Serotonin exerts a direct modulatory role on bladder afferent firing in mice.

KEY POINTS: Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non-5-HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5-HT. Whilst 5-HT3 receptors were not detected in mouse urothelium, 5-HT3 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-HT3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. ABSTRACT: 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/painful 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-HT3 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-HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5-HT bioavailability. Granisetron, a 5-HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5-HT exerts a direct effect on bladder afferents to enhance signalling. 5-HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

Prevalence of depression among young people with Type 1 diabetes: a systematic review.

AIMS: To determine: (1) prevalence of depression among young people with Type 1 diabetes compared with control groups or population norms; (2) implications of depression for HbA(1c) level; and (3) the relationship between history of depressive symptoms and future depressive symptoms. BACKGROUND: Among adults with Type 1 diabetes depression is higher than the general population, and has been associated with adverse implications for self-care and HbA(1c) level. The last published review of depression among young people with Type 1 diabetes only included studies up to 1999. METHOD: Systematic searches were conducted for articles published from January 1999 to December 2011 including young people (up to 25 years old) with Type 1 diabetes. RESULTS: Twenty-three articles met the inclusion criteria. Of five studies that reported prevalence of depression compared with control groups, three found no differences. Of the three studies that investigated prevalence of depression making reference to population norms, all three showed higher rates of depressive symptoms. Fourteen of 15 studies found associations between more depressive symptoms and higher HbA(1c) level either cross-sectionally or longitudinally. Past depressive symptoms were associated with later depressive symptoms. CONCLUSIONS: Current evidence is inconclusive about whether there is increased prevalence of depression among young adults with Type 1 diabetes, as established among adults, but those who are more depressed have higher HbA(1c) level. This review is limited by methodological problems and no identified work in the UK met the inclusion criteria. Given the adverse clinical outcomes, we conclude there is a case for routine mental health screening for young adults with Type 1 diabetes.

Eating problems in adolescents with Type 1 diabetes: a systematic review with meta-analysis.

AIMS: We report a systematic review to determine (1) prevalence of eating problems compared with peers and (2) the association between eating problems and glycaemic control in young adults with Type 1 diabetes. METHOD: We conducted a systematic literature search via electronic databases and meta-analysis. Cohen's d (the mean difference score between Type 1 diabetes and comparison groups) was calculated for 13 studies that met inclusion criteria. RESULTS: Eating problems [both disordered eating behaviour (39.3 and 32.5%; d = 0.52, 95% CI 0.10-0.94) and eating disorders (7.0 and 2.8%; d = 0.46, 95% CI 0.10-0.81)] were more common in adolescents with Type 1 diabetes compared with peers and both were associated with poorer glycaemic control (d = 0.40, 95% CI 0.17-0.64). In restricted analyses involving measures adapted for diabetes, associations between eating problems and poorer glycaemic control remained (d = 0.54, 95% CI 0.32-0.76). Disordered eating behaviour (51.8 and 48.1%; d = 0.06, 95% CI -0.05 to 0.21) and eating disorders (6.4 and 3.0%; d = 0.43, 95% CI -0.06 to 0.91) were more common in adolescents with Type 1 diabetes compared with peers, but differences were non-significant. CONCLUSIONS: Eating problems are common among this age group. Future work in populations with Type 1 diabetes should develop sensitive measures of eating problems and interventions, and establish predictors of eating problems. Screening in clinics is recommended.

Using the Medical Research Council framework to develop a complex intervention to improve delivery of care for young people with type 1 diabetes.

AIMS: We describe how we have used the development phase of the Medical Research Council (MRC) Guidelines to construct a complex intervention to improve physical and psychological health among young people (16-21 years) with Type 1 diabetes. METHODS: We consulted previous reviews where available and conducted systematic searches of electronic databases to determine physical and mental health among the population, audited medical records, surveyed self-reported psychological health among our clinic population; and interviewed staff (n = 13), young people (n = 27) and parents (n = 18) about their views of current care. RESULTS: Our audit (n = 96) confirmed a high HbA1c [86 mmol/mol (10.0%)] and one third (36.1%) reported significant eating problems. Young people did not attend 12% of their clinic appointments. Staff described difficulties communicating with young people who wanted staff to take account of their individual lifestyle when giving information. CONCLUSION: Based on the findings of the systematic reviews and our audit, we concluded that there was sufficient evidence to justify development of a model of care specific to this age group. The components of the complex intervention include changes to standard care, an optional 5-day self-management course directed at young people and a separate family communication programme. The MRC Guidelines provided a valuable structure to guide development and evaluation of this intervention.

Working with young adults with Type 1 diabetes: views of a multidisciplinary care team and implications for service delivery.

