ORCID Profile
0000-0002-2527-2905
Current Organisations
Flinders University
,
South Australian Health and Medical Research Institute
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Neurosciences | Central Nervous System | Animal Physiology - Cell | Animal Developmental and Reproductive Biology | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Biochemistry and Cell Biology | Physiology | Sensory Systems | Biologically Active Molecules | Crop and Pasture Biochemistry and Physiology | Peripheral Nervous System | Cellular Nervous System | Autonomic Nervous System | Proteins and Peptides | Nutritional Physiology | Biochemistry and Cell Biology not elsewhere classified |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Digestive System Disorders | Nervous System and Disorders | Expanding Knowledge in the Agricultural and Veterinary Sciences | Cardiovascular System and Diseases | Diabetes | Expanding Knowledge in the Medical and Health Sciences
Related Links
Publications
MP28-06 COLITIS INDUCES LONG-TERM BLADDER AFFERENT HYPERACTIVITY, WHICH IS ATTENUATED BY CHRONIC ORAL ADMINISTRATION OF THE GUANYLATE CYCLASE-C AGONIST LINACLOTIDE
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2016
TRPV1-expressing sensory fibres and IBS: Links with immune function
Publisher: BMJ
Date: 11-02-2009
Spinal Afferent Innervation of the Colon and Rectum
Publisher: Frontiers Media SA
Date: 04-12-2018
Innervation of the Gastrointestinal Tract by Spinal and Vagal Afferent Nerves
Publisher: Elsevier
Date: 2012
Identification of a Quorum Sensing-Dependent Communication Pathway Mediating Bacteria-Gut-Brain Cross Talk
Publisher: Elsevier BV
Date: 11-2020
5‐HT3 and 5‐HT4 receptors contribute to the anti‐motility effects of Garcinia buchananii bark extract in the guinea‐pig distal colon
Publisher: Wiley
Date: 10-11-2011
DOI: 10.1111/J.1365-2982.2011.01807.X
Abstract: Garcinia buchananii bark extract is an anti-motility diarrhea remedy. We investigated whether G. buchananii bark extract has components that reduce gastrointestinal peristaltic activity via 5-HT(3) and 5-HT(4) receptors. Aqueous G. buchananii extract was separated into fractions using preparative thin layer chromatography (PTLC), and major chemical components were identified using standard tests. The anti-motility effects of the extract and its fractions (PTLC1-5) were studied through pellet propulsion assays using isolated guinea-pig distal colons. Anti-motility (PTLC1 & PTLC5) and pro-motility (PTLC2) fractions were isolated from the extract. Flavonoids, steroids, alkaloids, tannins, and phenols were identified in the extract and PTLC1 . The potency of the extract applied via the mucosal surface was reduced by 5-HT, 5-HT(3) receptor agonist RS-56812, 5-HT(4) receptor agonists cisapride and CJ-033466, 5-HT(3) receptor antagonist granisetron, and 5-HT(4) receptor antagonist GR-113808. The anti-motility effects of the aqueous extract and PTLC1 when applied serosally were reversed by RS-56812, cisapride, and CJ-033466. The 5-HT(3) receptor antagonists, granisetron and ondansetron, reduced the effects of the extract to an extent and completely reversed the anti-motility effects of PTLC1 . GR-113808 inhibited the actions of the extract during the initial 10 min, but enhanced the extracts' anti-motility effects after 15 min. GR-113808 augmented the anti-motility activities of PTLC1 and PTLC5 by 30%. These results indicate that the anti-motility effects of G. buchananii aqueous extract are potentially mediated by compounds that affect 5-HT(3) and 5-HT(4) receptors. Identification and characterization of the bioactive compounds within G. buchananii could lead to the discovery of new non-opiate anti-diarrhea formulations.
The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1053/J.GASTRO.2004.08.061
Abstract: Visceral mechanoreceptors are critical for perceived sensations and autonomic reflex control of gastrointestinal function. However, the molecular mechanisms underlying visceral mechanosensation remain poorly defined. Degenerin/epithelial Na+ channel (DEG/ENaC) family ion channels are candidate mechanosensory molecules, and we hypothesized that they influence visceral mechanosensation. We examined the influence of the DEG/ENaC channel ASIC1 on gastrointestinal mechanosensory function, on gastric emptying, and on fecal output. We also compared its role in gastrointestinal and somatic sensory function. To assess the role of ASIC1 we studied wild-type and ASIC1-/- mice. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis determined expression of ASIC1 messenger RNA and protein in vagal and spinal sensory ganglia. Colonic, gastroesophageal, and cutaneous afferent fibers were characterized by functional subtype and their mechanical stimulus-response relationships were determined. Gastric emptying was determined by using a 13CO2 breath test. Behavioral tests assessed somatic mechanical and thermal sensitivity. ASIC1 was expressed in sensory ganglia and was lost after disruption of the ASIC1 gene. Loss of ASIC1 increased mechanosensitivity in all colonic and gastroesophageal mechanoreceptor subtypes. In addition, ASIC1-/- mice showed almost double the gastric emptying time of wild-type mice. In contrast, loss of ASIC1 did not affect function in any of the 5 types of cutaneous mechanoreceptors, nor did it affect paw withdrawal responses or fecal output. ASIC1 influences visceral but not cutaneous mechanoreceptor function, suggesting that different mechanisms underlie mechanosensory function in gut and skin. The role of ASIC1 is highlighted by prolonging gastric emptying of a meal in ASIC1-/- animals.
Linaclotide treatment reduces endometriosis-associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross-talk
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2019
DOI: 10.1097/J.PAIN.0000000000001657
Abstract: Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain. Here, we investigated the effects of linaclotide, a Food and Drug Administration–approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium transplantation into the intestinal mesentery, rats developed endometrial lesions as well as vaginal hyperalgesia to distension and decreased mechanical hind paw withdrawal thresholds. Daily oral administration of linaclotide, a peripherally restricted guanylate cyclase-C (GC-C) agonist peptide acting locally within the gastrointestinal tract, increased pain thresholds to vaginal distension and mechanical hind paw withdrawal thresholds relative to vehicle treatment. Furthermore, using a cross-over design, administering linaclotide to rats previously administered vehicle resulted in increased hind paw withdrawal thresholds, whereas replacing linaclotide with vehicle treatment decreased hind paw withdrawal thresholds. Retrograde tracing of sensory afferent nerves from the ileum, colon, and vagina revealed that central terminals of these afferents lie in close apposition to one another within the dorsal horn of the spinal cord. We also identified dichotomizing dual-labelled ileal/colon innervating afferents as well as colon/vaginal dual-labelled neurons and a rare population of triple traced ileal/colon/vaginal neurons within thoracolumbar DRG. These observations provide potential sources of cross-organ interaction at the level of the DRG and spinal cord. GC-C expression is absent in the vagina and endometrial cysts suggesting that the actions of linaclotide are shared through nerve pathways between these organs. In summary, linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but also for concurrent treatment of comorbid chronic pelvic pain syndromes.
Cytokine Modulation of Visceral Afferents via Cation Channels is Switched in Chronic Visceral Hypersensitivity
Publisher: Elsevier BV
Date: 05-2011
Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation
Publisher: Informa UK Limited
Date: 07-2013
DOI: 10.1586/17474124.2013.820045
Abstract: Preclinical experiments in rodent models have recently provided new information on the mechanisms underlying pain sensation in chronic visceral hypersensitivity, as well as insights into the mechanism of action of new drugs targeting abdominal pain in irritable bowel syndrome (IBS). This article describes the evidence base supporting the role of guanylate cyclase C (GC-C) activation in the modulation of gastrointestinal transit and, in particular, in visceral hypersensitivity. We propose that GC-C activation represents an important emerging target for pharmacotherapy in IBS with constipation (IBS-C), particularly given the recent regulatory approval of the GC-C agonist linaclotide as a treatment for IBS-C. More specifically, we address the following questions: "How is pain transmitted from the colon?" "How is abdominal pain increased in IBS-C?" "How can we reduce IBS-related abdominal pain - what drugs have been developed?" "Does linaclotide reduce abdominal pain in animals and humans?" and "How does linaclotide reduce abdominal pain?".
ASIC ion channels contribute to colonic mechanosensory function in mice
Publisher: Elsevier BV
Date: 04-2003
NaV1.6 regulates excitability of mechanosensitive sensory neurons
Publisher: Wiley
Date: 18-06-2019
DOI: 10.1113/JP278148
Colonic afferent input and dorsal horn neuron activation differs between the thoracolumbar and lumbosacral spinal cord
Publisher: American Physiological Society
Date: 09-2019
Abstract: The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli. NEW & NOTEWORTHY In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.
Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2016
DOI: 10.1038/NATURE17976
Guanylate cyclase-C receptor activation: unexpected biology
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.COPH.2012.10.005
Abstract: Guanylate cyclase-C (GC-C) is a transmembrane receptor activated by bacterial heat-stable enterotoxins and by the endogenous hormones guanylin and uroguanylin. GC-C plays key roles in the regulation of intestinal fluid and electrolyte homeostasis. This is highlighted by several recently identified human mutations in GUCY2C, the gene encoding GC-C, which leads to the respective gain or loss of function of GC-C, resulting in profound effects on gastrointestinal function. However, a wealth of recent studies indicates GC-C signalling extends to a multitude of erse additional functions. Recent pre-clinical and clinical studies demonstrate a novel first-in-class GC-C activating peptide, Linaclotide, provides effective relief from constipation and abdominal pain in patients with chronic constipation and constipation-predominant Irritable Bowel Syndrome. Accumulating evidence also suggests GC-C plays protective roles in mucosal barrier function, tissue injury and inflammation, whilst GC-C signalling is a key regulator of intestinal cell proliferation and apoptosis. Finally, recently identified extra-intestinal GC-C signalling pathways make novel contributions to the regulation of food intake and symptoms associated with Attention Deficit Hyperactivity Disorder. Consequently, these findings provide GC-C expression and its associated mutations as potential diagnostic markers for disease. They also provide current and future therapeutic potential for GC-C signalling within and outside the gastrointestinal tract.
Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome
Publisher: Proceedings of the National Academy of Sciences
Date: 16-07-2018
Abstract: Activated G protein-coupled receptors (GPCRs) internalize and can continue to signal from endosomes. The contribution of endosomal signaling to human disease is unknown. Proteases that are generated in the colon of patients with irritable bowel syndrome (IBS) can cleave protease-activated receptor-2 (PAR 2 ) on nociceptors to cause pain. We evaluated whether PAR 2 generates signals in endosomes of nociceptors that mediate persistent hyperexcitability and pain. Biopsies of colonic mucosa from IBS patients released proteases that induced PAR 2 endocytosis, endosomal signaling, and persistent hyperexcitability of nociceptors. When conjugated to the transmembrane lipid cholestanol, PAR 2 antagonists accumulated in endosomes and suppressed persistent hyperexcitability. The results reveal the therapeutic potential of endosomally targeted PAR 2 antagonists for IBS pain, and expand the contribution of endosomal GPCR signaling to encompass processes that are relevant to disease.
Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3′,5′- monophosphate
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1053/J.GASTRO.2013.08.017
Abstract: Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 μg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.
Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome
Publisher: American Chemical Society (ACS)
Date: 07-06-2021
Apelin targets gut contraction to control glucose metabolism via the brain
Publisher: BMJ
Date: 12-11-2015
DOI: 10.1136/GUTJNL-2015-310230
Abstract: The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific erometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.
Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors
Publisher: Wiley
Date: 08-11-2006
561 Chronic Oral Administration of the Guanylate Cyclase-C Agonist Linaclotide Attenuates Colitis Induced Bladder Afferent Hyperactivity
Publisher: Elsevier BV
Date: 04-2016
Gastrointestinal Sensation; General Principles
Publisher: Elsevier
Date: 2020
A Novel Role of Cyclic GMP in Colonic Sensory Neurotransmission in Healthy and TNBS-Treated Mice
Publisher: Elsevier BV
Date: 05-2011
Sprouting of colonic afferent central terminals and increased spinal mitogen-activated protein kinase expression in a mouse model of chronic visceral hypersensitivity
Publisher: Wiley
Date: 12-04-2012
DOI: 10.1002/CNE.23042
Abstract: Visceral pain following infection or inflammation is a major clinical problem. Although we have knowledge of how peripheral endings of colonic afferents change in disease, their central projections have been overlooked. With neuroanatomical tracing and colorectal distension (CRD), we sought to identify colonic afferent central terminals (CACTs), the dorsal horn (DH) neurons activated by colonic stimuli in the thoracolumbar (T10-L1) DH, and determine how they are altered by postinflammatory chronic colonic mechanical hypersensitivity. Retrograde tracing from the colon identified CACTs in the DH, whereas immunohistochemistry for phosphorylated MAP kinase ERK 1/2 (pERK) identified DH neurons activated by CRD (80 mmHg). In healthy mice, CACTs were located primarily in DH laminae I (LI) and V (LV) and projected down middle and lateral DH collateral pathways. CRD evoked pERK immunoreactivity in DH neurons, the majority of which were located in LI and LV, the same regions as CACTs. In postinflammatory mice, CACTs were significantly increased in T12-L1 compared with healthy mice. Although CACTs remained abundant in LI, they were more widespread and were now present in deeper laminae. After CRD, significantly more DH neurons were pERK-IR postinflammation (T12-L1), with abundant expression in LI and deeper laminae. In both healthy and postinflammatory mice, many pERK neurons were in close apposition to CACTs, suggesting that colonic afferents can stimulate specific DH neurons in response to noxious CRD. Overall, we demonstrate that CACT density and the number of responsive DH neurons in the spinal cord increase postinflammation, which may facilitate aberrant central representation of colonic nociceptive signaling following chronic peripheral hypersensitivity.
Identifying spinal sensory pathways activated by noxious esophageal acid
Publisher: Wiley
Date: 12-07-2013
DOI: 10.1111/NMO.12180
Abstract: The transient receptor potential vanilloid 1 (TRPV1) channel is critical for spinal afferent signaling of burning pain throughout the body. Such pain frequently originates from the esophagus, following acid reflux. The contribution of TRPV1 to spinal nociceptor signaling from the esophagus remains unclear. We aimed to identify the spinal afferent pathways that convey nociceptive signaling from the esophagus, specifically those sensitive to acid, and the extent to which TRPV1 contributes. Acid epsin (150 mM HCl/1 mg mL(-1) pepsin) or saline epsin was perfused into the esophageal lumen of anesthetized wild-type and TRPV1 null mice over 20 min, followed by atraumatic perfuse fixation and removal of the cervical and thoracic spinal cord and dorsal root ganglia (DRG). To identify neurons responsive to esophageal perfusate, immunolabeling for neuronal activation marker phosphorylated extracellular receptor-regulated kinase (pERK) was used. Labeling for calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) was then used to characterize responsive neurons. Esophageal acid epsin perfusion significantly increased the number of pERK-immunoreactive (IR) neurons in the DRG and the cervical and thoracic spinal cord dorsal horn (DH) relative to saline epsin (DRG P < 0.01 cervical DH P < 0.05 and thoracic DH P < 0.005). The number of pERK-IR neurons following acid perfusion was significantly attenuated in TRPV1 -/- mice (DH P < 0.05 and DRG P < 0.05). This study has identified populations of spinal afferent DRG neurons and DH neurons involved in signaling of noxious acid from the esophagus. There is a major contribution of TRPV1 to signaling within these pathways.
Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes
Publisher: BMJ
Date: 27-11-2009
Abstract: Nutrient feedback from the small intestine modulates upper gastrointestinal function and energy intake however, the molecular mechanism of nutrient detection is unknown. In the tongue, sugars are detected via taste T1R2 and T1R3 receptors and signalled via the taste G-protein alpha-gustducin (G alpha(gust)) and the transient receptor potential ion channel, TRPM5. These taste molecules are also present in the rodent small intestine, and may regulate gastrointestinal function. Absolute transcript levels for T1R2, T1R3, G alpha(gust) and TRPM5 were quantified in gastrointestinal mucosal biopsies from subjects with and without type 2 diabetes immunohistochemistry was used to locate G alpha(gust). Effects of luminal glucose on jejunal expression of taste molecules were also quantified in mice. T1R2, T1R3, G alpha(gust) and TRPM5 were preferentially expressed in the proximal small intestine in humans, with immunolabelling for G alpha(gust) localised to solitary cells dispersed throughout the duodenal villous epithelium. Expression of T1R2, T1R3, TRPM5 (all p<0.05) and G alpha(gust) (p<0.001) inversely correlated with blood glucose concentration in type 2 diabetes subjects but, as a group, did not differ from control subjects. Transcript levels of T1R2 were reduced by 84% following jejunal glucose perfusion in mice (p<0.05). Taste molecules are expressed in nutrient detection regions of the proximal small intestine in humans, consistent with a role in "tasting". This taste molecule expression is decreased in diabetic subjects with elevated blood glucose concentration, and decreased by luminal glucose in mice, indicating that intestinal "taste" signalling is under dynamic metabolic and luminal control.
A novel role for TRPM8 in visceral afferent function
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2011
DOI: 10.1016/J.PAIN.2011.01.027
Abstract: Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperatures and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of bowel hypersensitivity however, the underlying mechanisms of action are unclear. Here we determined the role of TRPM8 in colonic sensory pathways. Laser capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, and retrograde tracing were used to localise TRPM8 to colonic primary afferent neurons. In vitro extracellular single-fibre afferent recordings were used to determine the effect of TRPM8 channel activation on the chemosensory and mechanosensory function of colonic high-threshold afferent fibres. TRPM8 mRNA was present in colonic DRG neurons, whereas TRPM8 protein was present on nerve fibres throughout the wall of the colon. A subpopulation (24%, n=58) of splanchnic serosal and mesenteric afferents tested responded directly to icilin (5 μmol/L). Subsequently, icilin significantly desensitised afferents to mechanical stimulation (P<.0001 n=37). Of the splanchnic afferents responding to icilin, 21 (33%) also responded directly to the TRPV1 agonist capsaicin (3 μmol/L), and icilin reduced the direct chemosensory response to capsaicin. Icilin also prevented mechanosensory desensitization and sensitization induced by capsaicin and the TRPA1 agonist AITC (40 μmol/L), respectively. TRPM8 is present on a select population of colonic high threshold sensory neurons, which may also co-express TRPV1. TRPM8 couples to TRPV1 and TRPA1 to inhibit their downstream chemosensory and mechanosensory actions.
Small Bowel Homing T Cells Are Associated With Symptoms and Delayed Gastric Emptying in Functional Dyspepsia
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
DOI: 10.1038/AJG.2010.512
Abstract: Immune activation may have an important pathogenic role in the irritable bowel syndrome (IBS). While little is known about immunologic function in functional dyspepsia (FD), we have observed an association between cytokine secretion by peripheral blood mononuclear cells (PBMCs) and symptoms in IBS. Upper gastrointestinal inflammatory diseases are characterized by enhanced small bowel homing α4-, β7-integrin, chemokine receptor 9 (CCR9) positive T lymphocytes. We hypothesized that increased cytokine release and elevated circulating small bowel homing T cells are linked to the severity of symptoms in patients with FD. Thus, we aimed to (i) compare cytokine release in FD and healthy controls (HCs), (ii) quantify "gut homing" T cells in FD compared with HC and patients with IBS, and (iii) correlate the findings to symptom severity and gastric emptying. PBMC from 45 (Helicobacter pylori negative) patients with FD (Rome II) and 35 matched HC were isolated by density gradient centrifugation and cultured for 24 h. Cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10) was measured by enzyme-linked immunosorbent assay. CD4+ α4β7+CCR9+ T cells were quantified by flow cytometry in FD, HC and 23 patients with IBS. Gastric emptying was measured by scintigraphy. Symptom severity was assessed utilizing the standardized Gastrointestinal Symptom Score. FD patients had significantly higher TNF-α (107.2 ± 42.8 vs. 58.7 ± 7.4 pg/ml), IL-1β (204.8 ± 71.5 vs. 80.2 ± 17.4 pg/ml), and IL-10 (218 ± 63.3 vs. 110.9 ± 18.5 pg/ml) levels compared with HC, and enhanced gut homing lymphocytes compared with HC or IBS. Cytokine release and CD4+α4β7+CCR9+ lymphocytes were correlated with the symptom intensity of pain, cr s, nausea, and vomiting. Delayed gastric emptying was significantly associated (r = 0.78, P = 0.021) with CD4+α4β7+CCR9+ lymphocytes and IL-1β, TNF-α, and IL-10 secretion. Cellular immune activation with increased small bowel homing T cells may be key factors in the clinical manifestations of H. pylori-negative FD.
Conopeptide-Derived κ-Opioid Agonists (Conorphins)
Publisher: American Chemical Society (ACS)
Date: 22-02-2016
DOI: 10.1021/ACS.JMEDCHEM.5B00911
Abstract: Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.
Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BBI.2014.07.001
Abstract: Alterations in the neuro-immune axis contribute toward viscerosensory nerve sensitivity and symptoms in Irritable Bowel Syndrome (IBS). Inhibitory factors secreted from immune cells inhibit colo-rectal afferents in health, and loss of this inhibition may lead to hypersensitivity and symptoms. We aimed to determine the immune cell type(s) responsible for opioid secretion in humans and whether this is altered in patients with IBS. The β-endorphin content of specific immune cell lineages in peripheral blood and colonic mucosal biopsies were compared between healthy subjects (HS) and IBS patients. Peripheral blood mononuclear cell (PBMC) supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-Endorphin was identified predominantly in monocyte/macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in μ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte/macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.
Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2017
DOI: 10.1038/SREP42810
Abstract: Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (Na V ), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on Na V 1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective Na V toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all Na V subtypes, an increase in the inactivation time constant was observed only at Na V 1.8, while the slope factor of the conductance-voltage curves was significantly increased for Na V 1.7 and peak current was significantly increased for Na V 1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of Na V 1.8 and the tetrodotoxin-sensitive isoforms Na V 1.7 and Na V 1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of Na V isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
Chronic linaclotide treatment reduces colitis-induced neuroplasticity and reverses persistent bladder dysfunction.
Publisher: American Society for Clinical Investigation
Date: 04-10-2018
Gastric vagal afferent modulation by leptin is influenced by food intake status
Publisher: Wiley
Date: 18-02-2013
Pre-clinical Models of Endometriosis: A Focus on Chronic Pain
Publisher: Springer International Publishing
Date: 2023
Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons within thoracolumbar dorsal root ganglia
Publisher: Wiley
Date: 2007
DOI: 10.1002/CNE.21204
Abstract: Reducing colonic mechanosensitivity is an important potential strategy for reducing visceral pain. Mice lacking acid-sensing ion channels (ASIC) 1, 2, and 3 show altered colonic mechanosensory function, implicating ASICs in the mechanotransduction process. Deletion of ASICs affects mechanotransduction in visceral and cutaneous afferents differently, suggesting differential expression. We determined relative expression of ASIC1, 2, and 3 in mouse thoracolumbar dorsal root ganglia (DRG) by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (QPCR) and specifically in retrogradely traced colonic neurons isolated via laser capture microdissection. Localization of ASIC expression in DRG was determined with fluorescence in situ hybridization (FISH) and retrograde tracing. QPCR of whole thoracolumbar DRG revealed and abundance of ASIC2 > ASIC1 > ASIC3. Similarly, FISH of all neurons in thoracolumbar DRG demonstrated that ASIC2 was expressed in the most (40 +/- 1%) neurons, followed by ASIC3 (24 +/- 1%), then ASIC1 (18 +/- 1%). Retrograde tracing from the distal colon labeled 4 +/- 1% of neurons in T10-L1 DRG. In contrast to whole DRG, FISH of colonic neurons showed ASIC3 expression in 73 +/- 2%, ASIC2 in 47 +/- 0.5%, and ASIC1 in 30 +/- 2%. QPCR of laser captured colonic neurons revealed that ASIC3 was the most abundant ASIC transcript, followed by ASIC1, then ASIC2. We conclude that ASIC1, 2, and 3 are expressed preferentially in colonic neurons within thoracolumbar DRG. In particular ASIC3, the least abundant in the general population, is the most abundant ASIC transcript in colonic neurons. The prevalence of ASIC3 in neurons innervating the colon supports electrophysiological data showing that it makes a major contribution to colonic mechanotransduction and therefore may be a target for the treatment of visceral pain.
Activation of colo-rectal high-threshold afferent nerves by Interleukin-2 is tetrodotoxin-sensitive and upregulated in a mouse model of chronic visceral hypersensitivity.
Publisher: Wiley
Date: 14-10-2016
DOI: 10.1111/NMO.12696
Abstract: Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown. Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice. MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33% p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons. IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.
P139 OLORINAB, A PERIPHERALLY RESTRICTED, HIGHLY SELECTIVE AGONIST OF THE CANNABINOID RECEPTOR TYPE 2 FOR THE MANAGEMENT OF VISCERAL PAIN IN INFLAMMATORY BOWEL DISEASE (IBD) – PRECLINICAL AND EARLY CL
Publisher: Oxford University Press (OUP)
Date: 02-2019
MP42-05 CHRONIC ORAL ADMINISTRATION OF THE GUANYLATE CYCLASE-C AGONIST LINACLOTIDE ATTENUATES COLITIS INDUCED BLADDER AFFERENT AND DORSAL ROOT GANGLION HYPERACTIVITY
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2020
DOI: 10.1101/2020.12.18.423548
Abstract: Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Here we show in mice with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%) , either in idually or in combination, with high levels of co-expression with Trpv1 (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In ex vivo bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-clusterΔ −/− mice. In vitro whole-cell patch cl recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not Mrgpr-clusterΔ −/− mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors is not required for normal bladder function but does trigger hypersensitivity to distension, a critically valuable factor for therapeutic target development. Determining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.
Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents
Publisher: American Physiological Society
Date: 05-2007
Abstract: Ghrelin is a peptide released from gastric endocrine cells that has an orexigenic effect via a vagal pathway. Here we determine the effect of ghrelin on mechanosensitivity of upper-intestinal vagal afferent fibers in ferret and mouse. The responses of gastroesophageal vagal afferents to graded mechanical stimulation were determined in vitro before and during application of ghrelin to their peripheral endings. Three types of vagal afferent were tested: tension receptors responding to circumferential tension, mucosal receptors responding only to mucosal stroking, and tension/mucosal (TM) receptors in ferret esophagus that responded to both stimuli. In the mouse, ghrelin did not significantly affect the response of mucosal receptors to mucosal stroking with calibrated von Frey hairs. However, it significantly reduced responses of tension receptors to circumferential tension ( P 0.005 two-way ANOVA) by up to 40%. This inhibition was reversed by the ghrelin receptor antagonist [d-Lys-3]-growth hormone-releasing peptide (GHRP)-6. In the ferret, ghrelin significantly reduced the response of mucosal and TM receptors to mucosal stroking with calibrated von Frey hairs. Surprisingly, ghrelin did not significantly alter the response to circumferential tension in either tension or TM receptors. RT-PCR analysis indicated that both ghrelin and its receptor are expressed in vagal afferent cell bodies in mouse nodose ganglia. In conclusion, ghrelin selectively inhibits subpopulations of mechanically sensitive gastroesophageal vagal afferents there is also potential for ghrelin release from vagal afferents. However, the subpopulation of afferents inhibited differs between species. These data have broad implications for ghrelin's role in food intake regulation and reflex control of gastrointestinal function.
Orai1- and Orai2-, but not Orai3-mediated I
Publisher: Wiley
Date: 25-12-2022
DOI: 10.1113/JP282502
Abstract: Three Orai (Orai1, Orai2, and Orai3) and two stromal interaction molecule (STIM1 and STIM2) mammalian protein homologues constitute major components of the store‐operated Ca 2+ entry mechanism. When co‐expressed with STIM1, Orai1, Orai2 and Orai3 form highly selective Ca 2+ channels with properties of Ca 2+ release‐activated Ca 2+ (CRAC) channels. Despite the high level of homology between Orai proteins, CRAC channels formed by different Orai isoforms have distinctive properties, particularly with regards to Ca 2+ ‐dependent inactivation, inhibition otentiation by 2‐aminoethyl diphenylborinate and sensitivity to reactive oxygen species. This study characterises and compares the regulation of Orai1, Orai2‐ and Orai3‐mediated CRAC current ( I CRAC ) by intracellular pH (pH i ). Using whole‐cell patch cl ing of HEK293T cells heterologously expressing Orai and STIM1, we show that I CRAC formed by each Orai homologue has a unique sensitivity to changes in pH i . Orai1‐mediated I CRAC exhibits a strong dependence on pH i of both current litude and the kinetics of Ca 2+ ‐dependent inactivation. In contrast, Orai2 litude, but not kinetics, depends on pH i , whereas Orai3 shows no dependence on pH i at all. Investigation of different Orai1–Orai3 chimeras suggests that pH i dependence of Orai1 resides in both the N‐terminus and intracellular loop 2, and may also involve pH‐dependent interactions with STIM1. image It has been shown previously that Orai1/stromal interaction molecule 1 (STIM1)‐mediated Ca 2+ release‐activated Ca 2+ current ( I CRAC ) is inhibited by intracellular acidification and potentiated by intracellular alkalinisation. The present study reveals that CRAC channels formed by each of the Orai homologues Orai1, Orai2 and Orai3 has a unique sensitivity to changes in intracellular pH (pH i ). The litude of Orai2 current is affected by the changes in pH i similarly to the litude of Orai1. However, unlike Orai1, fast Ca 2+ ‐dependent inactivation of Orai2 is unaffected by acidic pH i . In contrast to both Orai1 and Orai2, Orai3 is not sensitive to pH i changes. Domain swapping between Orai1 and Orai3 identified the N‐terminus and intracellular loop 2 as the molecular structures responsible for Orai1 regulation by pH i . Reduction of I CRAC dependence on pH i seen in a STIM1‐independent Orai1 mutant suggested that some parts of STIM1 are also involved in I CRAC modulation by pH i .
Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2022
DOI: 10.1038/S41575-022-00682-Y
Abstract: The management of visceral pain in patients with disorders of gut-brain interaction, notably irritable bowel syndrome, presents a considerable clinical challenge, with few available treatment options. Patients are increasingly using cannabis and cannabinoids to control abdominal pain. Cannabis acts on receptors of the endocannabinoid system, an endogenous system of lipid mediators that regulates gastrointestinal function and pain processing pathways in health and disease. The endocannabinoid system represents a logical molecular therapeutic target for the treatment of pain in irritable bowel syndrome. Here, we review the physiological and pathophysiological functions of the endocannabinoid system with a focus on the peripheral and central regulation of gastrointestinal function and visceral nociception. We address the use of cannabinoids in pain management, comparing them to other treatment modalities, including opioids and neuromodulators. Finally, we discuss emerging therapeutic candidates targeting the endocannabinoid system for the treatment of pain in irritable bowel syndrome.
Increased κ-opioid receptor expression and function during chronic visceral hypersensitivity
Publisher: BMJ
Date: 27-11-2014
Identification of Colonic Afferent Central Terminals and Changes Following Colonic Inflammation
Publisher: Elsevier BV
Date: 05-2011
PTU-135 Mechanism of Action for Linaclotide-Induced Abdominal Pain Relief
Publisher: BMJ
Date: 06-2013
Identifying the ion channels responsible for signaling gastro-intestinal based pain
Publisher: MDPI AG
Date: 26-08-2010
DOI: 10.3390/PH3092768
A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-08-2021
Acute colitis chronically alters immune infiltration mechanisms and sensory neuro-immune interactions.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.BBI.2016.11.015
Abstract: Little is understood regarding how disease progression alters immune and sensory nerve function in colitis. We investigated how acute colitis chronically alters immune recruitment and the impact this has on re-activated colitis. To understand the impact of disease progress on sensory systems we investigated the mechanisms underlying altered colonic neuro-immune interactions after acute colitis. Inflammation was compared in mouse models of health, acute tri-nitrobenzene sulphonic acid (TNBS) colitis, Remission and Reactivated colitis. Cytokine concentrations were compared by ELISA in-situ and in explanted colon tissue. Colonic infiltration by CD11b/F4-80 macrophage, CD4 T Colonic damage, MPO activity, macrophage infiltration, IL-1β and IL-6 concentrations were lower in Reactivated compared to Acute colitis. T Acute colitis persistently alters immune responses and afferent nerve signalling pathways to successive episodes of colitis. These findings highlight the complexity of viscero-sensory neuro-immune interactions in painful remitting and relapsing diseases.
