| BackgroundIrritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, characterized by the abdominal pain or discomfort with altered bowel habits. The etiological factor and pathgenetic mechanism of IBS still not completely understood. The alterations in gut motility and visceral hypersensitivity are two main features of IBS. GLP-1is considered mainly to inhibit glucagon release, potentiate glucose-dependent insulin release and decreases the gastrointestinal motility. Exendin-4is a GLP-1R agonist. It exhibits biologic actions similar to GLP-1and has a longer half-life. Glucagon-like peptide-1(GLP-1) analogue ROSE-010is found to relieve abdominal pain in patients with IBS,but the mechanism of it is still unclear:to improve disordered smooth muscle activity or ameliorate sensory dysregulation, or even both? In our previous study, administration of exogenous GLP-1and exendin-4could inhibit colonic circular muscle contraction, especially in IBS with constipation group, suggesting that GLP-1may relief the pain attacks by improving disordered GI motility. Our previous studies have also shown that GLP-1R was expressed in the mucosal layer. So, we hypothesized that GLP-1may attenuate neonatal acetic acid-induced hyperalgesia in rats, and the5-HT closely related to visceral pain played what role in this process.AimsTo investigated the role of GLP-1agonist exendin-4for visceral sensitivity in visceral hypersensitivity rats and preliminarily explore its possible machanisms.Methods1. Group division:Fifty SD rats were divided into control rats, saline, exendin-4:1μg/kg,5μg/kg and10μg/kg, the posterior groups are the acetic acid rats.2. Establishment of animal model:Rat models of visceral hypersensitivity were established by intracolonic infusion of acetic acid (AA) in10-day-old rats. The experiments were performed at age of8-10weeks.3. Detection indexs:Abdominal withdrawal reflex (AWR) and behavioral responses Electromyogram (EMG) to colorectal distention were measured. The expression of GLP-1in colon was detected by immunohistochemistry. The levels of serotonin in serum and colonic mucous layer as well as serum content of GLP-1were measured by ELISA assay. Immunofluorescence method was used to observe the distribution of GLP-1R in EC cells in colonic mucosa.Results1. Compared to control rats, a higher AUC and AWR scores of the abdominal muscle contraction was detected in the acetic acid rats (P<0.05). In addition, no histologic signs of inflammation or tissue damage were observed in the colons of the acetic acid rats. These results suggested that the rat model of visceral hypersensitivity was successfully established.2. According to the immunohistochemistry results, the GLP-1in the colon of acetic acid rats was a significant decrease compared with control rats (P<0.05).3. The average serum level bioactive GLP-1in acetic acid rats was lower than that in control rats (P<0.05).4. In a certain dose range, GLP-1agonist exendin-4treatment (5μg/kg,10μg/kg) for7days significantly attenuated the nociceptive responses to CRD and produced a analgesic effect in acetic acid rats (ANOVA, P<0.05).5. A consistent with the above result, in a certain dose range, exendin-4could decrease the enhanced concentration of5-HT in serum and colonic mucous layer of acetic acid rats by treatment with exendin-4(5.0μg/kg,10μg/kg, ANOVA, P<0.05).6. GLP-1R was expressed in EC cells.ConclusionGLP-1analogue exendin-4may attenuate neonatal acetic acid-induced hyperalgesia in rats through impacting on synthesis and metabolic of5-HT. BackgroundIrritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, characterized by the abdominal pain or discomfort with altered bowel habits. The etiological factor and pathgenetic mechanism of IBS still not completely understood, resulting from comprehensive function of multiple factors. The alterations in gut motiiity and visceral hypersensitivity are two main features of IBS.AimsTo investigate the effect of changes in5-HT2B receptor on the pathogenetic mechanism of irritable bowel syndrome (IBS) subgroups in rat models.MethodsForty-five SD rats were divided into D-IBS group, C-IBS group and control group. The D-IBS model was created in rats by intracolonic instillation of acetic acid and by restraint stress. The C-IBS model was created in rats by gastric instillation of0-4℃cool water daily for14days. A control group was also made. Weight and water content of the feces expelled by the rats were calculated. Abdominal contractions induced by distension of a colonically inserted balloon (0-60mmHg) were recorded in rats by implanting electrodes in the abdominal external oblique muscle. Histological analysis of colonic tissue was performed. The distributions of5-HT2B receptor in D-IBS, C-IBS and control groups colon tissue were detected by immunohistochemistry. The expressions of5-HT2B receptor protein and mRNA in colon tissues in D-IBS, C-IBS and control groups were detected by Western blot and reverse transcription PCR respectively.Results1. The wet weight and water content of the feces expelled by the rats in the C-IBS were significantly lower than those in control group (P<0.05),while the D-IBS group were higher than the control group (P<0.05); There was higher amplitude of the abdominal muscle contraction in D-IBS group and C-IBS group compared with the control group when the balloon was distended at the pressure of40and60mmHg. Amplitude of the contraction in D-IBS group was higher than the C-IBS group (P<0.01). Histological analysis of the colon showed no colonic inflammation in any group. These aspects suggested that IBS subgroups were successfully made.2.1mmunohistochemistry demonstrated that5-HT2B receptor mainly localized in the myenteric nerve plexus, longitudinal muscle and colon mucosa..Compared to control rats, a higher AUC and AWR scores of the abdominal muscle contraction was detected in the acetic acid rats (P<0.05). In addition, no histologic signs of inflammation or tissue damage were observed in the colons of the acetic acid rats. These results suggested that the rat model of visceral hypersensitivity was successfully established.3. Western blot and reverse transcription PCR analyses showed that the expressions of5-HT2B receptor protein and mRNA in D-IBS group were higher than those in control group (P<0.05); however, the levels of5-HT2B receptor protein and mRNA in C-IBS group were lower than those in control group (P<0.05).ConclusionThe results indicate that5-HT2B receptor plays a role in the pathgenetic mechanism of IBS subgroups. |
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