated F11 cells as a model of DRG (dorsal root ganglia) neurons. In the current work, we employed F11 cells to identify regulators of antiretroviral-induced neuropathic pain combining functional and transcriptomic analysis. The antiretroviral zalcitabine (ddC) increased the excitability of differentiated F11 cells associated with calcium signaling without morphological changes in the neuronal phenotype, mimicking the observed increase of painful signaling in patients suffering from antiretroviral-induced neuropathic pain. Employing RNA sequencing, we observed that zalcitabine treatment upregulated genes related with oxidative stress and calcium homeostasis. The functional impact of the transcriptomic changes was explored, finding that the exposure to zalcitabine significantly increased intracellular oxidative stress and reduced store-operated calcium entry (SOCE). Because the functional and transcriptomic evidence points toward fundamental changes in calcium signaling and oxidative stress upon zalcitabine exposure, we identified that NAD(P)H quinone dehydrogenase and the sarcoplasmic/endoplasmic reticulum calcium ATPase 3 were involved in zalcitabine-induced hyperexcitability of F11 cells. Overexpression of those genes increases the calcium-elicited hyperexcitability response and reduces SOCE, as well as increases intracellular ROS levels. These data do not only mimic the effects of zalcitabine but also highlight the relevance of oxidative stress and of calcium-mediated signaling in antiretroviral-induced hyperexcitability of sensory neurons, shedding light on new therapeutic targets for antiviral-induced neuropathic paineng© 2021 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Neuropathic painAntiretroviralsHyperexcitability,Alcium transientsTranscriptomic assaysAdverse effectsjournal article10.1021/acschemneuro.1c00129open access