Auricular Vagal Nerve Stimulation Inhibited Central Nerve Growth Factor/Tropomyosin Receptor Kinase A/Phospholipase C-Gamma Signaling Pathway in Functional Dyspepsia Model Rats With Gastric Hypersensitivity.

OBJECTIVE: Functional dyspepsia (FD), which has a complicated pathophysiologic process, is a common functional gastrointestinal disease. Gastric hypersensitivity is the key pathophysiological factor in patients with FD with chronic visceral pain. Auricular vagal nerve stimulation (AVNS) has the therapeutic effect of reducing gastric hypersensitivity by regulating the activity of the vagus nerve. However, the potential molecular mechanism is still unclear. Therefore, we investigated the effects of AVNS on the brain-gut axis through the central nerve growth factor (NGF)/ tropomyosin receptor kinase A (TrkA)/phospholipase C-gamma (PLC-γ) signaling pathway in FD model rats with gastric hypersensitivity. MATERIALS AND METHODS: We established the FD model rats with gastric hypersensitivity by means of colon administration of trinitrobenzenesulfonic acid on ten-day-old rat pups, whereas the control rats were given normal saline. AVNS, sham AVNS, K252a (an inhibitor of TrkA, intraperitoneally), and K252a + AVNS were performed on eight-week-old model rats for five consecutive days. The therapeutic effect of AVNS on gastric hypersensitivity was determined by the measurement of abdominal withdrawal reflex response to gastric distention. NGF in gastric fundus and NGF, TrkA, PLC-γ, and transient receptor potential vanilloid 1 (TRPV1) in the nucleus tractus solitaries (NTS) were detected separately by polymerase chain reaction, Western blot, and immunofluorescence tests. RESULTS: It was found that a high level of NGF in gastric fundus and an upregulation of the NGF/TrkA/PLC-γ signaling pathway in NTS were manifested in model rats. Meanwhile, both AVNS treatment and the administration of K252a not only decreased NGF messenger ribonucleic acid (mRNA) and protein expressions in gastric fundus but also reduced the mRNA expressions of NGF, TrkA, PLC-γ, and TRPV1 and inhibited the protein levels and hyperactive phosphorylation of TrkA/PLC-γ in NTS. In addition, the expressions of NGF and TrkA proteins in NTS were decreased significantly after the immunofluorescence assay. The K252a + AVNS treatment exerted a more sensitive effect on regulating the molecular expressions of the signal pathway than did the K252a treatment. CONCLUSION: AVNS can regulate the brain-gut axis effectively through the central NGF/TrkA/PLC-γ signaling pathway in the NTS, which suggests a potential molecular mechanism of AVNS in ameliorating visceral hypersensitivity in FD model rats.

DNMT1 involved in the analgesic effect of folic acid on gastric hypersensitivity through downregulating ASIC1 in adult offspring rats with prenatal maternal stress.

AIMS: Gastric hypersensitivity (GHS) is a characteristic pathogenesis of functional dyspepsia (FD). DNA methyltransferase 1 (DNMT1) and acid-sensing ion channel 1 (ASIC1) are associated with GHS induced by prenatal maternal stress (PMS). The aim of this study was to investigate the mechanism of DNMT1 mediating the analgesic effect of folic acid (FA) on PMS-induced GHS. METHODS: GHS was quantified by electromyogram recordings. The expression of DNMT1, DNMT3a, DNMT3b, and ASIC1 were detected by western blot, RT-PCR, and double-immunofluorescence. Neuronal excitability and proton-elicited currents of dorsal root ganglion (DRG) neurons were determined by whole-cell patch clamp recordings. RESULTS: The expression of DNMT1, but not DNMT3a or DNMT3b, was decreased in DRGs of PMS rats. FA alleviated PMS-induced GHS and hyperexcitability of DRG neurons. FA also increased DNMT1 and decreased ASIC1 expression and sensitivity. Intrathecal injection of DNMT1 inhibitor DC-517 attenuated the effect of FA on GHS alleviation and ASIC1 downregulation. Overexpression of DNMT1 with lentivirus not only rescued ASIC1 upregulation and hypersensitivity, but also alleviated GHS and hyperexcitability of DRG neurons induced by PMS. CONCLUSIONS: These results indicate that increased DNMT1 contributes to the analgesic effect of FA on PMS-induced GHS by reducing ASIC1 expression and sensitivity.

microRNA-181a contributes to gastric hypersensitivity in rats with diabetes by regulating TLR4 expression.

