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Porcine DRG pain genes analysis Transcriptomics analysis of the caudal dorsal root ganglia of tail amputated pigs reveals long-term alterations in gene expression associated with wound healing, inflammation and neuropathic pain

ABSTRACT: Tail amputation by tail docking or as an extreme consequence of tail biting in commercial pig production has serious implications for animal welfare. Tail amputation causes peripheral nerve injury that might be associated with chronic lasting pain. The aim of this study was to investigate the short- and long-term effects of tail amputation in pigs on caudal DRG gene expression at different stages of development, particularly in relation to genes associated with nociception and pain. Microarray analysis was used to analyse whole DRG transcriptomes from tail amputated and sham-treated pigs 1, 8 and 16 weeks following tail treatment at either 3 or 63 days of age (8 pigs/treatment/age/time after treatment; n=96). Tail amputation induced marked changes in gene expression (up and down) compared to sham-treated intact controls for all treatment ages and time points after tail treatment. Sustained changes in gene expression in tail amputated pigs were still evident approximately 4 months after tail injury. Gene correlation network analysis revealed two gene coexpression clusters associated with amputation. Gene ontology (GO) enrichment analysis found the genes in Cluster A (124 genes) and Cluster B (61 genes) to be associated with both ‘inflammatory pain’ and ‘neuropathic pain ’. Key families of ion channels and receptors were significantly down-regulated compared to shams in Cluster A, in particular voltage-gated potassium channels and GABA receptors which are both linked to increased peripheral nerve excitability after axotomy. Up-regulated functional gene families in Cluster B were linked to transcription regulation, inflammation, tissue remodelling and regulatory neuropeptide activity. DRG gene expression profiles appear to reflect sustained tissue inflammation and repair (ca. 4 months) and pain signal modulation consistent with adaptive, compensatory responses linked to injury induced increases in peripheral somatosensory neuronal excitability in the tail stump. Tail amputation causes acute and sustained changes in peripheral somatosensory nerve function involving key mediators of inflammatory and neuropathic pain which have implications for long-term tail stump pain. The findings of this study may have ramifications for the effects of tail amputation in other species. We used microarray to investigate the effects of tail amputation on gene expression in the dorsal root ganglia of caudal nerves in pigs at 2 treatment ages and 3 time points after tail treatment

ORGANISM(S): Sus scrofa

PROVIDER: GSE119519 | GEO | 2019/01/01

REPOSITORIES: GEO

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Project description:The Mexican axolotl provides a powerful model to investigate mechanisms of tissue regeneration. A recent chemical screen found that HDAC inhibitor romidepsin, administered for only 1-minute post amputation (1 MPA), blocks axolotl tail regeneration. Here, we tested the potential for cobalt chloride (CoCl2), a chemical stabilizer of HIF1a and inducer of hypoxia, to rescue romidepsin-inhibition of tail regeneration. Tail regeneration was partially rescued when embryos with amputated tails were co-treated with romidepsin and CoCl2. However, extending the CoCl2 dosage window either inhibited regeneration (CoCl2:0-30 MPA) or was lethal (CoCl2:0-24 hours post amputation; HPA). CoCl2:0-30 MPA caused tissue damage, tissue loss, and cell death at the distal tail tip, and blocked regeneration. In contrast, CoCl2 treatment of non-amputated embryos or CoCl2:60-90 MPA treatment of amputated embryos did not affect wound healing or inhibit tail regeneration. To further investigate the contrasting effects of CoCl2, microarray analysis was performed to identify differentially expressed genes at 3 HPA. CoCl2-romidepsin:1 MPA treatment significantly increased the expression of transcription factors associated with appendage regeneration, while CoCl2:0-30 MPA significantly increased expression of hemoglobin and platelet-specific transcripts, consistent with hemorrhage and an impaired hemostatic response. Also, CoCl2:0-30 MPA significantly increased expression of hypoxia inducible genes, including genes that encode Hif1a interacting proteins and heat shock proteins (HSP); in contrast, genes encoding TGFB signaling components were significantly downregulated. Using additional chemical inhibitors of tail regeneration, we identified transcriptional responses associated with HSP90 activity and TGFB signaling. Notably, geldanamcin decreased transcription of matrix metalloproteinases and sustained muscle-specific gene expression, suggesting a role for HSP90 in regulating extracellular matrix remodeling and muscle dedifferentiation. Our study shows the power of using chemical tools to precisely identify temporal windows within which critical biological processes are enacted during tissue regeneration.

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Porcine DRG pain genes analysis Transcriptomics analysis of the caudal dorsal root ganglia of tail amputated pigs reveals long-term alterations in gene expression associated with wound healing, inflammation and neuropathic pain

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