Intestinal Neuropod GUCY2C regulates visceral pain
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PROVIDER: PRJNA857484 | ENA |
REPOSITORIES: ENA
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Project description:Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we reveal that intestinal GUCY2C is selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons, in mice and humans. GUCY2CHigh neuropod cells associate with co-cultured dorsal root ganglia neurons and induce hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient, but not GUCY2C-deficient, neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling and VP that was comparable to chemically-induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.
2023-02-09 | GSE207870 | GEO
Project description:Distinct representation of visceral and somatic pain by unique PVH neuronal ensembles and suggested that PVH as a pain sorting center that distinctly processes visceral and somatic pain, providing a new framework for comprehending how the brain processes nociceptive information and identifying potential molecular targets for specific pain processing.
2024-09-23 | GSE254504 | GEO
Project description:Chronic visceral pain (CVP) is extremely difficult to diagnose, and available analgesic treatment options are quite limited. Identifying the proteins secreted from the colonic nociceptors, or their neighbor cells within the tube walls, in the context of disorders that course with visceral pain, might be useful to decipher the mechanism involved in the establishment of CVP. Addressing this question in patients with gastrointestinal disorders entails multiple difficulties, as there is not a clear classification of disease severity, and colonic secretion is not easy to manage.We propose using of a murine model of colitis to identify new algesic molecules and pathways that could be explored as pain biomarkers or analgesia targets.Descending colons from naïve and colitis mice with visceral hyperalgesia were excised and maintained ex vivo. The proteins secreted in the perfusion fluid before and during acute noxious distension were evaluated using high-resolution mass spectrometry (MS). Haptoglobin (Hp), PZD and LIM domain protein 3 (Pdlim3), NADP-dependent malic enzyme (Me1), and Apolipoprotein A-I (Apoa1) were increased during visceral insult, whilst Triosephosphate isomerase (Tpi1), Glucose-6-phosphate isomerase (Gpi1), Alpha-enolase (Eno1), and Isoform 2 of Tropomyosin alpha-1 chain (Tpm1) were decreased.Most identified proteins have been described in the context of different chronic pain conditions and, according to gene ontology analysis, they are also involved in diverse biological processes of relevance.Thus, animal models that mimic human conditions in combination with unbiased omics approaches will ultimately help to identify new pathophysiological mechanisms underlying pain that might be useful in diagnosing and treating pain.
2023-01-11 | PXD033902 | Pride
Project description:Background & Aims: Irritable bowel syndrome (IBS) is a disorder characterized by chronic abdominal pain and is linked to post-inflammatory and stress-correlated factors that cause changes in the perception of visceral events. Increased evidence indicates that probiotic bacteria may be useful in treating IBS. Our aims were to evaluate the efficacy of treatment with VSL#3, a mixture of 8 probiotic bacteria strains, in the neonatal maternal separation (NMS)-induced visceral hypersensitivity rat model and to determine whether it modulates the colonic expression of pain-related genes. Methods: Male NMS pups were treated orally with placebo or VSL#3 at days 3-60, while normal, not separated rats were used as control. After 60 days from birth, perception of painful sensation induced by colorectal distension (CRD) was measured by assessing the abdominal withdrawal reflex (score 0-4). The colonic gene expression analysis was assessed by using Agilent Whole Rat Genome Oligo Microarrays. Results: NMS rats exhibited both hyperalgesia and allodynia when compared with controls. VSL#3 showed a potent analgesic effect on CRD-induced pain without modifying colorectal compliance. The microarray analysis demonstrated that NMS rats had both over- and downregulation of several genes involved in inflammatory and painful processes and VSL#3 was able to counteract these alterations. Conclusions: This study indicates that VSL#3 is effective in reducing visceral pain in an experimental model of IBS by induction or suppression of pain-modulating genes. These observations provide support for the use of VSL#3 in the treatment of painful conditions related to IBS. The dataset comprises 12 samples divided into three sample groups each representing a certain treatment condition of male rats.