Aim: The aim of this study is to investigate the mechanism and interaction of microRNA-181a (miR-181a), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in gastric hypersensitivity in diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in female SD rats. Gastric balloon distension technique was used to measure diabetic gastric hypersensitivity. Gastric-specific (T7-T10) dorsal root ganglion (DRG) neurons were acutely dissociated to measure excitability with patch-clamp techniques. Western blotting was employed to measure the expressions of TLR4, TRAF6 and NF-κB subunit p65 in T7-T10 DRGs. The expressions of microRNAs in T7-T10 DRGs were measured with quantitative real-time PCR and fluorescence in situ hybridization. Dual-luciferase reporter gene assay was used to detect the targeting regulation of microRNAs on TLR4. Results: (1) Diabetic rats were more sensitive to graded gastric balloon distention at 2 and 4 weeks. (2) The expression of TLR4 was significantly up-regulated in T7-T10 DRGs of diabetic rats. Intrathecal injection of CLI-095 (TLR4-selective inhibitor) attenuated diabetic gastric hypersensitivity, and markedly reversed the hyper-excitability of gastric-specific DRG neurons. (3) The expressions of miR-181a and miR-7a were significantly decreased in diabetic rats. MiR-181a could directly regulate the expression of TLR4, while miR-7a couldn't. (4) Intrathecal injection of miR-181a agomir down-regulated the expression of TLR4, reduced the hyper-excitability of gastric-specific neurons, and alleviated gastric hypersensitivity. (5) p65 and TLR4 were co-expressed in Dil-labeled DRG neurons. (6) Inhibition of p65 attenuated diabetic gastric hypersensitivity and hyper-excitability of gastric-specific DRG neurons. (7) The expression of TRAF6 was significantly up-regulated in diabetic rats. CLI-095 treatment also reduced the expression of TRAF6 and p65. Conclusion: The reduction of microRNA-181a in T7-T10 DRGs might up-regulate TLR4 expression. TLR4 activated NF-κB through MyD88-dependent signaling pathway, increased excitability of gastric-specific DRG neurons, and contributed to diabetic gastric hypersensitivity.

Eosinophil-associated microinflammation in the gastroduodenal tract contributes to gastric hypersensitivity in a rat model of early-life adversity.

Gastric hypersensitivity is a major pathophysiological feature of functional dyspepsia (FD). Recent clinical studies have shown that a large number of patients with FD present with gastroduodenal microinflammation, which may be involved in the pathophysiology of FD. However, no animal model reflecting this clinical characteristic has been established. The underlying mechanism between microinflammation and FD remains unknown. In this study, using a maternal separation (MS)-induced FD model, we aimed to reproduce the gastroduodenal microinflammation and reveal the interaction between gastroduodenal microinflammation and gastric hypersensitivity. The MS model was established by separating newborn Sprague-Dawley rats for 2 h a day from postnatal day 1 to day 10. At 7-8 wk of age, electromyography was used to determine the visceromotor response to gastric distention (GD) and immunohistochemistry was performed to detect distension-associated neuronal activation as well as immunohistological changes. Our results demonstrated that MS-induced FD rats underwent gastric hypersensitivity with GD at 60 and 80 mmHg, which are related to increased p-ERK1/2 expression in the dorsal horn of T9-T10 spinal cords. Eosinophils, but not mast cells, were significantly increased in the gastroduodenal tract, and the coexpression rate of CD11b and major basic protein significantly increased in MS rats. Treatment with dexamethasone reversed gastric hypersensitivity in MS-induced FD rats by inhibiting eosinophil infiltration. These findings indicated that neonatal MS stress induces eosinophil-associated gastroduodenal microinflammation and gastric hypersensitivity in adulthood in rats. Microinflammation contributes to gastric hypersensitivity; therefore, anti-inflammatory therapy may be effective in treating patients with FD with gastroduodenal microinflammation.NEW & NOTEWORTHY We showed for the first time that neonatal MS stress-induced FD rats undergo gastroduodenal eosinophil-associated microinflammation in adulthood. Suppression of microinflammation attenuated gastric hypersensitivity in MS rats. These findings established a functional link between microinflammation and gastric hypersensitivity, which may provide a potential clue for the clinical treatment of FD.