Cyclic analogues of α-conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain
Publisher: Wiley
Date: 13-02-2018
DOI: 10.1111/BPH.14115
Contribution of membrane receptor signalling to chronic visceral pain
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.BIOCEL.2018.02.017
Abstract: Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.
Neuroplasticity and dysfunction after gastrointestinal inflammation
Publisher: Springer Science and Business Media LLC
Date: 08-07-2014
DOI: 10.1038/NRGASTRO.2014.103
Abstract: The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most in iduals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.
Cross-organ sensitization between the colon and bladder: to pee or not to pee?
Publisher: American Physiological Society
Date: 03-2018
Abstract: Chronic abdominal and pelvic pain are common debilitating clinical conditions experienced by millions of patients around the globe. The origin of such pain commonly arises from the intestine and bladder, which share common primary roles (the collection, storage, and expulsion of waste). These visceral organs are located in close proximity to one another and also share common innervation from spinal afferent pathways. Chronic abdominal pain, constipation, or diarrhea are primary symptoms for patients with irritable bowel syndrome or inflammatory bowel disease. Chronic pelvic pain and urinary urgency and frequency are primary symptoms experienced by patients with lower urinary tract disorders such as interstitial cystitis ainful bladder syndrome. It is becoming clear that these symptoms and clinical entities do not occur in isolation, with considerable overlap in symptom profiles across patient cohorts. Here we review recent clinical and experimental evidence documenting the existence of “cross-organ sensitization” between the colon and bladder. In such circumstances, colonic inflammation may result in profound changes to the sensory pathways innervating the bladder, resulting in severe bladder dysfunction.
Gut nociceptors
Publisher: Springer Science and Business Media LLC
Date: 28-01-2020
Pruritogenic mechanisms and gut sensation: putting the “irritant” into irritable bowel syndrome
Publisher: American Physiological Society
Date: 06-2021
Abstract: Chronic abdominal pain is a common clinical condition experienced by patients with irritable bowel syndrome (IBS). A general lack of suitable treatment options for the management of visceral pain is the major contributing factor to the debilitating nature of the disease. Understanding the underlying causes of chronic visceral pain is pivotal to identifying new effective therapies for IBS. This review provides the current evidence, demonstrating that mediators and receptors that induce itch in the skin also act as “gut irritants” in the gastrointestinal tract. Activation of these receptors triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system leading to visceral hypersensitivity and visceral pain. Accumulating evidence points to significant roles of irritant mediators and their receptors in visceral hypersensitivity and thus constitutes potential targets for the development of more effective therapeutic options for IBS.
The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain
Publisher: Wiley
Date: 10-03-2023
DOI: 10.1111/JNC.15795
Abstract: Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis‐associated CPP remain underdeveloped. Here, we examined the role of the voltage‐gated sodium (Na V ) channel Na V 1.7 in (i) the sensitivity of vagina‐innervating sensory afferents and investigated whether (ii) Na V 1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis‐associated CPP. The mechanical responsiveness of vagina‐innervating sensory afferents was assessed with ex vivo single‐unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of Na V 1.7 with OD1 sensitised vagina‐innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina‐innervating pelvic afferents to mechanical stimuli. The highly selective Na V 1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a Na V 1.7‐dependent manner. Moreover, in vivo intra‐vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that Na V 1.7 plays a crucial role in endometriosis‐induced vaginal hyperalgesia. Importantly, Na V 1.7 inhibition selectively alleviated endometriosis‐associated CPP without the loss of normal sensation, suggesting that selective targeting of Na V 1.7 could improve the quality of life of women with endometriosis. image
Experimental colitis models
Publisher: Humana Press
Date: 2012
Tetrodotoxin-sensitive voltage-gated sodium channels regulate bladder afferent responses to distension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-08-2018
DOI: 10.1097/J.PAIN.0000000000001368
Abstract: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent, chronic bladder disorder that negatively impacts the quality of life for ∼5% of the western population. Hypersensitivity of mechanosensory afferents embedded within the bladder wall is considered a key component in mediating IC/BPS symptoms. Bladder infusion of voltage-gated sodium (Na v ) channel blockers show clinical efficacy in treating IC/BPS symptoms however, the current repertoire of Na v channels expressed by and contributing to bladder afferent function is unknown. We used single-cell reverse-transcription polymerase chain reaction of retrogradely traced bladder-innervating dorsal root ganglia (DRG) neurons to determine the expression profile of Na v channels, and patch-cl recordings to characterise the contribution of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na v channels to total sodium current and neuronal excitability. We determined the TTX-S and TTX-R contribution to mechanosensitive bladder afferent responses ex vivo and spinal dorsal horn activation in vivo. Single-cell reverse-transcription polymerase chain reaction of bladder-innervating DRG neurons revealed significant heterogeneity in Na v channel coexpression patterns. However, TTX-S Na v channels contribute the vast majority of the total sodium current density and regulate the neuronal excitability of bladder DRG neurons. Furthermore, TTX-S Na v channels mediate almost all bladder afferent responses to distension. In vivo intrabladder infusion of TTX significantly reduces activation of dorsal horn neurons within the spinal cord to bladder distension. These data provide the first comprehensive analysis of Na v channel expression within sensory afferents innervating the bladder. They also demonstrate an essential role for TTX-S Na v channel regulation of bladder-innervating DRG neuroexcitability, bladder afferent responses to distension, and nociceptive signalling to the spinal cord.
Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract
Publisher: American Chemical Society (ACS)
Date: 09-06-2020
Activation of splanchnic and pelvic colonic afferents by bradykinin in mice
Publisher: Wiley
Date: 18-11-2005
DOI: 10.1111/J.1365-2982.2005.00710.X
Abstract: Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here, we determined whether these pathways differ also in their chemosensitivity to bradykinin. Using a novel in vitro mouse colon preparation, serosal afferents were recorded from the LSN and PN and distinguished based on their mechanosensitivity to von Frey filaments (70-4000 mg) and insensitivity to colonic stretch (1-5 g) or fine mucosal stroking (10 mg). Bradykinin was applied into a ring around mechanoreceptive fields. The LSN and PN afferents had different dynamic responses to mechanical stimuli: PN afferents required lower intensity stimuli, evoked larger responses, and displayed more maintained responses than LSN afferents. Bradykinin (1 micromol L-1) excited 66% (27 of 41) of LSN afferents. Responses to probing were potentiated after bradykinin. The concentration-dependent (EC50: 0.16 micromol L-1) response was reversed by the B2-receptor antagonist HOE-140 (10 nmol L-)). Twelve bradykinin responsive afferents were mechanically insensitive. More LSN serosal afferents responded to bradykinin than PN afferents (11%, P<0.001) , with larger responses (P<0.05). No mechanically insensitive PN afferents were recruited by bradykinin. Bradykinin potently stimulates most splanchnic serosal afferents via B2-receptors, but few pelvic afferents. Mechanically insensitive afferents recruited by bradykinin are exclusive to the LSN.
Synthesis of Multivalent [Lys(8)]-Oxytocin Dendrimers that Inhibit Visceral Nociceptive Responses
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/CH16407
Abstract: Peptide dendrimers are a novel class of precisely defined macromolecules of emerging interest. Here, we describe the synthesis, structure, binding affinity, receptor selectivity, functional activity, and antinociceptive properties of oxytocin-related dendrimers containing up to 16 copies of [Lys8]-oxytocin or LVT. These were generated using a copper(i)-catalyzed azide–alkyne cycloaddition (CuAAc) reaction with azido-pegylated LVT peptides on an alkyne–polylysine scaffold. 2D NMR analysis demonstrated that each attached LVT ligand was freely rotating and maintained identical 3D structures in each dendrimeric macromolecule. The binding affinity Ki at the oxytocin receptor increased approximately 17-, 12-, 3-, and 1.5-fold respectively for the 2-, 4-, 8-, and 16-mer dendrimeric LVT conjugates, compared with monomer azido-pegylated LVT (Ki = 9.5 nM), consistent with a multivalency effect. A similar trend in affinity was also observed at the related human V1a, V1b, and V2 receptors, with no significant selectivity change observed across this family of receptors. All LVT dendrimers were functionally active in vitro on human oxytocin receptors and inhibited colonic nociceptors potently in a mouse model of chronic abdominal pain.
Chronic Oral Administration of Linaclotide Inhibits Nociceptive Signalling in Response to Noxious Colorectal Distension in a Model of Chronic Visceral Hypersensitivity
Publisher: Elsevier BV
Date: 04-2017
Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif
Publisher: Wiley
Date: 07-03-2016
Abstract: α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the ersity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.
Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain
Publisher: American Chemical Society (ACS)
Date: 24-06-2021
Voltage-gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception.
Publisher: Wiley
Date: 06-02-2018
DOI: 10.1113/JP273461
TRP channels in visceral pain
Publisher: Bentham Science Publishers Ltd.
Date: 08-03-2013
DOI: 10.2174/1876386301306010023
Abstract: Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.
Serotonin exerts a direct modulatory role on bladder afferent firing in mice
Publisher: Wiley
Date: 13-10-2019
DOI: 10.1113/JP278751
Abstract: Functional disorders (i.e. interstitial cystitis ainful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non‐5‐HT 3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5‐HT. Whilst 5‐HT 3 receptors were not detected in mouse urothelium, 5‐HT 3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5‐HT 3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. Serotonin (5‐HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut–brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis ainful bladder syndrome, which manifests due to cross‐sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5‐HT in bladder afferent signalling and its role in colon–bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5‐HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid‐induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5‐HT receptor subtypes, the serotonin transporter (SERT) and 5‐HT‐producing enzymes was determined in the urothelium using RT‐PCR. Retrograde labelling of bladder‐projecting dorsal root ganglion neurons was used to investigate expression of 5‐HT 3 receptors using single cell RT‐PCR, while sensory neuronal and urothelial responses to 5‐HT were determined by live cell calcium imaging. 5‐HT elicited bladder afferent firing predominantly via 5‐HT 3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5‐HT bioavailability. Granisetron, a 5‐HT 3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5‐HT exerts a direct effect on bladder afferents to enhance signalling. 5‐HT 3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.
