Differential DNA Methylation in the PFC across the transition from acute to chronic pain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE146215 | GEO | 2020/05/26
REPOSITORIES: GEO
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Project description:Chronic pain is associated with persistent but reversible structural and functional changes in prefrontal cortex (PFC). This stable yet malleable plasticity implicates epigenetic mechanisms, including DNA methylation, as a potential mediator of chronic pain-induced changes. We have previously demonstrated that chronic oral administration of the methyl donor S-adenosyl methionine (SAM) is capable of attenuating long-term peripheral neuropathic pain and affecting global PFC DNA methylation. However, there was no evidence as of yet that alterations in DNA methylation underlie SAM-mediated pain attenuation. To elucidate these mechanisms, we performed epigenome-wide analysis of mouse PFC after 4 months of SAM treatment initiated 3 months following induction of peripheral nerve injury. Over injury triggered chronic pain was associated with 4000 differentially methylated genomic regions which were enriched in intracellular signaling, cell locomotion and migration, cytoskeletal structure, and cell adhesion pathways. A third of the regions that were differentially methylated in chronic pain mice (1415 regions representing 1030 genes) were reversed by SAM treatment. 100 genes with known pain-related function were differentially methylated following nerve injury; several of which were reversed by SAM treatment. These results demonstrate that DNA methylation alterations in the PFC caused by chronic pain and reversed by SAM treatment providing at least partially a mechanism of action. These data point to the possibility of epigenetic modulators such as SAM as novel approach to treat chronic pain.
2020-11-24 | GSE162016 | GEO
Project description:DNA methylation profiles of prefrontal cortec (PFC) comparing 9 months post Spared Nerve Injury (SNI) rats with Sham rats.
2015-10-01 | GSE70006 | GEO
Project description:Differential DNA Methylation in the PFC across the transition from acute to chronic pain
| PRJNA609721 | ENA
Project description:DNA Methylation in the PFC in response to peripheral neuropathic pain and therapeutic treatment with s-adenosylmethionine
| PRJNA680318 | ENA
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).
2014-09-29 | E-GEOD-60033 | biostudies-arrayexpress
Project description:To further reveal the mechanism of neuropathic pain, we simulated neuropathic pain by constructing a chronic constriction injury of the sciatic nerve (CCI) model, followed by quantitative proteomic analysis of rat spinal cord cell nuclei at 1 day, 7 days and sham-operated groups after CCI. A total of 3 samples from each group were used. A total of 5039 proteins were identified in this study, of which 4469 proteins contained quantitative information. Differential proteins were defined by a threshold of change >1.3-fold and t-test p-value <0.05.v
2023-01-17 | PXD034960 | Pride
Project description:Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period. We used microarrays to detail the global programme of gene expression underlying the differences in nerve injury between along the postnatal development and identified distinct classes of regulated genes during the injury Experiment Overall Design: We have performed a microarray analysis of the rat L4/L5 dorsal root ganglia, 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour.
2010-01-30 | E-GEOD-15041 | biostudies-arrayexpress
Project description:To investigate the role of DNA methylation in modulating chronic neuropathic pain (NPP), and identify possible target genes of DNA methylation involved in this process. The chronic constriction injury (CCI) induced NPP model was used. The Arraystar Rat RefSeq Promoter Arrays were used to identify the methylation profiles at the genome-wide level in the DNA promoter regions of the lumbar spinal cord in rats 14 Days following CCI surgery. The underlying genes with differential methylation were then identified and submitted to Gene Ontology and pathway analysis. Methyl-DNA immunoprecipitation quantitative PCR (MeDIP-qPCR) and quantitative reverse transcription-PCR (RT‒qPCR) were used to confirm gene methylation and expression.
2022-12-07 | GSE219038 | GEO
Project description:Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
2022-06-15 | GSE206043 | GEO
Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].
2011-07-14 | E-GEOD-30691 | biostudies-arrayexpress