Electroacupuncture Ameliorates Gastric Hypersensitivity via Adrenergic Pathway in a Rat Model of Functional Dyspepsia.

OBJECTIVE: Electroacupuncture (EA) is effective in treating visceral pain associated with functional dyspepsia (FD). The aim of this study was to explore the effect of chronic EA (CEA) on gastric hypersensitivity and the involvement of sympathetic nervous system in a rodent model of FD. MATERIALS AND METHODS: Gastric hypersensitivity in adulthood was induced by iodoacetamide (IA) in neonatal rats. The IA-treated rats were randomized to receive no treatment (control), sham-CEA, CEA, or adrenergic antagonists, for one week. Gastric sensitivity to graded gastric distensions was then assessed by electromyogram (EMG) analysis. Autonomic functions were assessed from the spectral analysis of heart rate variability (HRV) to derive the low-frequency (LF, sympathetic activity) and high-frequency (HF, mainly vagal activity) components expressed as percentage of total spectral power. Blood was collected for the measurement of corticosterone (CORT) and norepinephrine (NE). RESULTS: 1) CEA, but not sham-CEA, reduced the EMG response to graded gastric distension in IA-treated control rats at 40 mmHg (128 ± 6% vs. 171 ± 15%, p = 0.009), 60 mmHg (204 ± 14% vs. 271 ± 24%, p = 0.010) and 80 mmHg (269 ± 19% vs. 364 ± 33%, p = 0.025), respectively. 2) CEA, but not sham CEA, increased HF component (0.61 ± 0.02 vs. 0.46 ± 0.04 in IA-treated rats, p = 0.003) and decreased LF component (0.39 ± 0.02 vs. 0.54 ± 0.04, p = 0.003). 3) Adrenergic antagonists reduced the EMG response to graded gastric distension. 4) CEA significantly reduced plasma CORT and NE in IA-treated rats. CONCLUSIONS: EA ameliorates gastric hypersensitivity in IA-treated rats and the effect may be related to the improved sympathovagal balance and the decrease of stress hormones.

Chronic stress induces hypersensitivity of murine gastric vagal afferents.

BACKGROUND: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. METHODS: Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. KEY RESULTS: The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. CONCLUSIONS AND INFERENCES: In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.

Postprandial distress syndrome: stratification and management.

INTRODUCTION: Functional dyspepsia (FD), defined by the Rome consensus as the presence of functional symptoms originating from the gastroduodenum, is one of the most common functional gastrointestinal disorders. FD is subdivided into postprandial distress syndrome (PDS), with meal-related symptoms such as postprandial fullness and early satiation, and epigastric pain syndrome (EPS), with meal-unrelated symptoms such as epigastric pain or burning. We used a literature search for a narrative review on the current state of knowledge regarding PDS. Areas covered: Epidemiological studies support PDS as a separate entity and the biggest FD subgroup. The pathophysiology of PDS is heterogeneous, and disorders of gastric sensorimotor function as well as low grade duodenal inflammation have been implicated. Although prokinetic agents may provide the most pathophysiology-oriented treatment option, there is a paucity of suitable agents, and proton pump inhibitors are the traditional first-line therapy. Other options include agents that enhance gastric accommodation, such as acotiamide and 5-HT1A agonists, neuromodulators such as mirtazapine, and traditional medicine approaches. Expert commentary: PDS is highly prevalent, with probably heterogeneous underlying pathophysiology. Motility modifying agents and neuromodulators are the cornerstone of PDS therapy, but there is a need for high quality studies of new therapeutic approaches.

A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function.

KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach, respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. ABSTRACT: Tenascin-X (TNX) is a glycoprotein that regulates tissue structure via anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers-Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB-deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved using GABAB agonists.

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress.

AIM: To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress. METHODS: Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined. RESULTS: Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group). CONCLUSION: Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.

Inhibitory Effects and Mechanisms of Electroacupuncture via Chronically Implanted Electrodes on Stress-Induced Gastric Hypersensitivity in Rats With Neonatal Treatment of Iodoacetamide.

