Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways. (August 2022)

• Record Type: Journal Article
• Authors: Pohóczky, Krisztina; Kun, József; Szentes, Nikolett; Aczél, Tímea; Urbán, Péter; Gyenesei, Attila; Bölcskei, Kata; Szőke, Éva; Sensi, Serena; Dénes, Ádám; Goebel, Andreas; Tékus, Valéria; Helyes, Zsuzsanna
• Is Part Of: Pharmacological research. Volume 182(2022)
• Publication Date: 2022-08
• Subjects: ANOVA analysis of variance -- Avg rank average rank -- Cd27 CD27 antigen -- CNS central nervous system -- CPIP chronic post-ischemic pain -- CRPS Complex Regional Pain Syndrome -- DAB diaminobenzidine tetrahydrochloride -- DE differentially expressed -- DRG dorsal root ganglia -- FC fold change -- GFAP glial fibrillary acidic protein -- GO Gene Ontology -- GPCRs G-protein coupled receptors -- Hoxc11 homeobox C11 -- I.p. intraperitoneal -- Iba1 ionized calcium-binding adapter molecule 1 -- ID identifier of the respective functional term -- IgG immunoglobulin G -- IL-1 interleukin-1 -- IL-6 interleukin-6 -- IL-10 interleukin-10 -- JAK Janus kinase -- JAK-STAT Janus kinase-signal transducer and activator of transcription -- KEGG Kyoto Encyclopedia of Genes and Genomes -- L lumbal -- L-PAG lateral periaqueductal grey matter -- Olig1 oligodendrocyte transcription factor 1 -- PAG periaqueductal grey -- PBS phosphate-buffered saline -- PFA paraformaldehyde -- PTT passive transfer-trauma -- RNA-seq Ribonucleic acid sequencing -- S.c. subcutan -- SEM standard errors of means -- SSC somatosensory cortex -- TBS tris-buffered saline -- TG trigeminal ganglia -- TMM trimmed mean of M values -- TNF tumor necrosis factor -- TPM transcripts per million; Complex regional pain syndrome -- Passive transfer-trauma mouse model -- Unbiased transcriptome profiling of the dorsal root ganglia -- Neuroinflammation; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106347
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Complex Regional Pain Syndrome (CRPS) represents severe chronic pain, hypersensitivity, and inflammation induced by sensory-immune-vascular interactions after a small injury. Since the therapy is unsatisfactory, there is a great need to identify novel drug targets. Unbiased transcriptomic analysis of the dorsal root ganglia (DRG) was performed in a passive transfer-trauma mouse model, and the predicted pathways were confirmed by pharmacological interventions. In the unilateral L3–5 DRGs 125 genes were differentially expressed in response to plantar incision and injecting IgG of CRPS patients. These are related to inflammatory and immune responses, cytokines, chemokines and neuropeptides. Pathway analysis revealed the involvement of Tumor Necrosis Factor (TNF) and Janus kinase (JAK-STAT) signaling. The relevance of these pathways was proven by abolished CRPS IgG-induced hyperalgesia and reduced microglia and astrocyte markers in pain-associated central nervous system regions after treatment with the soluble TNF alpha receptor etanercept or JAK inhibitor tofacitinib. These results provide the first evidence for CRPS-related neuroinflammation and abnormal cytokine signaling at the level of the primary sensory neurons in a translational mouse model and suggest that etanercept and tofacitinib might have drug repositioning potentials for CRPS-related pain. Graphical Abstract: ga1