Sex differences in gene regulation in the dorsal root ganglion after nerve injury

Stephens, K; Zhou, Weiqiang; Ji, Zhicheng; He, Shaoqiu; Guan, Yun; Taverna, Sean D.

doi:10.1101/152652

Cited by 7 publications

(15 citation statements)

References 54 publications

(44 reference statements)

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“…Thus, it is not possible to compare our data with those results. In contrast with our findings, chronic constriction injury increased Gabra5 mRNA in female rat L4‐L5‐L6 DRG, but also in male DRG (Stephens et al., 2019). It is likely that Gabra5 overexpression in L4 DRG may explain this discrepancy, since we found an increase in male L4 DRG, which was processed independently to L5‐L6 DRG, tissue where we observed the decrease of Gabra5 .…”

Section: Discussioncontrasting

confidence: 99%

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

Franco-Enzástiga

García

Murbartián

et al. 2020

Journal of Neurochemistry

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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.

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Section: Discussioncontrasting

confidence: 99%

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

Franco-Enzástiga

García

Murbartián

et al. 2020

Journal of Neurochemistry

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“…Future investigation should include a larger sample size to determine if meaningful differences exist in pain inhibition and gene expression between males and females in response to SCS. 31…”

Section: Discussionmentioning

confidence: 99%

RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation

et al. 2018

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Spinal cord stimulation has become an important modality in pain treatment especially for neuropathic pain conditions refractory to pharmacotherapy. However, the molecular control of inhibitory and excitatory mechanisms observed after spinal cord stimulation are poorly understood. Here, we used RNA-seq to identify differences in the expression of genes and gene networks in spinal cord tissue from nerve-injured rats with and without repetitive conventional spinal cord stimulation treatment. Five weeks after chronic constrictive injury to the left sciatic nerve, male and female rats were randomized to receive repetitive spinal cord stimulation or no treatment. Rats receiving spinal cord stimulation underwent epidural placement of a miniature stimulating electrode and received seven sessions of spinal cord stimulation (50 Hz, 80% motor threshold, 0.2 ms, constant current bipolar stimulation, 120 min/session) over four consecutive days. Within 2 h after the last spinal cord stimulation treatment, the L4-L6 spinal segments ipsilateral to the side of nerve injury were harvested and used to generate libraries for RNA-seq. Our RNA-seq data suggest further increases of many existing upregulated immune responses in chronic constrictive injury rats after repetitive spinal cord stimulation, including transcription of cell surface receptors and activation of non-neuronal cells. We also demonstrate that repetitive spinal cord stimulation represses transcription of several key synaptic signaling genes that encode scaffold proteins in the post-synaptic density. Our transcriptional studies suggest a potential relationship between specific genes and the therapeutic effects observed in patients undergoing conventional spinal cord stimulation after nerve injury. Furthermore, our results may help identify new therapeutic targets for improving the efficacy of conventional spinal cord stimulation and other chronic pain treatments.

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“…Current evidence supports the association between changes in gene expression and the transition from acute to chronic pain states in a number of preclinical and clinical models [17,33].…”

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confidence: 52%

“…GO analysis for enriched GO biological processes in each set of differentially enriched genes (DEGs) identified by DESeq2 was performed using Metascape [40]. We previously validated our RNA-seq data using qPCR in biological replicates [33].…”

Section: Methodsmentioning

confidence: 99%

Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

Stephens

Zhou

Renfro

et al. 2021

Preprint

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Efforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freund’s Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.SummaryShared transcriptomic and epigenetic changes in two animal models improves our understanding of how chromatin structural changes alter DRG gene expression under persistent pain conditions.

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Sex differences in gene regulation in the dorsal root ganglion after nerve injury

Cited by 7 publications

References 54 publications

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

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

RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation

Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

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Sex differences in gene regulation in the dorsal root ganglion after nerve injury

Cited by 7 publications

References 54 publications

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

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

RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation

Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain

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

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