Migrating Motor Complex Research Articles

The Involvement of GABA in the Modulation of the Rhythm of Electrical Activity in the Small Intestine during Food Deprivation.

In experiments on male Wistar rats, the stages of adaptive changes in the rhythm of periodic electrical activity in the small intestine during food deprivation were identified and the effect of GABA on changes of the rhythm under these conditions was assessed. It was found that on days 1-3 of food deprivation, the migrating myoelectric complex (MMC) in the small intestine is preserved, but the cycle becomes rarer. On days 4-6, MMC disappears, irregular and regular activity with no periods of quiescence is recorded. On days 7-9, predominantly irregular activity of the small intestine with short quiescence periods is observed. Enteral administration of GABA at different stages of food deprivation modulates electrical activity and preserves small intestinal MMC.

Decreases in mucosally-evoked tachykinin signaling pathways can explain age-related reductions in murine colonic motility patterns.

Increasing age increases the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to this phenotype is unclear. This study explored the effects of age on key motility patterns in the murine colon and determined the contribution that altered neurokinin 2 (NK2) -mediated signaling made to the aging phenotype. Mucosal reflexes, colonic migrating motor complexes (CMMCs) and colonic motility assays were explored in isolated exvivo colons from 3, 12-14, 18- and 24-months old mice and the NK2-mediated response determined. Electrical field stimulation (EFS) or exogenous drug application were used to explore the role of the mucosa in colonic segments. Aging reduced the force of contraction of the distal colon mucosal reflex, the frequency and force of contraction of CMMCs and the NK2-mediated component of both motility patterns. Ondansetron, a 5-HT3 receptor antagonist, blocked a component of both motility patterns in full thickness but not in mucosa-free segments of the distal colon. 5, hydroxytryptamine (5-HT) and EFS-evoked NK2-dependent contractions were reduced with increasing age. Smooth muscle sensitivity to 5-HT or neurokinin A (NKA) was not altered with age. In isolated colon motility assays application of NKA decreased transit time in 24-months colon and the NK2 antagonist GR159897 increased transit times in both 3- and 24-months old colons. Aging impairs key motility patterns in the murine colon. These changes involve a decrease in mucosally-evoked NK2-mediated signaling. Targeting NK2-mediated signaling may provide a novel approach to treating age-related motility disorders in the lower bowel.

Post-infection gastrointestinal disorders and treatment options

The development of post-infectious pathology is determined by the type of pathogen, the genesis of damage to the intestinal barrier and the premorbid background of the child. On the scale of recent epidemiological events, attention is drawn to the SARS-CoV-2 virus, which has tropism for cells of the gastrointestinal tract, distorts the composition and function of the intestinal microbiome. The importance of the functions of intestinal microbes in the genesis and outcome of SARS-CoV-2 infection has been highlighted. It has been proven that a microbiota disorder with a new coronavirus infection affects not only the duration and severity of the infectious process, but also the risk of the formation of systemic diseases and malignant neoplasms. After the acute phase of SARS-CoV-2 infection, post-COVID-19 syndrome may occur, the pathophysiology of which has not yet been fully established. Although it is believed that the main reason for its appearance is the diversification of the intestinal microbial landscape against the background of the direct effect of SARS-CoV-2 on the ACE2 receptors of intestinal epitheliocytes, followed by a pathoimmune response and impaired hemostasis. Established post-COVID-19 dysbiosis underlies functional gastrointestinal disorders with pronounced impairment in the brain-gut-microbiota axis and imbalance of the migrating motor complex, leading to the development of constipation. Post-infectious constipation debut within the first 3 months after an acute infection. The main goal of therapy for post-infectious constipation is to achieve regular painless defecation with soft-consistency stool and prevent feces. Numerous foreign studies and clinical guidelines indicate that stimulating laxatives are effective and safe in the treatment of constipation, include the children’s practice. Sodium picosulfate is considered one of the topical drugs of this group of laxatives.

Effect of particle size on gastric emptying of enteric-coated granules in fasted beagle dogs: Relationship with interdigestive migrating motor complex

This study investigates the particle size threshold at which the interdigestive migrating motor complex (IMMC) becomes active in gastric emptying for fasted beagle dogs. Enteric-coated granules containing cetirizine dihydrochloride (CET) were prepared in three particle sizes, 200, 660, and 1,200 µm (D50). To mark IMMC timing and water movement from the stomach, enteric-coated aspirin tablets and acetaminophen solution were used. To six fasted beagle dogs with 50 mL of acetaminophen solution was administered each granule size as a multiple-unit and a single enteric-coated aspirin tablet (3-period crossover study). No significant difference in pharmacokinetic parameters of CET after oral administration of different particle sizes was observed. However, the appearance time of CET in plasma with smaller granules (200 and 660 µm) was significantly faster than that of salicylic acid (a major metabolite of aspirin) in all dogs. In the case of the largest granules (1,200 µm), no significant time difference was observed in the appearance of both compounds in plasma. Furthermore, in two dogs, both compounds appeared at the same time, implying IMMC-regulated gastric emptying for the largest CET granules. These results support a particle size threshold between 660 and 1,200 µm for gastric emptying without IMMC action in fasted beagle dogs.