AIMS: Young adults with Type 1 diabetes experience difficulties achieving glucose targets. Clinic attendance can be poor, although health and self-care tend to be better among those who attend regularly. Our aims were to describe staff views about challenges working with this age-group (16-21 years). METHODS: Semistructured interviews were conducted with 14 staff from Sheffield Teaching Hospitals diabetes care team. Interviews were audio-recorded, transcribed and analysed using thematic analysis. RESULTS: Three main themes emerged. Unique challenges working with young adults included staff emotional burden, the low priority given to self-care by young adults and the complexity of the diabetes regimen. Working in a multidisciplinary team was complicated by differences in consultation styles, poor team cohesion and communication. An ideal service should include psychological support for the professional team, identification of key workers, and development of individualized care plans. CONCLUSIONS: Staff differed in their views about how to achieve optimal management for young adults, but emphasized the need for greater patient-centred care and a range of interventions appropriate for individual levels of need. They also wanted to increase their own skills and confidence working with this age-group. While these results reflect the views of staff working in only one diabetes centre, they are likely to reflect the views of professionals delivering care to individuals of this age; replication is needed to determine their generalizability.

Shine a light: Under-ice light and its ecological implications in a changing Arctic Ocean.

The Arctic marine ecosystem is shaped by the seasonality of the solar cycle, spanning from 24-h light at the sea surface in summer to 24-h darkness in winter. The amount of light available for under-ice ecosystems is the result of different physical and biological processes that affect its path through atmosphere, snow, sea ice and water. In this article, we review the present state of knowledge of the abiotic (clouds, sea ice, snow, suspended matter) and biotic (sea ice algae and phytoplankton) controls on the underwater light field. We focus on how the available light affects the seasonal cycle of primary production (sympagic and pelagic) and discuss the sensitivity of ecosystems to changes in the light field based on model simulations. Lastly, we discuss predicted future changes in under-ice light as a consequence of climate change and their potential ecological implications, with the aim of providing a guide for future research.

Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses.

OBJECTIVE: 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. DESIGN: 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 individual colonic afferents. RESULTS: 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. CONCLUSIONS: 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.

Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes.

OBJECTIVE: 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. SUBJECTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Post-inflammatory modification of colonic afferent mechanosensitivity.

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 Campylobacter 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 colo-rectal high-threshold afferent nerves by Interleukin-2 is tetrodotoxin-sensitive and upregulated in a mouse model of chronic visceral hypersensitivity.

BACKGROUND: 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. METHODS: 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. KEY RESULTS: 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. CONCLUSIONS & INFERENCES: 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.

Activation of splanchnic and pelvic colonic afferents by bradykinin in mice.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

How standard is standard care? Exploring control group outcomes in behaviour change interventions for young people with type 1 diabetes.

OBJECTIVE: Poor descriptions of standard care may compromise interpretation of results in randomised controlled trials (RCTs) of health interventions. We investigated quality of standard care in RCTs of behaviour change interventions for young people with type 1 diabetes and consider implications for evaluating trial outcomes. DESIGN: We conducted systematic searches for articles published between 1999 and 2012. We extracted standard care descriptions and contacted trial authors to complete a checklist of standard care activities. The relationship between standard care quality and outcomes was examined via subgroup meta-analyses and meta-regression. MAIN OUTCOME MEASURES: Standard care descriptions, standard care quality, and relationships between standard care quality with medical and psychological outcomes. RESULTS: We identified 20 RCTs described across 26 articles. Published descriptions of standard care were limited to service-level features. Author responses indicated standard care provision extended beyond published accounts. Subgroup analyses suggested control groups receiving higher standard care quality showed larger improvements in both medical and psychological outcomes, although standard care quality did not predict outcomes significantly. CONCLUSION: The quality of care delivered to control group participants can influence outcomes of RCTs. Inadequate reporting exacerbates this issue by masking variations between trials. We argue for increased clarity in reporting standard care in future trials.

Neural mechanisms underlying migrating motor complex formation in mouse isolated colon.

