Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity.
View Article and Find Full Text PDFType I interferons (IFNs) increase the excitability of dorsal root ganglia (DRGs) neurons via MNK-eIF4E signaling to promote pain sensitization in mice. Activation of stimulator of interferon response cGAMP interactor 1 (STING) signaling is pivotal for type I IFN induction. We hypothesized that vinorelbine, a chemotherapeutic and activator of STING, would cause a neuropathic pain-like state in mice via STING signaling in DRG neurons associated with IFN production.
View Article and Find Full Text PDFThe sigma 2 receptor (σR) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σR/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σR/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for we find that a σR/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice.
View Article and Find Full Text PDFType I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas.
View Article and Find Full Text PDFThe Sigma 2 receptor (σR) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σR/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σR/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for we find that a new σR/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice.
View Article and Find Full Text PDFWe aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP both given intrathecally, blocked, and reversed hyperalgesic priming only in females.
View Article and Find Full Text PDFIn the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis-associated synovial macrophages, and pancreatic tumor tissue.
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