BACKGROUND: Stress is considered an independent factor causing and aggravating gastrointestinal symptoms, including visceral pain. The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on stress-induced gastric hypersensitivity in rats treated with neonatal iodoacetamide mimicking human functional dyspepsia (FD). METHODS: Neonatal rats were treated with gavage of 0.2 mL of 0.1% iodoacetamide in 2% sucrose daily for six days starting on tenth day after birth. The control group was given 0.2 mL of 2% sucrose. When the rats were eight weeks old, acute restraint stress was performed on them for 90 min. EA at ST36 (ZuSanLi) was performed during the acute stress or 30 min after the stress. Adrenoceptor blocking drugs (propranolol and phentolamine) were injected intraperitoneally 30 min before acute restraint stress to explore possible sympathetic mechanisms. Visceral-motor responses to gastric distention were assessed by electromyogram (EMG). RESULTS: 1) Stress-induced gastric hypersensitivity was significantly more severe in the FD rats, compared to the control rats. It was blocked by the adrenoceptor antagonists. 2) EA inhibited stress-induced gastric hypersensitivity; the preventive effect of EA (given during stress) was more remarkable than the curative effect (given after stress). Stress resulted in a higher sympathovagal ratio and this was suppressed by EA. CONCLUSIONS: Rats treated with neonatal iodoacetamide mimicking FD are more vulnerable to stress. Stress-induced gastric hypersensitivity can be prevented or suppressed by EA at ST36 via the restoration of sympathovagal balance.

Establishment of an anxiety-like gastric hypersensitivity rat model of functional dyspepsia induced by a new method of sequential stress / 中国实验动物学报

Objective To establish an anxiety-like gastric hypersensitivity ( GHS) rat model of functional dyspep-sia induced by new sequential stress. Methods Twenty-six male 1-day-old Sprague-Dawley rat pups were randomly di-vided into control and model groups ( n=13 in each group) . The model rats received sequential stress from postnatal day 2:neonatal maternal separation (NMS), acute gastric irritation (AGI) and restraint stress (RS). The control rats were reared freely with their mothers without undergoing the sequential stress. From postnatal 8th week all rats started to receive elevated plus maze ( EPM ) , open field test ( OF ) , abdominal withdrawal reflex ( AWR ) and electromyographic test ( EMG) . Results EPM and OF experiments depicted that the model rats showed obvious anxiety-like behavior ( P<0. 05 or P<0. 01). AWR and EMG tests exhibited that the model rats had elevated gastric hypersensitivity to gastric distention (P<0. 05 or P<0. 01). Conclusions An anxiety-like GHS rat model of functional dyspepsia can be successfully estab-lished with our new method of sequential stress.

Establishment of an anxiety-like gastric hypersensitivity rat model of functional dyspepsia induced by a new method of sequential stress / 中国实验动物学报

Objective To establish an anxiety-like gastric hypersensitivity ( GHS) rat model of functional dyspep-sia induced by new sequential stress. Methods Twenty-six male 1-day-old Sprague-Dawley rat pups were randomly di-vided into control and model groups ( n=13 in each group) . The model rats received sequential stress from postnatal day 2:neonatal maternal separation (NMS), acute gastric irritation (AGI) and restraint stress (RS). The control rats were reared freely with their mothers without undergoing the sequential stress. From postnatal 8th week all rats started to receive elevated plus maze ( EPM ) , open field test ( OF ) , abdominal withdrawal reflex ( AWR ) and electromyographic test ( EMG) . Results EPM and OF experiments depicted that the model rats showed obvious anxiety-like behavior ( P<0. 05 or P<0. 01). AWR and EMG tests exhibited that the model rats had elevated gastric hypersensitivity to gastric distention (P<0. 05 or P<0. 01). Conclusions An anxiety-like GHS rat model of functional dyspepsia can be successfully estab-lished with our new method of sequential stress.

