Abstract
BackgroundEfforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms.MethodsTo 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.ResultsOur 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.ConclusionsOur 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.
Highlights
Despite intense research efforts to develop novel analgesic classes, few novel molecular targets have been successfully translated into effective pain therapy [1]
Differential gene expression changes after injury in neuropathic pain and inflammatory pain models To determine how gene expression is altered in the lumbar dorsal root ganglion (DRG) following the establishment of two widely used rat models of persistent pain, we compared RNA-seq data obtained 14 days following nerve injury (i.e., constriction injury (CCI) model) to naïve rats and 48 h following hind paw inflammation (i.e., complete Freund’s adjuvant (CFA)) to naïve rats (Fig. 1A)
We identified 2620 (17.8%) Differentially expressed gene (DEG) in the DRG following CCI
Summary
Despite intense research efforts to develop novel analgesic classes, few novel molecular targets have been successfully translated into effective pain therapy [1]. 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 [4, 5] As these models are developed using nerve injury, administration of chemical agents, or evoking a significant inflammatory response, difficulties arise when disentangling gene expression profiles due to the effects of pain behaviors versus the initiating insults. Another factor that complicates the interpretation of transcriptional changes across different pain states is that existing microarray datasets from various preclinical models of persistent pain suffer from poor accuracy for genes expressed in low abundance and at lower coverage. Efforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms
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