Co‐expression of μ and δ opioid receptors by mouse colonic nociceptors
Publisher: Wiley
Date: 22-05-2018
DOI: 10.1111/BPH.14222
Nitric Oxide Mechanism of Action on Visceral Nociceptors
Publisher: Elsevier BV
Date: 05-2011
All ahead stop! How intestinal motility adapts to cope with inflammation induced ulceration
Publisher: Wiley
Date: 26-02-2010
Experimentally induced bladder permeability evokes bladder afferent hypersensitivity in the absence of inflammation
Publisher: Frontiers Media SA
Date: 23-10-2020
Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1
Publisher: American Physiological Society
Date: 02-2020
DOI: 10.1152/AJPRENAL.00435.2019
Abstract: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited “silent afferents” that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes ( Hrh1– Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca 2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H 1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H 1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.
Peripheral and central neuroplasticity in a mouse model of endometriosis
Publisher: Wiley
Date: 22-05-2023
DOI: 10.1111/JNC.15843
Abstract: Chronic pelvic pain (CPP) is the most debilitating symptom of gynaecological disorders such as endometriosis. However, it remains unclear how sensory neurons from pelvic organs affected by endometriosis, such as the female reproductive tract, detect and transmit nociceptive events and how these signals are processed within the central nervous system (CNS). Using a previously characterized mouse model of endometriosis, we investigated whether the increased pain sensitivity occurring in endometriosis could be attributed to (i) changes in mechanosensory properties of sensory afferents innervating the reproductive tract, (ii) alterations in sensory input from reproductive organs to the spinal cord or (iii) neuroinflammation and sensitization of spinal neural circuits. Mechanosensitivity of vagina‐innervating primary afferents was examined using an ex vivo single‐unit extracellular recording preparation. Nociceptive signalling from the vagina to the spinal cord was quantified by phosphorylated MAP kinase ERK1/2 immunoreactivity. Immunohistochemistry was used to determine glial and neuronal circuit alterations within the spinal cord. We found that sensory afferents innervating the rostral, but not caudal portions of the mouse vagina, developed mechanical hypersensitivity in endometriosis. Nociceptive signalling from the vagina to the spinal cord was significantly enhanced in mice with endometriosis. Moreover, mice with endometriosis developed microgliosis, astrogliosis and enhanced substance P neurokinin‐1 receptor immunoreactivity within the spinal cord, suggesting the development of neuroinflammation and sensitization of spinal circuitry in endometriosis. These results demonstrate endometriosis‐induced neuroplasticity occurring at both peripheral and central sites of sensory afferent pathways. These findings may help to explain the altered sensitivity to pain in endometriosis and provide a novel platform for targeted pain relief treatments for this debilitating disorder. image
Translating peripheral bladder afferent mechanosensitivity to neuronal activation within the lumbosacral spinal cord of mice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-12-2018
DOI: 10.1097/J.PAIN.0000000000001453
Abstract: Primary afferent neurons transduce distension of the bladder wall into action potentials that are relayed into the spinal cord and brain, where autonomic reflexes necessary for maintaining continence are coordinated with pathways involved in sensation. However, the relationship between spinal circuits involved with physiological and nociceptive signalling from the bladder has only been partially characterised. We used ex vivo bladder afferent recordings to characterise mechanosensitive afferent responses to graded distension (0-60 mm Hg) and retrograde tracing from the bladder wall to identify central axon projections within the dorsal horn of the lumbosacral (LS) spinal cord. Labelling of dorsal horn neurons with phosphorylated-MAP-kinase (pERK), combined with labelling for neurochemical markers (calbindin, calretinin, gamma aminobutyric acid, and parvalbumin) after in vivo bladder distension (20-60 mm Hg), was used to identify spinal cord circuits processing bladder afferent input. Ex vivo bladder distension evoked an increase in primary afferent output, and the recruitment of both low- and high-threshold mechanosensitive afferents. Retrograde tracing revealed bladder afferent projections that localised with pERK-immunoreactive dorsal horn neurons within the superficial laminae (superficial dorsal horn), dorsal gray commissure, and lateral collateral tracts of the LS spinal cord. Populations of pERK-immunoreactive neurons colabelled with calbindin, calretinin, or gamma aminobutyric acid, but not parvalbumin. Noxious bladder distension increased the percentage of pERK-immunoreactive neurons colabelled with calretinin. We identified LS spinal circuits supporting autonomic and nociceptive reflexes responsible for maintaining continence and bladder sensations. Our findings show for the first time that low- and high-threshold bladder afferents relay into similar dorsal horn circuits, with nociceptive signalling recruiting a larger number of neurons.
Molecular basis of mechanosensitivity
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.AUTNEU.2009.07.017
Abstract: An organism's ability to perceive mechanical stimuli is vital in determining how it responds to environmental challenges. External mechanosensation is responsible for the senses of touch, hearing, proprioception and aspects of somatic pain. Internally, mechanosensation underlies the initiation of autonomic reflex control and all manner of visceral sensations including chronic pain. Despite our increased knowledge of the molecular identity of invertebrate proteins that convert mechanical stimuli into electrical signals, understanding the complete molecular basis of mammalian mechanotransduction is currently a major challenge. Although the number of candidate molecules that serve as mechanotransducers is ever increasing, debate currently rages as to whether or not they contribute directly or indirectly to mammalian mechanotransduction. Despite these controversies novel molecules have been identified and their contribution to mechanosensation, be it direct or indirect, have improved our understanding of the mechanisms underlying visceral mechanosensation. Moreover, they have provided potential new pharmacological strategies for the control of visceral pain.
Trefoil Factor Family: Unresolved Questions and Clinical Perspectives
Publisher: Elsevier BV
Date: 05-2019
Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Publisher: Springer Science and Business Media LLC
Date: 30-01-2014
DOI: 10.1038/NCOMMS4165
Abstract: Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general.
Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function
Publisher: BMJ
Date: 10-2005
Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia
Publisher: American Physiological Society
Date: 05-2008
Abstract: Protease-activated receptor (PAR 2 ) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR 2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR 2 -induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR 2 , and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4 +/+ mice, intraluminal PAR 2 activating peptide (PAR 2 -AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR 2 -induced hyperalgesia was not observed in TRPV4 −/− mice. PAR 2 -AP evoked discharge of action potentials from colonic afferent neurons in TRPV4 +/+ mice, but not from TRPV4 −/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR 2 -AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR 2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR 2 -induced mechanical hyperalgesia and excitation of colonic afferent neurons.
Comparative localization of colorectal sensory afferent central projections in the mouse spinal cord dorsal horn and caudal medulla dorsal vagal complex
Publisher: Wiley
Date: 14-10-2023
DOI: 10.1002/CNE.25546
P139 OLORINAB, A PERIPHERALLY RESTRICTED, HIGHLY SELECTIVE AGONIST OF THE CANNABINOID RECEPTOR TYPE 2 FOR THE MANAGEMENT OF VISCERAL PAIN IN INFLAMMATORY BOWEL DISEASE (IBD) – PRECLINICAL AND EARLY CL
Publisher: Elsevier BV
Date: 02-2019
Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice
Publisher: Wiley
Date: 08-2005
Chronic intra-colonic linaclotide administration alters glial activation in a mouse model of chronic visceral hypersensitivity
Publisher: Elsevier BV
Date: 05-2020
Food for thought about the immune drivers of gut pain
Publisher: Springer Science and Business Media LLC
Date: 13-01-2021
The Enteric Nervous System II
Publisher: Springer International Publishing
Date: 2022
Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice
Publisher: Elsevier BV
Date: 07-2004
DOI: 10.1053/J.GASTRO.2004.04.008
Abstract: Mechanosensory information from the colon is conducted via lumbar splanchnic nerves (LSN) and sacral pelvic nerves (PN) to the spinal cord. The precise nature of mechanosensory information encoded by each pathway has remained elusive. Here, we characterize and directly compare the properties of mechanosensitive primary afferents from these 2 pathways. Using a novel in vitro mouse colon preparation, mechanosensitive primary afferents were recorded from the LSN and PN and distinguished based on their response to receptive field stimulation with 3 distinct mechanical stimuli: probing (70 mg-4 g), circular stretch (1-5 g), and mucosal stroking (10-1000 mg). Five different classes of afferent were recorded from the LSN and PN. Three of these classes of afferent (serosal, muscular, and mucosal) were conserved between both pathways however, their respective proportions, receptive field distributions, and response properties differed greatly. In general, these 3 classes of afferent recorded from the PN responded to lower stimulation intensities, displayed greater response magnitudes, and adapted less completely to mechanical stimulation compared with their LSN counterparts. In addition, the LSN and PN each contain a specialized class of afferent (mesenteric and muscular/mucosal), which is unique to their respective pathway. The splanchnic and pelvic pathways contain distinct populations of mechanosensitive afferents. These afferents are capable of detecting an array of mechanical stimuli and are in idually tuned to detect the type, magnitude, and duration of the stimulus. This knowledge contributes to our understanding of the role that these 2 pathways play in conveying mechanical information from the colon.
TRP channels: New targets for visceral pain
Publisher: BMJ
Date: 10-12-2010
Innate immune response to bacterial urinary tract infection sensitises high-threshold bladder afferents and recruits silent nociceptors
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-08-2020
DOI: 10.1097/J.PAIN.0000000000001692
Abstract: The bladder is innervated by primary afferent nerve fibres that detect bladder distension and, through projections into the spinal cord, provide sensory input to the central nervous system circuits regulating bladder sensation and function. Uropathogenic E. coli (UPEC) bacteria are the primary cause of urinary tract infection (UTI) in adults, inducing clinical symptoms characterised by exaggerated bladder sensation, including urgency, frequency, and pelvic pain. However, the mechanisms underlying UTI-induced modulation of bladder afferent function are yet to be explored. Here, we isolated supernatants from the bladders of female mice acutely infected with UPEC (strain CFT073), or those sham-treated with phosphate buffered saline. Supernatants were then applied into the bladder lumen of healthy donor mice, and multiunit bladder afferent nerve responses to distension measured ex-vivo. Supernatant constituents from UPEC or sham-treated mice were analysed using a mouse cytokine multiplex assay. Supernatants from UPEC-infected mice significantly enhanced bladder afferent firing to distension in the absence of changes in muscle compliance. Further evaluation revealed that UPEC supernatants exclusively sensitised high-threshold bladder mechanoreceptors to graded bladder distension and also recruited a population of “silent nociceptors” to become mechanosensitive, thereby lifying bladder afferent responses to physiological stimuli. UPEC supernatants contained significantly elevated concentrations of a range of cytokines released from innate immune cells, including but not limited to TNF-α, IL-1β, IL-6, IL-17, IFN-gamma, and MCP-1. These data provide novel mechanistic insight into how UPEC-mediated UTI induces bladder hypersensitivity and the symptoms of frequency, urgency, and pelvic pain.