2013-06-26 | E-GEOD-38942 | biostudies-arrayexpress
Project description:Background & Aims: Irritable bowel syndrome (IBS) is a disorder characterized by chronic abdominal pain and is linked to post-inflammatory and stress-correlated factors that cause changes in the perception of visceral events. Increased evidence indicates that probiotic bacteria may be useful in treating IBS. Our aims were to evaluate the efficacy of treatment with VSL#3, a mixture of 8 probiotic bacteria strains, in the neonatal maternal separation (NMS)-induced visceral hypersensitivity rat model and to determine whether it modulates the colonic expression of pain-related genes. Methods: Male NMS pups were treated orally with placebo or VSL#3 at days 3-60, while normal, not separated rats were used as control. After 60 days from birth, perception of painful sensation induced by colorectal distension (CRD) was measured by assessing the abdominal withdrawal reflex (score 0-4). The colonic gene expression analysis was assessed by using Agilent Whole Rat Genome Oligo Microarrays. Results: NMS rats exhibited both hyperalgesia and allodynia when compared with controls. VSL#3 showed a potent analgesic effect on CRD-induced pain without modifying colorectal compliance. The microarray analysis demonstrated that NMS rats had both over- and downregulation of several genes involved in inflammatory and painful processes and VSL#3 was able to counteract these alterations. Conclusions: This study indicates that VSL#3 is effective in reducing visceral pain in an experimental model of IBS by induction or suppression of pain-modulating genes. These observations provide support for the use of VSL#3 in the treatment of painful conditions related to IBS.
2013-06-26 | GSE38942 | 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:HIF2 regulates intestinal Wnt5a expression
| PRJNA776829 | ENA
Project description:Visceral sensory neurons encode distinct sensations from healthy organs and initiate pain states that are resistant to common analgesics. Transcriptome analysis is transforming our understanding of sensory neuron subtypes but has generally focused on somatic sensory neurons or the total population of neurons in which visceral neurons form the minority. Our aim was to define transcripts specifically expressed by sacral visceral sensory neurons, as a step towards understanding the unique biology of these neurons and potentially lead to identification of new analgesic targets for pelvic visceral pain. Our strategy was to identify genes differentially expressed between sacral dorsal root ganglia (DRG) that include somatic neurons and sacral visceral neurons, and adjacent lumbar DRG that comprise exclusively somatic sensory neurons. This was performed in male and female mice (adult and E18.5). By developing a method to restrict analyses to nociceptive Trpv1 neurons, a larger group of genes were detected as differentially expressed between spinal level. We identified many novel genes not previously been associated with pelvic visceral sensation or nociception. Limited sex differences were detected across the transcriptome of sensory ganglia, but more were revealed in sacral levels and especially in Trpv1 nociceptive neurons. These data will facilitate development of new tools to modify mature and developing sensory neurons and nociceptive pathways.
2020-03-02 | GSE131622 | GEO
Project description:Visceral sensory neurons encode distinct sensations from healthy organs and initiate pain states that are resistant to common analgesics. Transcriptome analysis is transforming our understanding of sensory neuron subtypes but has generally focused on somatic sensory neurons or the total population of neurons in which visceral neurons form the minority. Our aim was to define transcripts specifically expressed by sacral visceral sensory neurons, as a step towards understanding the unique biology of these neurons and potentially lead to identification of new analgesic targets for pelvic visceral pain. Our strategy was to identify genes differentially expressed between sacral dorsal root ganglia (DRG) that include somatic neurons and sacral visceral neurons, and adjacent lumbar DRG that comprise exclusively somatic sensory neurons. This was performed in male and female mice (adult and E18.5). By developing a method to restrict analyses to nociceptive Trpv1 neurons, a larger group of genes were detected as differentially expressed between spinal level. We identified many novel genes not previously been associated with pelvic visceral sensation or nociception. Limited sex differences were detected across the transcriptome of sensory ganglia, but more were revealed in sacral levels and especially in Trpv1 nociceptive neurons. These data will facilitate development of new tools to modify mature and developing sensory neurons and nociceptive pathways.
2020-03-02 | GSE131621 | GEO
Project description:Visceral sensory neurons encode distinct sensations from healthy organs and initiate pain states that are resistant to common analgesics. Transcriptome analysis is transforming our understanding of sensory neuron subtypes but has generally focused on somatic sensory neurons or the total population of neurons in which visceral neurons form the minority. Our aim was to define transcripts specifically expressed by sacral visceral sensory neurons, as a step towards understanding the unique biology of these neurons and potentially lead to identification of new analgesic targets for pelvic visceral pain. Our strategy was to identify genes differentially expressed between sacral dorsal root ganglia (DRG) that include somatic neurons and sacral visceral neurons, and adjacent lumbar DRG that comprise exclusively somatic sensory neurons. This was performed in male and female mice (adult and E18.5). By developing a method to restrict analyses to nociceptive Trpv1 neurons, a larger group of genes were detected as differentially expressed between spinal level. We identified many novel genes not previously been associated with pelvic visceral sensation or nociception. Limited sex differences were detected across the transcriptome of sensory ganglia, but more were revealed in sacral levels and especially in Trpv1 nociceptive neurons. These data will facilitate development of new tools to modify mature and developing sensory neurons and nociceptive pathways.
2020-03-02 | GSE131619 | GEO