Diana Tavares‐Ferreira

The University of Texas at Dallas

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Theodore J. Price

The University of Texas at Dallas

Salim Megat

Inserm

Ishwarya Sankaranarayanan

The University of Texas at Dallas

Pradipta Ray

Bristol-Myers Squibb (United States)

Gregory Dussor

The University of Texas at Dallas

Paulino Barragán‐Iglesias

The University of Texas at Dallas

Andi Wangzhou

The University of Texas at Dallas

Stephanie Shiers

The University of Texas at Dallas

Armen N. Akopian

The University of Texas Health Science Center at San Antonio

Ruta Uttarkar

The University of Texas Southwestern Medical Center

Cooperative Institutions

The University of Texas at Dallas

Center for Research and Advanced Studies of the National Polytechnic Institute

Carolinas Center for Advanced Management of Pain

University of Arizona

The University of Texas Southwestern Medical Center

Instituto Politécnico Nacional

Universidad Nacional Autónoma de México

Institute of Pharmacology

Yale University

Inserm

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Transcriptome Analysis of the Human Tibial Nerve Identifies Sexually Dimorphic Expression of Genes Involved in Pain, Inflammation, and Neuro-Immunity

Frontiers in Molecular Neuroscience (2019)

Pradipta Ray Jawad Khan Andi Wangzhou Diana Tavares‐Ferreira Armen N. Akopian

Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.

Sexual dimorphism

10.3389/fnmol.2019.00037

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Citations (47)

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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Sex differences in the role of atypical PKC within the basolateral nucleus of the amygdala in a mouse hyperalgesic priming model

Neurobiology of Pain (2020)

Daniela Baptista-de-Souza Diana Tavares‐Ferreira Salim Megat Ishwarya Sankaranarayanan Stephanie Shiers

Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E2 (PGE2) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male Prkcz-/- mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain.

Basolateral amygdala

Priming (agriculture)

Stimulus (psychology)

10.1016/j.ynpai.2020.100049

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Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Journal of Neuroscience (2019)

Salim Megat Pradipta Ray Diana Tavares‐Ferreira Jamie K. Moy Ishwarya Sankaranarayanan

Nociceptors located in the trigeminal ganglion (TG) and DRG are the primary sensors of damaging or potentially damaging stimuli for the head and body, respectively, and are key drivers of chronic pain states. While nociceptors in these two tissues show a high degree of functional similarity, there are important differences in their development lineages, their functional connections to the CNS, and recent genome-wide analyses of gene expression suggest that they possess some unique genomic signatures. Here, we used translating ribosome affinity purification to comprehensively characterize and compare mRNA translation in Scn10a-positive nociceptors in the TG and DRG of male and female mice. This unbiased method independently confirms several findings of differences between TG and DRG nociceptors described in the literature but also suggests preferential utilization of key signaling pathways. Most prominently, we provide evidence that translational efficiency in mechanistic target of rapamycin (mTOR)-related genes is higher in the TG compared with DRG, whereas several genes associated with the negative regulator of mTOR, AMP-activated protein kinase, have higher translational efficiency in DRG nociceptors. Using capsaicin as a sensitizing stimulus, we show that behavioral responses are greater in the TG region and this effect is completely reversible with mTOR inhibition. These findings have implications for the relative capacity of these nociceptors to be sensitized upon injury. Together, our data provide a comprehensive, comparative view of transcriptome and translatome activity in TG and DRG nociceptors that enhances our understanding of nociceptor biology. SIGNIFICANCE STATEMENT The DRG and trigeminal ganglion (TG) provide sensory information from the body and head, respectively. Nociceptors in these tissues are critical first neurons in the pain pathway. Injury to peripheral neurons in these tissues can cause chronic pain. Interestingly, clinical and preclinical findings support the conclusion that injury to TG neurons is more likely to cause chronic pain and chronic pain in the TG area is more intense and more difficult to treat. We used translating ribosome affinity purification technology to gain new insight into potential differences in the translatomes of DRG and TG neurons. Our findings demonstrate previously unrecognized differences between TG and DRG nociceptors that provide new insight into how injury may differentially drive plasticity states in nociceptors in these two tissues.