HIGHLIGHTS IN BASIC AUTONOMIC NEUROSCIENCES
Publisher: Elsevier BV
Date: 2010
The hot mustard receptor's role in gut motor function
Publisher: Elsevier BV
Date: 08-2011
Olorinab (APD371), a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2, reduces colitis-induced acute and chronic visceral hypersensitivity in rodents
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-04-2022
DOI: 10.1097/J.PAIN.0000000000002314
Abstract: Abdominal pain is a key symptom of inflammatory bowel disease and irritable bowel syndrome, for which there are inadequate therapeutic options. We tested whether olorinab—a highly selective, full agonist of the cannabinoid receptor 2 (CB 2 )—reduced visceral hypersensitivity in models of colitis and chronic visceral hypersensitivity (CVH). In rodents, colitis was induced by intrarectal administration of nitrobenzene sulfonic acid derivatives. Control or colitis animals were administered vehicle or olorinab (3 or 30 mg/kg) twice daily by oral gavage for 5 days, starting 1 day before colitis induction. Chronic visceral hypersensitivity mice were administered olorinab (1, 3, 10, or 30 mg/kg) twice daily by oral gavage for 5 days, starting 24 days after colitis induction. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs) to colorectal distension. Ex vivo afferent recordings determined colonic nociceptor firing evoked by mechanical stimuli. Colitis and CVH animals displayed significantly elevated VMRs to colorectal distension and colonic nociceptor hypersensitivity. Olorinab treatment significantly reduced VMRs to control levels in colitis and CVH animals. In addition, olorinab reduced nociceptor hypersensitivity in colitis and CVH states in a concentration- and CB 2 -dependent manner. By contrast, olorinab did not alter VMRs nor nociceptor responsiveness in control animals. Cannabinoid receptor 2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate that olorinab reduces visceral hypersensitivity through CB 2 agonism in animal models, suggesting that olorinab may provide a novel therapy for inflammatory bowel disease– and irritable bowel syndrome–associated abdominal pain.
Visceral Pain
Publisher: Annual Reviews
Date: 10-02-2019
DOI: 10.1146/ANNUREV-PHYSIOL-020518-114525
Abstract: Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for % of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs. In this review, we highlight key mechanisms underlying chronic abdominal and pelvic pain associated with functional and inflammatory disorders of the gastrointestinal and urinary tracts. This includes how the colon and bladder are innervated by specialized subclasses of spinal afferents, how these afferents become sensitized in highly dynamic signaling environments, and the subsequent development of neuroplasticity within visceral pain pathways. We also highlight key contributing factors, including alterations in commensal bacteria, altered mucosal permeability, epithelial interactions with afferent nerves, alterations in immune or stress responses, and cross talk between these two adjacent organs.
A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-12-2022
DOI: 10.1097/J.PAIN.0000000000002552
Abstract: Endometriosis is a chronic and debilitating condition, commonly characterised by chronic pelvic pain (CPP) and infertility. Chronic pelvic pain can be experienced across multiple pelvic organs, with comorbidities commonly effecting the bowel, bladder, and vagina. Despite research efforts into endometriosis pathophysiology, little is known about how endometriosis induces CPP, and as such, therapeutic interventions are lacking. The aim of this study was to characterise a syngeneic mouse model of endometriosis that mimics naturally occurring retrograde menstruation, thought to precede endometriosis development in patients, and determine whether these mice exhibit signs of CPP and altered behaviour. We characterised the development of endometriosis over 10 weeks following uterine tissue inoculation, measured in vivo and ex vivo hypersensitivity to mechanical stimuli across multiple visceral organs, and assessed alterations in animal spontaneous behaviour. We confirmed that inoculated uterine horn tissue formed into endometriosis lesions throughout the peritoneal cavity, with significant growth by 8 to 10 weeks post inoculation. Additionally, we found that mice with fully developed endometriosis displayed hypersensitivity evoked by (1) vaginal distension, (2) colorectal distension, (3) bladder distension, and (4) cutaneous thermal stimulation, compared to their sham counterparts. Moreover, endometriosis mice displayed alterations in spontaneous behaviour indicative of (5) altered bladder function and (6) anxiety. This model creates a foundation for mechanistical studies into the diffuse CPP associated with endometriosis and the development of targeted therapeutic interventions to improve the quality of life of women with endometriosis.
Pharmacological modulation of voltage-gated sodium (NaV) channels alters nociception arising from the female reproductive tract
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-08-2021
DOI: 10.1097/J.PAIN.0000000000002036
Abstract: Dyspareunia, also known as vaginal hyperalgesia, is a prevalent and debilitating symptom of gynaecological disorders such as endometriosis and vulvodynia. Despite this, the sensory pathways transmitting nociceptive information from female reproductive organs remain poorly characterised. As such, the development of specific treatments for pain associated with dyspareunia is currently lacking. Here, we examined, for the first time, (1) the mechanosensory properties of pelvic afferent nerves innervating the mouse vagina (2) the expression profile of voltage-gated sodium (Na V ) channels within these afferents and (3) how pharmacological modulation of these channels alters vaginal nociceptive signalling ex vivo, in vitro, and in vivo. We developed a novel afferent recording preparation and characterised responses of pelvic afferents innervating the mouse vagina to different mechanical stimuli. Single-cell reverse transcription-polymerase chain reaction determined mRNA expression of Na V channels within vagina-innervating dorsal root ganglia neurons. Vagina-innervating dorsal root ganglia neuroexcitability was measured using whole-cell patch-cl electrophysiology. Nociception evoked by vaginal distension was assessed by dorsal horn neuron activation within the spinal cord and quantification of visceromotor responses. We found that pelvic afferents innervating the vagina are tuned to detect various mechanical stimuli, with Na V channels abundantly expressed within these neurons. Pharmacological modulation of Na V channels (with veratridine or tetrodotoxin) correspondingly alters the excitability and mechanosensitivity of vagina-innervating afferents, as well as dorsal horn neuron activation and visceromotor responses evoked by vaginal distension. This study identifies potential molecular targets that can be used to modulate vaginal nociceptive signalling and aid in the development of approaches to manage endometriosis and vulvodynia-related dyspareunia.
The T type calcium channel CaV3.2 regulates bladder afferent responses to mechanical stimuli.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-10-2022
DOI: 10.1097/J.PAIN.0000000000002795
Abstract: The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. Despite this, the full array of ion channels that regulate bladder afferent responses to mechanical stimuli have yet to be determined. Here, we investigated the role of low-voltage-activated T-type calcium (Ca V 3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V 3.2, but not Ca V 3.1 or Ca V 3.3, in in idual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V 3.2 with TTA-A2 and ABT-639, selective blockers of T-type calcium channels, dose-dependently attenuated ex-vivo bladder afferent responses to distension in the absence of changes to muscle compliance. Further evaluation revealed that Ca V 3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.
Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways
Publisher: Elsevier BV
Date: 06-2017
Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity
Publisher: American Society for Clinical Investigation
Date: 17-10-2019
G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease.
Publisher: The American Association of Immunologists
Date: 05-2017
Abstract: G-CSF or CSF-3, originally defined as a regulator of granulocyte lineage development via its cell surface receptor (G-CSFR), can play a role in inflammation, and hence in many pathologies, due to its effects on mature lineage populations. Given this, and because pain is an extremely important arthritis symptom, the efficacy of an anti–G-CSFR mAb for arthritic pain and disease was compared with that of a neutrophil-depleting mAb, anti-Ly6G, in both adaptive and innate immune-mediated murine models. Pain and disease were ameliorated in Ag-induced arthritis, zymosan-induced arthritis, and methylated BSA/IL-1 arthritis by both prophylactic and therapeutic anti–G-CSFR mAb treatment, whereas only prophylactic anti-Ly6G mAb treatment was effective. Efficacy for pain and disease correlated with reduced joint neutrophil numbers and, importantly, benefits were noted without necessarily the concomitant reduction in circulating neutrophils. Anti–G-CSFR mAb also suppressed zymosan-induced inflammatory pain. A new G-CSF–driven (methylated BSA/G-CSF) arthritis model was established enabling us to demonstrate that pain was blocked by a cyclooxygenase-2 inhibitor, suggesting an indirect effect on neurons. Correspondingly, dorsal root ganglion neurons cultured in G-CSF failed to respond to G-CSF in vitro, and Csf3r gene expression could not be detected in dorsal root ganglion neurons by single-cell RT-PCR. These data suggest that G-CSFR/G-CSF targeting may be a safe therapeutic strategy for arthritis and other inflammatory conditions, particularly those in which pain is important, as well as for inflammatory pain per se.
Involvement of metabotropic glutamate 5 receptor in visceral pain
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-07-2008
DOI: 10.1016/J.PAIN.2007.09.008
Abstract: Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague-Dawley rats were subjected to repeated, isobaric CRD (12 x 80 mmHg, for 30s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1-10 micromol/kg, i.v.) and MTEP (1-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52+/-8% (p<0.01) and 25+/-11% (p<0.05), respectively, without affecting colonic compliance. MPEP (10 micromol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33+/-9% (p<0.01) and 35+/-8% (p<0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0-5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55-78% by 10 microM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents their responses were reduced 50% by 10 microM MTEP (p<0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.
A Visceral Representation of Itch
Publisher: Elsevier BV
Date: 04-2201
Purinergic receptor mediated calcium signalling in urothelial cells
Publisher: Springer Science and Business Media LLC
Date: 06-11-2019
DOI: 10.1038/S41598-019-52531-9
Abstract: Non-neuronal ATP released from the urothelium in response to bladder stretch is a key modulator of bladder mechanosensation. Whilst non-neuronal ATP acts on the underlying bladder afferent nerves to facilitate sensation, there is also the potential for ATP to act in an autocrine manner, modulating urothelial cell function. The aim of this study was to systematically characterise the functional response of primary mouse urothelial cells (PMUCs) to ATP. PMUCs isolated from male mice (14–16 weeks) were used for live-cell fluorescent calcium imaging and qRT-PCR to determine the expression profile of P2X and P2Y receptors. The majority of PMUCs (74–92%) responded to ATP (1 μM–1 mM), as indicted by an increase in intracellular calcium (iCa 2+ ). PMUCs exhibited dose-dependent responses to ATP (10 nM–1 mM) in both calcium containing (2 mM, EC 50 = 3.49 ± 0.77 μM) or calcium free (0 mM, EC 50 = 9.5 ± 1.5 μM) buffers. However, maximum iCa 2+ responses to ATP were significantly attenuated upon repetitive applications in calcium containing but not in calcium free buffer. qRT-PCR revealed expression of P2X 1–6 , and P2Y 1–2 , P2Y 4 , P2Y 6 , P2Y 11–14 , but not P2X 7 in PMUCs. These findings suggest the major component of ATP induced increases in iCa 2+ are mediated via the liberation of calcium from intracellular stores, implicating functional P2Y receptors that are ubiquitously expressed on PMUCs.
