Hemokinin-1 induces transcriptomic alterations in pain-related signalling processes
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PROVIDER: PRJEB59866 | ENA |
REPOSITORIES: ENA
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Project description:Neuropathic pain is a highly prevalent condition for which treatments are hampered by low efficacy and dose-limiting side-effects. Injury to the somatosensory nervous system causes maladaptive plasticity that initiates and maintains chronic pain. Emerging evidence suggests that inflammatory cells of the innate immune system shape the injured nervous system and drive pain pathogenesis. Data from preclinical models and human patient biopsies have specifically implicated peripheral macrophage populations for a pro-algesic role, yet how these cell types influence damaged sensory neurons and whether they directly sensitise their neuronal activity is unclear. Here, we have developed an iPSC co-culture system to study the interactions of macrophages and sensory neurons in a fully humanised experimental model. We found that analogous to endogenous counterparts, iPSC-derived macrophages (iMacs) display a dynamic molecular and functional profile that is highly dependent on neuronal context. Co-culture with injured iPSC-derived sensory neurons (iSNs) induces morphological, gene expression, and secretory profile changes in iMacs that are consistent with in vivo nerve injury datasets. iMacs in turn amplify spontaneous firing in damaged sensory neurons, implicating macrophages in a cardinal feature of neuropathic pain. These results illustrate the utility of an iPSC-based model to study signalling between these two cell types; they support a role for macrophages in directly amplifying damaged sensory neuron activity and highlight disrupting pathological signalling between these cell types as a promising strategy for future analgesic drug development.
2025-05-28 | GSE298326 | GEO
Project description:Neuropathic pain is a highly prevalent condition for which treatments are hampered by low efficacy and dose-limiting side-effects. Injury to the somatosensory nervous system causes maladaptive plasticity that initiates and maintains chronic pain. Emerging evidence suggests that inflammatory cells of the innate immune system shape the injured nervous system and drive pain pathogenesis. Data from preclinical models and human patient biopsies have specifically implicated peripheral macrophage populations for a pro-algesic role, yet how these cell types influence damaged sensory neurons and whether they directly sensitise their neuronal activity is unclear. Here, we have developed an iPSC co-culture system to study the interactions of macrophages and sensory neurons in a fully humanised experimental model. We found that analogous to endogenous counterparts, iPSC-derived macrophages (iMacs) display a dynamic molecular and functional profile that is highly dependent on neuronal context. Co-culture with injured iPSC-derived sensory neurons (iSNs) induces morphological, gene expression, and secretory profile changes in iMacs that are consistent with in vivo nerve injury datasets. iMacs in turn amplify spontaneous firing in damage sensory neurons, implicating macrophages in a cardinal feature of neuropathic pain. These results illustrate the utility of an iPSC-based model to study signalling between these two cell types; supporting a role for macrophages in directly amplifying damaged sensory neuron activity and suggesting that disrupting pathological signalling between these cell types could be a fruitful avenue for analgesic drug development.
2025-05-28 | GSE298325 | GEO
Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.
2015-04-23 | E-GEOD-62405 | biostudies-arrayexpress
Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
2021-01-27 | GSE165553 | GEO
Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
2021-01-27 | GSE165566 | GEO
Project description:CircRNA parent genes were mainly enriched in MAPK and neurodevelopmental signalling pathways. CircAkt3 and circMap4k1 were significantly up-regulated in the bone cancer pain group. CircaAkt3 may increase p-ERK expression by upregulating Col8a1, which may further activate the MAPK pathway.
2023-02-14 | GSE224978 | GEO
Project description:This study aims to identify the molecular mechanism in the sensory cortex underlying pain-relief effect of electroacupuncture
2021-01-09 | E-MTAB-9987 | biostudies-arrayexpress
Project description:There is an imminent need for safe and efficient chronic pain medications. Regulator of G-protein signaling 4 (RGS4) is a multi-functional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominentrole in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice, we show a dynamicrole of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hindpaw inflammation or hindlimb nerveinjury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in themouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states anddemonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
2019-09-26 | GSE138024 | GEO
Project description:Inflammatory pain associated with tissue injury and infection largely results from the heightened sensitivity of the peripheral terminals of nociceptor sensory neurons as a consequence of exposure to inflammatory mediators. Targeting immune-derived inflammatory ligands, such as prostaglandin E2, reduces inflammatory pain, but more effective and safer therapies are needed. However, the diversity of immune cell and sensory neuron types, their ligands, and receptors make it challenging to map the immune mechanisms that contribute to inflammatory pain. We, therefore, used single-cell transcriptomics to explore which specific immune cell types affect the development of pain in diverse inflammatory pain models. We found that both the magnitude of macrophage and neutrophil recruitment and the injury-triggered transcriptional program in Cx3cr1 high and MHCII+ dermal macrophages closely mirror the kinetics of inflammatory pain hypersensitivity. We constructed a comprehensive list of potential cell-cell interactions covering receptors, ligands, and metabolites, and generated injury-specific neuroimmune interactomes based on immune cell and sensory neuron single-cell transcriptomic data. This analysis revealed both interactions common to multiple inflammatory pain models and those specific to a particular condition and uncovered immune mediators not previously identified as pain modulators.
2024-05-28 | GSE255686 | GEO
Project description:Our perception of pain changes according to expectation, context and mood illustrating how top-down-circuits affect sensory processing. Here we developed an intersectional platform for identifying supraspinal descending neurons that are engaged when an animal experiences pain. Amongst these, we identified a cluster of cells in the pontine micturition center (Barrington’s nucleus), expressing corticotropin-releasing-hormone (BarCrh) that detect painful but not innocuous stimuli. When activated, BarCrh-neurons attenuate nocifensive responses as well as tactile neuropathic pain. Mechanistically, pain related input from the ventrolateral periaqueductal gray activates BarCrh-neurons, which in turn project to the spinal dorsal horn to mediate analgesia. In combination, our data demonstrate that Barrington’s nucleus is not just a relay station dedicated to triggering micturition but also powerfully controls painful sensory input to the brain.
2025-02-17 | GSE237054 | GEO