1. Little is known about the intrinsic enteric reflex pathways associated with migrating motor complex (MMC) formation. Acetylcholine (ACh) mediates the rapid component of the MMC, however a non-cholinergic component also exists. The present study investigated the possible role of endogenous tachykinins (TKs) in the formation of colonic MMCs and the relative roles of excitatory and inhibitory pathways. 2. MMCs were recorded from the circular muscle at four sites (proximal, proximal-mid, mid-distal and distal) along the mouse colon using force transducers. 3. The tachykinin (NK(1) and NK(2)) receptor antagonists SR-140 333 (250 nM) and SR-48 968 (250 nM) reduced the amplitude of MMCs at all recording sites, preferentially abolishing the long duration contraction. Residual MMCs were abolished by the subsequent addition of atropine (1 microM). 4. The neuronal nitric oxide synthase inhibitor, N(omega)nitro-L-arginine (L-NOARG, 100 microM), increased MMC amplitude in the distal region, whilst reducing the amplitude in the proximal region. In preparations where MMCs did not migrate to the distal colon, addition of L-NOARG resulted in the formation of MMCs. Subsequent addition of apamin (250 nM) or suramin (100 microM) further increased MMC amplitude in the distal region, whilst suramin increased MMC amplitude in the mid-distal region. Apamin but not suramin reduced MMC amplitude in the proximal region. Subsequent addition of SR-140 333 and SR-48 968 reduced MMC amplitude at all sites. Residual MMCs were abolished by atropine (1 microM). 5. In conclusion, TKs, ACh, nitric oxide (NO) and ATP are involved in the neural mechanisms underlying the formation of MMCs in the mouse colon. Tachykinins mediate the long duration component of the MMC via NK(1) and NK(2) receptors. Inhibitory pathways may be involved in determining whether MMCs are formed.

The effectiveness of a group discrete trial instructional approach for preschoolers with developmental disabilities.

Group behavioral classroom instruction for children with developmental disabilities has been shown to allow for increased efficiency, approximation to naturalistic arrangements, and enhanced opportunity for interaction, social teaching and observational learning. This study examines the effectiveness of a group instructional extension of one to one discrete trial teaching, which involves the overlapping of trials between students along with the use of sequential and choral group teaching. A multiple baseline design across tasks was employed to examine the effectiveness of the group instructional approach in promoting acquisition of educational skills among preschoolers with autism and other developmental disabilities. A time sample interval assessment of components of the group instruction was also conducted. The approach was demonstrated to consistently increase correct responding across the task areas. Results are discussed in terms of the advantages of the group instructional approach as an adjunct to one to one discrete trial instruction.

An emergency department tackles bed management and home-based care.

Ipswich Hospital Emergency Department played a vital role in the Post Acute Treatment in the Home Program (PATH) of West Moreton District Health Service. PATH used two strategies to reduce the district reliance on acute hospital beds: a short-stay unit for rapid assessment, treatment and early discharge of patients with simple conditions; and a hospital-in-the-home program utilising community health services to treat acute conditions. The program enhanced existing services to create a new treatment stream for acute patients and to promote a cultural shift from fragmented care to district responsibility for total episode of patient care.

Identifying spinal sensory pathways activated by noxious esophageal acid.

BACKGROUND: 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. METHODS: Acid/pepsin (150 mM HCl/1 mg mL(-1) pepsin) or saline/pepsin 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. KEY RESULTS: Esophageal acid/pepsin 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/pepsin (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). CONCLUSIONS & INFERENCES: 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.

5-HT(3) and 5-HT(4) receptors contribute to the anti-motility effects of Garcinia buchananii bark extract in the guinea-pig distal colon.

BACKGROUND: 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. METHODS: 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. KEY RESULTS: 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&5. 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&5 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&5. 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%. CONCLUSIONS & INFERENCES: 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.

Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function.

AIMS: Members of the acid sensing ion channel (ASIC) family are strong candidates as mechanical transducers in sensory function. The authors have shown that ASIC1a has no role in skin but a clear influence in gastrointestinal mechanotransduction. Here they investigate further ASIC1a in gut mechanoreceptors, and compare its influence with ASIC2 and ASIC3. METHODS AND RESULTS: Expression of ASIC1a, 2, and 3 mRNA was found in vagal (nodose) and dorsal root ganglia (DRG), and was lost in mice lacking the respective genes. Recordings of different classes of splanchnic colonic afferents and vagal gastro-oesophageal afferents revealed that disruption of ASIC1a increased the mechanical sensitivity of all afferents in both locations. Disruption of ASIC2 had varied effects: increased mechanosensitivity in gastro-oesophageal mucosal endings, decreases in gastro-oesophageal tension receptors, increases in colonic serosal endings, and no change in colonic mesenteric endings. In ASIC3-/- mice, all afferent classes had markedly reduced mechanosensitivity except gastro-oesophageal mucosal receptors. Observations of gastric emptying and faecal output confirmed that increases in mechanosensitivity translate to changes in digestive function in conscious animals. CONCLUSIONS: These data show that ASIC3 makes a critical positive contribution to mechanosensitivity in three out of four classes of visceral afferents. The presence of ASIC1a appears to provide an inhibitory contribution to the ion channel complex, whereas the role of ASIC2 differs widely across subclasses of afferents. These findings contrast sharply with the effects of ASIC1, 2, and 3 in skin, suggesting that targeting these subunits with pharmacological agents may have different and more pronounced effects on mechanosensitivity in the viscera.