The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-freemore »
Global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain
Abstract Background Efforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. Methods 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. Results 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 more »
- Award ID(s):
- 1933303
- Publication Date:
- NSF-PAR ID:
- 10341646
- Journal Name:
- Journal of Neuroinflammation
- Volume:
- 18
- Issue:
- 1
- ISSN:
- 1742-2094
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Publisher's Version of Record
- https://doi.org/10.1186/s12974-021-02228-6