Pain in Endometriosis
Publisher: Frontiers Media SA
Date: 06-10-2020
Disengaging spinal afferent nerve communication with the brain in live mice
Publisher: Springer Science and Business Media LLC
Date: 14-09-2022
DOI: 10.1038/S42003-022-03876-X
Abstract: Our understanding of how abdominal organs (like the gut) communicate with the brain, via sensory nerves, has been limited by a lack of techniques to selectively activate or inhibit populations of spinal primary afferent neurons within dorsal root ganglia (DRG), of live animals. We report a survival surgery technique in mice, where select DRG are surgically removed (unilaterally or bilaterally), without interfering with other sensory or motor nerves. Using this approach, pain responses evoked by rectal distension were abolished by bilateral lumbosacral L5-S1 DRG removal, but not thoracolumbar T13-L1 DRG removal. However, animals lacking T13-L1 or L5-S1 DRG both showed reduced pain sensitivity to distal colonic distension. Removal of DRG led to selective loss of peripheral CGRP-expressing spinal afferent axons innervating visceral organs, arising from discrete spinal segments. This method thus allows spinal segment-specific determination of sensory pathway functions in conscious, free-to-move animals, without genetic modification.
NaV1.1 inhibition can reduce visceral hypersensitivity
Publisher: American Society for Clinical Investigation
Date: 07-06-2018
Garcinia buchananii bark extract is an effective anti-diarrheal remedy for lactose-induced diarrhea
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JEP.2012.05.034
Abstract: The extract from the stem bark of Garcinia buchananii trees is used as an anti-diarrhea remedy in sub-Saharan Africa. We tested the hypothesis that G. buchananii bark extract and its anti-motility fractions are effective treatments against lactose-induced diarrhea. A high-lactose (35%) diet was used to induce diarrhea in Wistar rats, which were then treated with either G. buchananii bark extract (0.1, 0.5, 1.0 and 5.0 g bark powder), and its anti-motility fractions isolated using preparative thin layer chromatography termed PTLC1 (15 mg) and PTLC5 (3.8 mg) or loperamide (8.4 mg). Drug preparations were dissolved in 1L except PTCL1 and PTLC5 that were dissolved in 100mL tap water. Numerous parameters were measured in each condition including consistency, fluid and mucus content of feces, body weight, water and food consumption, urine production and bloating. Diarrheic rats produced watery or loose, mucuoid, sticky, feces. Fluids constituted 86% of stool mass compared with only 42% for control rats fed standard chow. Compared with controls, diarrheic rats produced more urine, lost weight and had bloated ceca and colons. All doses of the extract, its anti-motility fractions and loperamide in idually stopped diarrhea within 6-24 h of administration, whilst significantly reducing mucus and fecal fluid content, urine production and intestinal bloating. Rats treated with 0.1g extract, PTLC1 and PTLC5 gained weight, whilst PTLC5 also increased water intake. Garcinia buchananii extract and its anti-motility fractions are effective remedies against lactose-induced diarrhea. The extract contains compounds that reverse weight loss, promote food and water intake, supporting the notion that characterization of the compounds could lead to new therapies against diarrheal diseases.
The Ion Channel TRPA1 Is Required for Normal Mechanosensation and Is Modulated by Algesic Stimuli
Publisher: Elsevier BV
Date: 12-2009
Extrinsic Sensory Afferent Nerves Innervating the Gastrointestinal Tract in Health and Disease
Publisher: Elsevier
Date: 2018
Effects and sites of action of a M1 receptor positive allosteric modulator on colonic motility in rats and dogs compared with 5-HT4 agonism and cholinesterase inhibition
Publisher: Wiley
Date: 26-04-2020
DOI: 10.1111/NMO.13866
Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses
Publisher: BMJ
Date: 25-03-2009
Abstract: Intestinal infection evokes hypersensitivity in a subgroup of patients with irritable bowel syndrome (IBS) long after healing of the initial injury. Trinitrobenzene sulfonic acid (TNBS)-induced colitis in rodents likewise results in delayed maintained hypersensitivity, regarded as a model of some aspects of IBS. The colon and rectum have a complex sensory innervation, comprising five classes of mechanosensitive afferents in the splanchnic and pelvic nerves. Their plasticity may hold the key to underlying mechanisms in IBS. Our aim was therefore to determine the contribution of each afferent class in each pathway towards post-inflammatory visceral hypersensitivity. TNBS was administered rectally and mice were studied after 7 (acute) or 28 (recovery) days. In vitro preparations of mouse colorectum with attached pelvic or splanchnic nerves were used to examine the mechanosensitivity of in idual colonic afferents. Mild inflammation of the colon was evident acutely which was absent at the recovery stage. TNBS treatment did not alter proportions of the five afferent classes between treatment groups. In pelvic afferents little or no difference in response to mechanical stimuli was apparent in any class between control and acute mice. However, major increases in mechanosensitivity were recorded from serosal afferents in mice after recovery, while responses from other subtypes were unchanged. Both serosal and mesenteric splanchnic afferents were hypersensitive at both acute and recovery stages. Colonic afferents with high mechanosensory thresholds contribute to inflammatory hypersensitivity, but not those with low thresholds. Pelvic afferents become involved mainly following recovery from inflammation, whereas splanchnic afferents are implicated during both inflammation and recovery.
Acid sensing ion channels 2 and 3 are required for inhibition of visceral nociceptors by benzamil
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2007
DOI: 10.1016/J.PAIN.2007.03.019
Abstract: The Deg/ENaC family of ion channels, including ASIC1, 2 and 3, are candidate mechanotransducers in visceral and somatic sensory neurons, although each channel may play a different role in different sensory pathways. Here we determined which distinct populations of visceral sensory neurons are sensitive to the non-selective Deg/ENaC blocker benzamil, and which ASIC channels are targets for benzamil by studying its actions in knockout mice. Single afferent fiber recordings were made in vitro from mouse high threshold colonic thoracolumbar splanchnic afferents and low threshold gastroesophageal vagal afferents. mRNA expression of ASIC subtypes was compared between colonic and gastroesophageal afferents by quantitative RT-PCR of transcripts following laser capture microdissection of retrogradely labeled cell bodies. Mechanosensitivity of colonic afferents was potently reduced by benzamil (10(-6)-3 x 10(-4)M), whereas gastroesophageal afferents were marginally inhibited. Inhibition of colonic afferent mechanosensitivity by benzamil was markedly diminished in ASIC2-/- and ASIC3-/- mice, but unchanged in ASIC1a-/-. Therefore ASIC2 and 3 are targets for benzamil to inhibit colonic afferent mechanosensitivity. Conversely, gastroesophageal afferents are less sensitive to benzamil, and its action depends less on ASIC expression. mRNA for ASIC3 showed higher and ASIC1a showed lower relative expression in colonic afferents from thoracolumbar dorsal root ganglia than in gastric afferents from nodose (vagal) ganglia. These data indicate that ASICs on colonic afferents present distinct pharmacological targets for visceral pain.
Post-inflammatory modification of colonic afferent mechanosensitivity
Publisher: Wiley
Date: 10-2009
DOI: 10.1111/J.1440-1681.2009.05248.X
Abstract: 1. The present review discusses interactions between the immune and nervous systems in post-infectious irritable bowel syndrome (PI-IBS). 2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology. 3. The PI-IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as C ylobacter or Salmonella. Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli. 4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1-mediated inflammatory response, consistent with clinical observations in PI-IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage. 5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI-IBS.
Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension
Publisher: Society for Neuroscience
Date: 16-03-2021
DOI: 10.1523/JNEUROSCI.0033-21.2021
Abstract: Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signaling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that subpopulations of DRG neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either in idually or in combination, with high levels of coexpression with Trpv1 (81%-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22, and neuropeptide FF) activated subpopulations of bladder-innervating DRG neurons, showing functional evidence of coexpression between MrgprA3, MrgprC11, and TRPV1. In ex vivo bladder-nerve preparations, chloroquine, BAM8-22, and neuropeptide FF all evoked mechanical hypersensitivity in subpopulations (20%-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-cluster Δ −/− mice. In vitro whole-cell patch-cl recordings showed that application of an MrgprA3/C11 agonist mixture induced neuronal hyperexcitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist mixture into the bladder of WT mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of WT, but not Mrgpr-cluster Δ −/− mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors triggers hypersensitivity to distension, a critically valuable factor for therapeutic target development. SIGNIFICANCE STATEMENT Determining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitization may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.
Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain
Publisher: Elsevier BV
Date: 02-2022
TGR5 agonists induce peripheral and central hypersensitivity to bladder distension
Publisher: Springer Science and Business Media LLC
Date: 15-06-2022
DOI: 10.1038/S41598-022-14195-W
Abstract: The mechanisms underlying chronic bladder conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder syndrome (OAB) are incompletely understood. However, targeting specific receptors mediating neuronal sensitivity to specific stimuli is an emerging treatment strategy. Recently, irritant-sensing receptors including the bile acid receptor TGR5, have been identified within the viscera and are thought to play a key role in neuronal hypersensitivity. Here, in mice, we identify mRNA expression of TGR5 ( Gpbar1 ) in all layers of the bladder as well as in the lumbosacral dorsal root ganglia (DRG) and in isolated bladder-innervating DRG neurons. In bladder-innervating DRG neurons Gpbar1 mRNA was 100% co-expressed with Trpv1 and 30% co-expressed with Trpa1 . In vitro live-cell calcium imaging of bladder-innervating DRG neurons showed direct activation of a sub-population of bladder-innervating DRG neurons with the synthetic TGR5 agonist CCDC, which was diminished in Trpv1 −/− but not Trpa1 −/− DRG neurons. CCDC also activated a small percentage of non-neuronal cells. Using an ex vivo mouse bladder afferent recording preparation we show intravesical application of endogenous (5α-pregnan-3β-ol-20-one sulphate, Pg5α) and synthetic (CCDC) TGR5 agonists enhanced afferent mechanosensitivity to bladder distension. Correspondingly, in vivo intravesical administration of CCDC increased the number of spinal dorsal horn neurons that were activated by bladder distension. The enhanced mechanosensitivity induced by CCDC ex vivo and in vivo was absent using Gpbar1 −/− mice. Together, these results indicate a role for the TGR5 receptor in mediating bladder afferent hypersensitivity to distension and thus may be important to the symptoms associated with IC/BPS and OAB.