Nociceptor

Dorsal root ganglion

Trigeminal ganglion

10.1523/jneurosci.2663-18.2019

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Citations (85)

Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Diana Tavares‐Ferreira Pradipta Ray Ishwarya Sankaranarayanan Galo L. Mejia Andi Wangzhou

ABSTRACT Background There are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences. Methods We used Translating Ribosome Affinity Purification (TRAP) sequencing and behavioral pharmacology to test the hypothesis that nociceptor (Nav1.8 expressing neurons) translatomes would differ by sex. Results We found 66 genes whose mRNA were sex-differentially bound to nociceptor ribosomes. Many of these genes have known neuronal functions but have not been explored in sex differences in pain. We focused on Ptgds , which was increased in female mice. The mRNA encodes the prostaglandin D 2 (PGD 2 ) synthesizing enzyme. We observed increased Ptgds protein and PGD 2 in female mouse DRG. The Ptgds inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in females. Conversely, female mice responded more robustly to another major prostaglandin, PGE 2 , than did male mice. Ptgds protein expression was also higher in female cortical neurons, suggesting DRG findings may be generalizable to other nervous system structures. Conclusions Nociceptor TRAP sequencing (TRAP-seq) reveals unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins. Our results demonstrate that translatome analysis reveals physiologically relevant sex differences important for fundamental protective behaviors driven by nociceptors.

Nociceptor

Dorsal root ganglion

10.1101/2020.07.31.231753

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Citations (10)

Using Translating Ribosome Affinity Purification (TRAP) to Understand Cell-Specific Translatomes in Pain States

Neuromethods (2022)

Diana Tavares‐Ferreira Salim Megat Theodore J. Price

Translating ribosome affinity purification (TRAP) is a method that allows the study of translational changes through identification of mRNAs associated with tagged ribosomes in specific cell types, in vivo. We have used Nav1.8-Cre mice crossed with mice that have a floxed L10a-GFP fusion. Because L10a protein is associated with translating ribosomes, this crossing generates mice with tagged ribosomes exclusively expressed in Nav1.8-positive neurons, most of which are nociceptors. These mice give new insight into the functional properties of nociceptors and how the translatome of these cells changes following injury. Herein, we describe a detailed protocol that can be used to identify differentially translated mRNAs and study translational control mechanisms in nociceptors in vivo. This protocol can be used to investigate nociceptor translatomes in other chronic pain contexts, and it can be applied to other cell types within sensory ganglia using a variety of genetic lines.

Nociceptor

10.1007/978-1-0716-2039-7_4

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Citations (1)

GAPDH, β-actin, and β-tubulin display age-dependent protein expression changes in the mouse cortex during development

Developmental Neuroscience (2025)

Dannys Rivero Rodríguez Michelle Nguyen Tejas Devata Dilan Patel Diana Tavares‐Ferreira

GAPDH, β-actin, and β-tubulin are essential housekeeping proteins commonly used as reference controls for protein expression studies. GAPDH is a key glycolytic enzyme that facilitates the production of cellular energy, while β-actin and β-tubulin are major structural components of the cytoskeleton. Besides their well-established housekeeping functions, emerging studies have demonstrated critical roles for these proteins in brain developmental and pathological processes. However, few studies have examined how the expression patterns of these proteins change throughout mammalian brain development to adulthood. Considering the dynamic structural and functional changes that occur during brain development and the roles of GAPDH, β-actin, and β-tubulin in related biological processes, we investigated the developmental expression levels of these proteins in the mouse cortex at various embryonic (E15-P0) and postnatal (P0-P20, adult) stages using western blotting analysis with total protein normalization. We identified a substantial increase in GAPDH protein levels and a decrease in β-actin and β-tubulin in protein levels in the mouse cortex between birth and early adulthood, which occurred during the second week of postnatal life. Analysis of RNA-seq data from the ENCODE Consortium revealed correlated changes at the RNA transcript level. Overall, our study reveals robust age-dependent changes in cortical GAPDH, β-actin, and β-tubulin expression levels during mouse postnatal development and suggests precautions when using these proteins as reference controls in cortical development studies.

Glyceraldehyde 3-phosphate dehydrogenase

Housekeeping gene

Stathmin

10.1159/000544064

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Sex Differences in Nociceptor Translatomes Contribute to Divergent Prostaglandin Signaling in Male and Female Mice

Biological Psychiatry (2020)

Diana Tavares‐Ferreira Pradipta Ray Ishwarya Sankaranarayanan Galo L. Mejia Andi Wangzhou

Nociceptor

Adult male

10.1016/j.biopsych.2020.09.022

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Citations (56)