| BackgroundIrritable bowel syndrome(IBS) is one of the most common functional gastrointestinal disorders, but therapeutic options currently available are limited and was often disappointing in efficacy. Recently, Hellstr?m et al. demonstrated that glucagon-like peptide-1(GLP-1) analogue ROSE-010 was effective at relieving pain in IBS patients. However, the mechanism underlying its anti-nociception effect remains largely unknown.The alterations in gut motility and visceral hypersensitivity are two main features of IBS. GLP-1 is a gut-derived hormone released from intestinal L-cells following a meal. GLP-1 is associated with potentially beneficial effects related to gut motility, however, the effect of GLP-1 on visceral hypersensitivity has not been studied. Therefore, we investigated that whether GLP-1 analogs also affect visceral sensitivity of IBS patients to alleviate symptoms of abdominal pain. In addition, serotonin(5-hydroxytryptamine, 5-HT), as an important neurotransmitter, plays an important role in the transmission of visceral sensation and regulation. So, we speculated whether serotonin take part in the complex process. Due to the short half-life, clinical application of GLP-1 is limited. Exendin-4, a natural GLP-1 receptor agonist, has a similar biological role of GLP-1 and has used as a GLP-1 analogue in clinical. Therefore, we designed and carried out the following research.AimsTo investigate the role of GLP-1 analogue Exendin-4 for visceral sensitivity in rats with neonatal colon sensitivity and preliminarily explore its possible machanisms.Methods1. Modeling method: neonatal male SD rats were randomly divided into two groups, namely the control group and model group. In ten-day-old rat pups, model group received an infusion of 0.2 m L of 0.5% acetic acid solution in saline into the colon 2 cm from the anus, and controls received an equal volume of saline.2. Visceral sensitivity:(1) Abdominal withdrawal reflex(AWR) and electromyography(EMG) by grading the response(eight-week-old) to colorectal distention(CRD) were used for assessing visceral sensitivity.(2) Evaluation of colon inflammation/damage was by H&E-staining and Myeloperoxidase(MPO) assays.3. Groups: model rats were randomly divided into four groups as follows: vehicle group(saline), different dose of exendin-4 groups(exendin-4 at a dose of 1.0, 5.0 and 10μg kg-1), were intraperitoneally injected for 7 days respectively.4. Detection indexs: AWR and EMG by CRD were measured. The levels of GLP-1 in serum of model and control groups were measured by a standardized ELISA assay. The levels of serotonin(5-HT) in serum and colonic tissue were measured by ELISA. The expressions of serotonin transporter(SERT) and tryptophan hydroxylase-1(TPH1) in colonic tissue were detected by RT-PCR and western blot, respectively.Results1. Neonatal acetic acid treatment determined a higher sensitivity to colorectal distension(CRD) in adult rats compared with controls(P<0.05). In addition, no histologic signs of inflammation or tissue damage were observed in the colons of the model rats. These results suggested that the rat model of visceral hypersensitivity was successfully established.2. The rats with neonatal colon sensitivity showed high levels of 5-HT in serum and colon tissue, as well as low serotonin transporter(SERT) expression in colon.3. Exendin-4 dose-dependently reduced visceral hypersensitivity as well as the high levels of 5-HT in colonic sensitized rats. Rats with colonic sensitivity treated with exendin-4 showed lower TPH1 level, and higher SERT expression in the coloncompared to the vehicle group.ConclusionThese findings suggest that exendin-4 produced visceral analgesia, which might be mediated in part by endogenous 5-HT pathways, is associated with increasing the expression of SERT and decreasing the expression of TPH-1 in rats with visceral hypersensitivity.ObjectiveThe aim was to investigate the effect of vagal afferents on visceral hypersensitivity in rats with neonatal colon sensitivity induced by acetic acid.MethodsRat models of visceral hypersensitivity were established by intra-colonic infusion of acetic acid(AA) at the age of 10 days. Visceral sensitivity was assessed by measuring abdominal withdrawal reflex(AWR) and electromyography(EMG) in response to graded colorectal distension(CRD). Spontaneous discharge of cervical vagus nerve to CRD was recorded between the model rats and controls. The expressions of c-fos in neuron of nucleus of solitary tract(NST) and colon were detected by immunohistochemical staining.ResultsNeonatal acetic acid treatment induced visceral hypersensitivity in adult rats, compared with controls. No evidence of inflammation in colon was found in both groups by H&E-staining and MPO values. The discharge of cervical vagus nerve was higher than the control group(P<0.05), and the expressions of c-fos in neuron of NST and the myenteric nerve plexus of colon were increased compared with the controls(P<0.05).ConclusionThe rats with neonatal colon sensitivity induced by acetic acid had higher vagal afferent activition, and the expressions of c-fos in nucleus of solitary tract and colonincreased, these indicated that visceral hypersensitivity model rats had abnormal vagus nerve activation. |
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