Effect of Gastrodin on Gastric Sensitivity and Anxiety-like Behavior in FD Rats With Anxiety-like Gastric Hypersensitivity / 胃肠病学

Background:Functional dyspepsia (FD)with anxiety and gastric hypersensitivity is still one of the therapeutic difficulties in clinic. Gastrodin (Gas)may have dual effects of modulating gastric sensitivity and anxiety. Aims:To investigate the effect of Gas on gastric sensitivity and anxiety-like behavior in FD with anxiety-like gastric hypersensitivity in rats. Methods:Forty rats were randomly divided into control group,model group,buspirone group,low-dose Gas group and high-dose Gas group. Maternal separation,acute gastric irritation and restraint stress were sequentially performed to induce FD model with anxiety-like gastric hypersensitivity. At the 8th week,rats in control group and model group were intraperitoneally injected with 0. 9% NaCl solution 2. 0 mL/ kg,rats in buspirone group were given buspirone 3. 125 mg/kg,and rats in low- and high-dose Gas groups were given 62. 5,125. 0 mg/ kg Gas,respectively. The course was 7 days. Then elevated plus maze (EPM),open field test,abdominal withdrawal reflex (AWR)and electromyography (EMG) were performed. Results:Compared with control group,EPM test showed that proportions of open arms entries and duration were significantly decreased (P < 0. 01);open field test showed that virtual central grids duration (P < 0. 05),number of virtual grids climbed and times of lifting were significantly decreased (P < 0. 01);when gastric balloon dilatation pressure was equal or greater than 40 mm Hg,AWR score,area under ROC curve (AUC)of EMG was significantly increased in model group (P < 0. 05). Compared with model group,above-mentioned indices in low- and high-dose Gas groups were significantly ameliorated (P < 0. 05). Conclusions:Gas could influence the gastric sensitivity and anxiety-like behavior of the brain-stomach axis regulated anxiety-like gastric hypersensitivity in FD rat model.

Inhibitory effect of the selective serotonin 5-HT3 receptor antagonist ramosetron on duodenal acidification-induced gastric hypersensitivity in rats.

Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are both functional gastrointestinal disorders and frequently co-occur in patients. While one cause of FD appears to be gastric hypersensitivity, whether the hypersensitivity is affected by IBS treatments remains unclear, given the lack of appropriate animal models for testing. Here, we established an experimental model of duodenal acidification-induced gastric hypersensitivity in conscious rats. The model involved duodenal acidification induced by the infusion of hydrochloric acid into the proximal duodenum, with the nociceptive response being determined as the change in mean arterial pressure (MAP) during gastric distension via an indwelling latex balloon. Using our model we evaluated the effects of duodenal acidification, increased distension pressure, and orally administered therapeutic agents for IBS with diarrhea (IBS-D). Duodenal acidification enhanced the pressor response during gastric distension, and pretreatment with the opioid κ-receptor agonist fedotozine (10mg/kg, intra-arterial) inhibited the pressor response. Pressure levels of 15-60 mm Hg increased MAP in response to gastric distension. The serotonin 5-HT3 receptor antagonist ramosetron (30 µg/kg) inhibited MAP increase induced by duodenal acidification, with no other IBS-D therapeutic agents showing any effect. In contrast, the serotonin 5-HT3 receptor agonist m-chlorophenylbiguanide (1mg/kg) significantly enhanced the pressor response during gastric distension. These findings indicate that the serotonin 5-HT3 receptor plays a key role in duodenal acidification-induced gastric hypersensitivity in rats, suggesting that ramosetron may reduce FD symptoms by ameliorating sensitized gastric perception.

Change of mast cell in gastric mucosa of patients with gastric hypersensitivity / 中华消化杂志

Objective To investigate whether gastric hypersensitivity exists in functional dyspepsia patients, and to observe the number of mast cells in proximal gastric mucosa in gastric hypersensitivity patients and the change of mast cell degranulation after stimulation so as to evaluate the role of mast cells in gastric hypersensitivity. Methods Gastric sensation threshold was determined using barostat in 40 functional dyspepsia (FD) patients and 15 controls. Twenty three patients were divided into two groups on the basis of perception threshold: hypersensitivity group (FD H) and normal sensation group (FD N). Mast cells were stained by immunohistochemistry method, mast cell number was calculated by microscopy and the average optical density valves( A ) of mast cell were obtained by microspectrophotometry (MSP). The ultrastructure of mast cell was observed under electromicroscopy. Results Gastric sensation threshold (i.e. perception, discomfort and pain threshold) was significantly lower in FD patients than in controls ( P