Structure–Activity Studies Reveal the Molecular Basis for GABAB-Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α-Conotoxin Vc1.1
Publisher: American Chemical Society (ACS)
Date: 10-05-2018
DOI: 10.1021/ACSCHEMBIO.8B00190
Abstract: α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABA
Post-inflammatory colonic afferent sensitisation: Different subtypes, different pathways and different time courses (Gut (2009) 58, (1333-1341))
Publisher: BMJ
Date: 10-12-2011
A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities
Publisher: Wiley
Date: 22-03-2021
366 Guanylate Cyclase-C Expression Is Down-Regulated in Colonic Biopsies From Female Irritable Bowel Syndrome Patients With Constipation
Publisher: Elsevier BV
Date: 04-2016
Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression
Publisher: Society for Neuroscience
Date: 23-07-2014
TRPA1 contributes to specific mechanically activated currents and sensory neuron mechanical hypersensitivity
Publisher: Wiley
Date: 15-07-2011
NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation
Publisher: American Physiological Society
Date: 10-2018
DOI: 10.1152/AJPRENAL.00106.2018
Abstract: Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the litude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.
Differentiation of the 50B11 dorsal root ganglion cells into NGF and GDNF responsive nociceptor subtypes
Publisher: SAGE Publications
Date: 2021
Abstract: The embryonic rat dorsal root ganglion (DRG) neuron-derived 50B11 cell line is a promising sensory neuron model expressing markers characteristic of NGF and GDNF-dependent C-fibre nociceptors. Whether these cells have the capacity to develop into distinct nociceptive subtypes based on NGF- or GDNF-dependence has not been investigated. Here we show that by augmenting forskolin (FSK) and growth factor supplementation with NGF or GDNF, 50B11 cultures can be driven to acquire differential functional responses to common nociceptive agonists capsaicin and ATP respectively. In addition, to previous studies, we also demonstrate that a differentiated neuronal phenotype can be maintained for up to 7 days. Western blot analysis of nociceptive marker proteins further demonstrates that the 50B11 cells partially recapitulate the functional phenotypes of classical NGF-dependent (peptidergic) and GDNF-dependent (non-peptidergic) neuronal subtypes described in DRGs. Further, 50B11 cells differentiated with NGF/FSK, but not GDNF/FSK, show sensitization to acute prostaglandin E2 treatment. Finally, RNA-Seq analysis confirms that differentiation with NGF/FSK or GDNF/FSK produces two 50B11 cell subtypes with distinct transcriptome expression profiles. Gene ontology comparison of the two subtypes of differentiated 50B11 cells to rodent DRG neurons studies shows significant overlap in matching or partially matching categories. This transcriptomic analysis will aid future suitability assessment of the 50B11 cells as a high-throughput nociceptor model for a broad range of experimental applications. In conclusion, this study shows that the 50B11 cell line is capable of partially recapitulating features of two distinct types of embryonic NGF and GDNF-dependent nociceptor-like cells.
Extracellular CGMP Reduces the Excitability of Sensory Dorsal Root Ganglion Neurons via an Extracellular Mechanism
Publisher: Elsevier BV
Date: 04-2017
Involvement of galanin receptors 1 and 2 in the modulation of mouse vagal afferent mechanosensitivity
Publisher: Wiley
Date: 30-08-2007
Use of natural products in gastrointestinal therapies
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.COPH.2011.09.007
Abstract: Altered motility, discomfort and pain are common debilitating symptoms of patients with functional gastrointestinal disorders. However, these conditions represent a significant and unmet need for mainstream medical treatment, particularly after high profile therapeutic drug withdrawals due to safety concerns. As such an increasing number of sufferers are turning to alternative medicines in an effort to seek relief from their symptoms. Alternative medicines have traditionally been looked at by mainstream medicine with cynicism. However, new evidence demonstrates that the active components in natural products have actions on specific ion channels and receptors, many of which are located in sensory systems distributed throughout the body. These findings may not only explain the symptomatic benefit of these alternative medicines but also provide novel therapeutic targets for mainstream drug development. As such natural products represent a wealth of untapped potential which is waiting to be unlocked.
Sensory neuro-immune interactions differ between Irritable Bowel Syndrome subtypes
Publisher: BMJ
Date: 05-07-2013
DOI: 10.1136/GUTJNL-2011-301856
Abstract: The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves. Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents. D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels. Distinct patterns of immune dysfunction and interaction with sensory pathways occur in different patient groups and through different intracellular pathways. Our results indicate IBS patient subgroups would benefit from selective targeting of the immune system.
Mechanisms Underlying Overactive Bladder and Interstitial Cystitis/Painful Bladder Syndrome
Publisher: Frontiers Media SA
Date: 12-12-2018
Protease-activated receptor 1 is implicated in irritable bowel syndrome mediators-induced signaling to thoracic human sensory neurons.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2018
DOI: 10.1097/J.PAIN.0000000000001208
Abstract: Proteases and protease-activated receptors (PARs) are major mediators involved in irritable bowel syndrome (IBS). Our objectives were to decipher the expression and functionality (calcium signaling) of PARs in human dorsal root ganglia (DRG) neurons and to define mechanisms involved in human sensory neuron signaling by IBS patient mediators. Human thoracic DRG were obtained from the national disease resource interchange. Expression of PAR 1 , PAR 2 , and PAR 4 was assessed by immunohistochemistry and quantitative reverse transcription PCR (RT-qPCR) in whole DRG or in primary cultures of isolated neurons. Calcium signaling in response to PAR agonist peptides (PAR-AP), their inactive peptides (PAR-IP), thrombin (10 U/mL), supernatants from colonic biopsies of patients with IBS, or healthy controls, with or without PAR 1 or PAR 4 antagonist were studied in cultured human DRG neurons. PAR 1 , PAR 2 , and PAR 4 were all expressed in human DRG, respectively, in 20%, 40%, and 40% of the sensory neurons. PAR 1 -AP increased intracellular calcium concentration in a dose-dependent manner. This increase was inhibited by PAR 1 antagonism. By contrast, PAR 2 -AP, PAR 4 -AP, and PAR-IP did not cause calcium mobilization. PAR 1 -AP–induced calcium flux was significantly reduced by preincubation with PAR 4 -AP, but not with PAR 2 -AP. Thrombin increased calcium flux, which was inhibited by a PAR 1 antagonist and increased by a PAR 4 antagonist. Supernatants from colonic biopsies of patients with IBS induced calcium flux in human sensory neurons compared with healthy controls, and this induction was reversed by a PAR 1 antagonist. Taken together, our results highlight that PAR 1 antagonism should be investigated as a new therapeutic target for IBS symptoms.
Neural mechanisms underlying migrating motor complex formation in mouse isolated colon
Publisher: Wiley
Date: 2001
Pain-Causing Venom Peptides: Insights into Sensory Neuron Pharmacology
Publisher: MDPI AG
Date: 27-12-2017
Visualising vagal afferent neurons and their terminals whilst silencing TRPV1
Publisher: Wiley
Date: 29-10-2010
α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors.
Publisher: BMJ
Date: 17-02-2016
The Enteric Nervous System
Publisher: Springer International Publishing
Date: 2016
Clodronate Treatment Prevents Vaginal Hypersensitivity in a Mouse Model of Vestibulodynia
Publisher: Frontiers Media SA
Date: 18-01-2022
DOI: 10.3389/FCIMB.2021.784972
Abstract: Improved understanding of vestibulodynia pathophysiology is required to develop appropriately targeted treatments. Established features include vulvovaginal hyperinnervation, increased nociceptive signalling and hypersensitivity. Emerging evidence indicates macrophage-neuron signalling contributes to chronic pain pathophysiology. Macrophages are broadly classified as M1 or M2, demonstrating pro-nociceptive or anti-nociceptive effects respectively. This study investigates the impact of clodronate liposomes, a macrophage depleting agent, on nociceptive signalling in a mouse model of vestibulodynia. Microinjection of complete Freund’s adjuvant (CFA) at the vaginal introitus induced mild chronic inflammation in C57Bl/6J mice. A subgroup was treated with the macrophage depleting agent clodronate. Control mice received saline. After 7 days, immunolabelling for PGP9.5, F4/80+CD11c+ and F4/80+CD206+ was used to compare innervation density and presence of M1 and M2 macrophages respectively in experimental groups. Nociceptive signalling evoked by vaginal distension was assessed using immunolabelling for phosphorylated MAP extracellular signal-related kinase (pERK) in spinal cord sections. Hyperalgesia was assessed by visceromotor response to graded vaginal distension. CFA led to increased vaginal innervation (p & 0.05), increased pERK-immunoreactive spinal cord dorsal horn neurons evoked by vaginal-distension (p & 0.01) and enhanced visceromotor responses compared control mice (p & 0.01). Clodronate did not reduce vaginal hyperinnervation but significantly reduced the abundance of M1 and M2 vaginal macrophages and restored vaginal nociceptive signalling and vaginal sensitivity to that of healthy control animals. We have developed a robust mouse model of vestibulodynia that demonstrates vaginal hyperinnervation, enhanced nociceptive signalling, hyperalgesia and allodynia. Macrophages contribute to hypersensitivity in this model. Macrophage-sensory neuron signalling pathways may present useful pathophysiological targets.
SPARC ‐ Mapping Gut‐Spinal Cord Connections in Visceral Pain
Publisher: Wiley
Date: 04-2020
Selective Role for TRPV4 Ion Channels in Visceral Sensory Pathways
Publisher: Elsevier BV
Date: 06-2008
Gut enterochromaffin cells drive visceral pain and anxiety
Publisher: Springer Science and Business Media LLC
Date: 22-03-2023
MP42-20 IDENTIFICATION OF NOVEL IRRITANT SENSING MECHANISMS IN THE BLADDER
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
Altered Ion Channel/Receptor Expression and Function in Extrinsic Sensory Neurons: The Cause of and Solution to Chronic Visceral Pain?
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/978-3-319-27592-5_9
Abstract: The gastrointestinal tract is unique in that it is innervated by several distinct populations of neurons, whose cell bodies are either intrinsic (enteric, viscerofugal) or extrinsic (sympathetic, sensory afferents) to the wall of the gut. We are usually completely unaware of the continuous, complicated orchestra of functions that these neurons conduct. However, for patients with Inflammatory Bowel Disease (IBD) or functional gastrointestinal disorders, such as Functional Dyspepsia (FD) and Irritable Bowel Syndrome (IBS) altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Whilst bouts of inflammation underlie the symptoms associated with IBD, over the past few years there is increased pre-clinical and clinical evidence that infection and inflammation are key risk factors for the development of several functional gastrointestinal disorders, in particular IBS. There is a strong correlation between prior exposure to gut infection and symptom occurrence with the duration and severity of the initial illness the strongest associated risk factors. This review discusses the current body of evidence for neuroplasticity during inflammation and how in many cases fails to reset back to normal, long after healing of the damaged tissues. Recent evidence suggests that the altered expression and function of key ion channels and receptors within extrinsic sensory neurons play fundamental roles in the aberrant pain sensation associated with these gastrointestinal diseases and disorders.
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Location: Australia
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