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.

Background & Aims The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRP ankyrin 1 (TRPA1) is implicated in inflammatory pain; it interacts with G-protein-coupled receptors, but little is known about its role in the gastrointestinal (GI) tract. Sensory information from the GI tract is conducted via 5 afferent subtypes along 3 pathways. Methods Nodose and dorsal root ganglia whose neurons innnervate 3 different regions of the GI tract were analyzed from wild-type and TRPA1^−/− mice using quantitative reverse-transcription polymerase chain reaction, retrograde labeling, and in situ hybridization. Distal colon sections were analyzed by immunohistochemistry. In vitro electrophysiology and pharmacology studies were performed, and colorectal distension and visceromotor responses were measured. Colitis was induced by administration of trinitrobenzene sulphonic acid. Results TRPA1 is required for normal mechano- and chemosensory function in specific subsets of vagal, splanchnic, and pelvic afferents. The behavioral responses to noxious colonic distension were substantially reduced in TRPA1^−/− mice. TRPA1 agonists caused mechanical hypersensitivity, which increased in mice with colitis. Colonic afferents were activated by bradykinin and capsaicin, which mimic effects of tissue damage; wild-type and TRPA1^−/− mice had similar direct responses to these 2 stimuli. After activation by bradykinin, wild-type afferents had increased mechanosensitivity, whereas, after capsaicin exposure, mechanosensitivity was reduced: these changes were absent in TRPA1^−/− mice. No interaction between protease-activated receptor-2 and TRPA1 was evident. Conclusions These findings demonstrate a previously unrecognized role for TRPA1 in normal and inflamed mechanosensory function and nociception within the viscera.

We used a novel in vitro mouse vagus-gastro-esophageal preparation to study the properties of peripheral vagal afferent endings. We found two types of mechanoreceptive fiber, mucosal receptors and tension receptors. These were distinguished by their sensitivity to mucosal stroking with von Frey hairs and circular tension applied via a claw-cantilever system. A comparison was made with gastro-esophageal afferents found in a similar preparation of ferret tissue. Responses of mouse tension receptors to circular tension were significantly greater than ferret tension and tension/mucosal receptors. Similarly the responses of mouse mucosal receptors to mucosal stroking were significantly greater than ferret mucosal and tension/mucosal receptors. Forty-seven percent of mouse mucosal receptors and 50% of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. These included α,β-methylene ATP (10⁻⁶ to 10⁻³ M), 5-hydroxytryptamine (10⁻⁶ to 10⁻³ M), and hydrochloric acid (10⁻² to 10⁻¹ M). Drug responses were concentration dependent. One hundred percent of mucosal receptors and 61% of tension receptors tested responded to bile (1:8 to 1:1 dilution). A third type of fiber was recruited by bile. These fibers were mechanically insensitive and silent prior to bile exposure. In conclusion, we have shown three types of gastro-esophageal vagal afferent fibers in the mouse: mucosal mechanoreceptors, tension receptors, and specific chemoreceptors activated by bile.

A novel preparation of the oesophagus with attached vagus nerve from the ferret maintained in vitro was used to study the properties of single vagal afferent nerve fibres with identified receptive fields. Recordings were made from three types of gastro‐oesophageal vagal afferent fibres that were classified on the basis of their sensitivity to mechanical stimulation. There were those responding to mucosal stroking (mucosal receptors), to circular tension (tension receptors) and those responding to mucosal stroking and circular tension, which we have termed tension/mucosal (TM) receptors. The conduction velocities for mucosal, TM and tension receptor fibres were 6.38 ± 1.22 m s⁻¹ (n= 22), 6.20 ± 1.49 m s⁻¹ (n= 13) and 5.33 ± 0.86 m s⁻¹ (n= 22), respectively. Receptive fields of afferents showed random topographical distribution by fibre type and conduction velocity. They were found mainly distal but also occasionally proximal to the point of vagal dissection. Twenty‐eight per cent of mucosal, 63 % of TM and 43 % of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. In conclusion, this experimental preparation provides evidence for the existence of three types of oesophageal vagal afferent fibre, namely mucosal, tension and the newly identified tension/mucosal receptors.