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Úrzula Franco‐Enzástiga

The University of Texas at Dallas

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Theodore J. Price

The University of Texas at Dallas

Vinicio Granados‐Soto

Center for Research and Advanced Studies of the National Polytechnic Institute

Rodolfo Delgado‐Lezama

Center for Research and Advanced Studies of the National Polytechnic Institute

Keerthana Natarajan

The University of Texas at Dallas

Yarim Elideth De la Luz-Cuellar

Center for Research and Advanced Studies of the National Polytechnic Institute

Janet Murbartián

Center for Research and Advanced Studies of the National Polytechnic Institute

Paulino Barragán‐Iglesias

The University of Texas at Dallas

Ana Belen Salinas-Abarca

Center for Research and Advanced Studies of the National Polytechnic Institute

Jorge E. Torres‐López

Universidad Juárez Autónoma de Tabasco

Guadalupe Raya‐Tafolla

Instituto Politécnico Nacional

Cooperative Institutions

The University of Texas at Dallas

Center for Research and Advanced Studies of the National Polytechnic Institute

Instituto Politécnico Nacional

Universidad Nacional Autónoma de México

Universidad Complutense de Madrid

Universidade Estadual de Londrina

Weatherford College

Universidad Rey Juan Carlos

University of California, San Diego

University of Vienna

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Sex‐dependent pronociceptive role of spinal α₅‐GABA_A receptor and its epigenetic regulation in neuropathic rodents

Journal of Neurochemistry (2020)

Úrzula Franco‐Enzástiga Guadalupe García Janet Murbartián Rodrigo González‐Barrios Ana Belen Salinas-Abarca

Extrasynaptic α5 -subunit containing GABAA (α5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17β-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5 -GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of α5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α5 -GABAA receptor is a suitable target to treat chronic pain in females.

Allodynia

GABAB receptor

Nerve Injury

10.1111/jnc.15140

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Citations (36)

Multi-omic integration with human DRG proteomics highlights TNFα signalling as a relevant sexually dimorphic pathway

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Allison M. Barry Julia Regina Sondermann Joseph B. Lesnak Feng Xian Úrzula Franco‐Enzástiga

Abstract The peripheral nervous system has been widely implicated in pathological conditions that exhibit distinct clinical presentations in men and women, most notably in chronic pain disorders. Here, we explored this sexual dimorphism at a molecular level. We expanded the available omics landscape in the PNS to include quantitative proteomics of the human dorsal root ganglia (hDRG) and nerve. Using data-independent acquisition mass spectrometry, we uncovered an extensive protein landscape, validated against tissue-specific differences between the nerve and hDRG. Using a combination of multi-omic analyses and in vitro functional support, we then examined sex-differences, highlighting TNFα signalling as a relevant sexually dimorphic pathway in males. These results support a functional sexually dimorphism in the periphery, which is of particular importance to sensory– and pain-related clinical translation.

Sexual dimorphism

Omics

10.1101/2024.12.06.626968

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Citations (0)

Contributors

Elsevier eBooks (2021)

Mario A. Acuña Rohit Aiyer Sergiu Albu Ahmad Altarifi Duygun Altıntaş Aykan

10.1016/b978-0-12-820589-1.09991-7

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Citations (0)

Chronic Administration of S-Allylcysteine Activates Nrf2 Factor and Enhances the Activity of Antioxidant Enzymes in the Striatum, Frontal Cortex and Hippocampus

Neurochemical Research (2017)

Úrzula Franco‐Enzástiga Ricardo A. Santana-Martínez Carlos Alfredo Silva‐Islas Diana Barrera‐Oviedo María Elena Chánez‐Cárdenas

Glutathione reductase

10.1007/s11064-017-2337-2

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Citations (14)

The role of spinal cord extrasynaptic α ₅ GABA _A receptors in chronic pain

Physiological Reports (2021)

Rodolfo Delgado‐Lezama Mariana Bravo‐Hernández Úrzula Franco‐Enzástiga Yarim Elideth De la Luz-Cuellar Nara S. Alvarado‐Cervantes

Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABA

10.14814/phy2.14984

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Citations (12)

Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes

Pain (2025)

Úrzula Franco‐Enzástiga Nikhil Nageshwar Inturi Keerthana Natarajan Juliet M. Mwirigi Khadijah Mazhar

Abstract Cell states are influenced by the regulation of gene expression orchestrated by transcription factors capable of binding to accessible DNA regions. To uncover if sex differences exist in chromatin accessibility in the human dorsal root ganglion (hDRG), where nociceptive neurons innervating the body are found, we performed bulk and spatial assays for transposase-accessible chromatin technology followed by sequencing (ATAC-seq) from organ donors without a history of chronic pain. Using bulk ATAC-seq, we detected abundant sex differences in the hDRG. In women, differentially accessible regions (DARs) mapped mostly to the X chromosome, whereas in men, they mapped to autosomal genes. Hormone-responsive transcription factor binding motifs such as EGR1/3 were abundant within DARs in women, while JUN, FOS, and other activating protein 1 factor motifs were enriched in men, suggesting a higher activation state of cells compared with women. These observations were consistent with spatial ATAC-seq data. Furthermore, we validated that EGR1 expression is biased to female hDRG using RNAscope. In neurons, spatial ATAC-seq revealed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in women and in Ca 2+ -signaling-related genes in men. Strikingly, XIST, responsible for inactivating 1 X chromosome by compacting it and maintaining at the periphery of the nucleus, was found to be highly dispersed in female neuronal nuclei. This is likely related to the higher chromatin accessibility in X in female hDRG neurons observed using both ATAC-seq approaches. We have documented baseline epigenomic sex differences in the hDRG which provide important descriptive information to test future hypotheses.

Epigenomics

Dorsal root ganglion

10.1097/j.pain.0000000000003508

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Citations (1)

Human Dorsal Root Ganglion spatial ATAC-seq protocol v1

Úrzula Franco‐Enzástiga Theodore J. Price

In this protocol, we describe how to perform spatial ATAC-seq on fresh-frozen human dorsal root ganglion.

Dorsal root ganglion

10.17504/protocols.io.36wgqn5n5gk5/v1

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Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain

Journal of Neuroscience (2020)

Paulino Barragán‐Iglesias Úrzula Franco‐Enzástiga Vivekanand Jeevakumar Stephanie Shiers Andi Wangzhou

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies. SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Nociceptor

Dorsal root ganglion

10.1523/jneurosci.3055-19.2020

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Citations (78)

Blockade of spinal α5-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats

European Journal of Pharmacology (2019)

Yarim Elideth De la Luz-Cuellar Erick J. Rodríguez‐Palma Úrzula Franco‐Enzástiga Ana Belen Salinas-Abarca Rodolfo Delgado‐Lezama

Reserpine

Allodynia

Lumbar Spinal Cord

10.1016/j.ejphar.2019.172443