Enteric neural stem cell transplant restores gut motility in mice with Hirschsprung disease.

The goal of this study was to determine if transplantation of enteric neural stem cells (ENSCs) can rescue the enteric nervous system, restore gut motility, reduce colonic inflammation, and improve survival in the Ednrb-KO mouse model of Hirschsprung disease (HSCR). ENSCs were isolated from mouse intestine, expanded to form neurospheres, and microinjected into the colons of recipient Ednrb-KO mice. Transplanted ENSCs were identified in recipient colons as cell clusters in "neo-ganglia." Immunohistochemical evaluation demonstrated extensive cell migration away from the sites of cell delivery and across the muscle layers. Electrical field stimulation and optogenetics showed significantly enhanced contractile activity of aganglionic colonic smooth muscle following ENSC transplantation and confirmed functional neuromuscular integration of the transplanted ENSC-derived neurons. ENSC injection also partially restored the colonic migrating motor complex. Histological examination revealed a significant reduction in inflammation in ENSC-transplanted aganglionic recipient colon compared with that of sham-operated mice. Interestingly, mice that received cell transplant also had prolonged survival compared with controls. This study demonstrates that ENSC transplantation can improve outcomes in HSCR by restoring gut motility and reducing the severity of Hirschsprung-associated enterocolitis, the leading cause of death in human HSCR.

Alterations in gastrointestinal motility assessed by high-resolution antroduodenal manometry in patients with severe disorders of gut-brain interaction.

Data are limited regarding gastrointestinal motility disturbance in disorders of gut-brain interaction (DGBI). This study aimed to characterize antroduodenal motor alterations in patients with high-resolution antroduodenal manometry (HR-ADM). HR-ADM was performed in patients with severe DGBI and compared with healthy volunteers (HV). HR-ADM used a commercially available probe composed of 36 electronic sensors spaced 1 cm apart and positioned across the pylorus. Antral and duodenal motor high-resolution profiles were analyzed, based on the frequency, amplitude, and contractile integral/sensor (CI/s) calculated for each phase of the migrating motor complex (MMC). Eighteen HV and 64 patients were investigated, 10 with irritable bowel syndrome (IBS), 24 with functional dyspepsia (FD), 15 with overlap IBS-FD, and 15 with other DGBI. Compared with HV, patients had a lower frequency of phase II duodenal contractions (27 vs. 51 per hour; P = 0.002) and a lower duodenal phase II contraction amplitude (70 vs. 100 mmHg; P = 0.01), resulting in a lower CI/s of phase II (833 vs. 1,901 mmHg·cm·s; P < 0.001) in the duodenum. In addition, the frequency of phase II propagated antroduodenal contractions was lower (5 vs. 11 per hour; P < 0.001) in patients compared with HV. Interestingly, the antral CI/s of phase III was decreased in FD patients but not in IBS patients. Patients with severe DGBI display alterations in antral and intestinal motility assessed by commercially available HR-ADM. Whether these alterations may explain symptom profiles in such patients remains to be confirmed (NCT04918329 and NCT01519180).NEW & NOTEWORTHY Gastrointestinal dysmotility has been assessed poorly in disorders of gut-brain interaction (DGBI), especially with high-resolution antroduodenal manometry. Plots of DGBI patients showed lower duodenal contractions during phase II regarding amplitude, frequency, and contractile integral/sensor (CI/s) compared with healthy volunteers. A lower frequency of propagated antroduodenal contractions was also reported. Finally, antral CI/s was lower in patients with functional dyspepsia during phase III. Further studies are needed to assess the clinical significance of these alterations.

Phosphatase and Tensin Homolog Inhibition in Proteolipid Protein 1-Expressing Cells Stimulates Neurogenesis and Gliogenesis in the Postnatal Enteric Nervous System.

Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7-12 weeks of age; n = 4-15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3-4 days post-DSS) and (2) late (3-4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders).

The role of free fatty acid receptor-1 in gastric contractions in Suncus murinus.

Motilin is an important hormonal regulator in the migrating motor complex (MMC). Free fatty acid receptor-1 (FFAR1, also known as GPR40) has been reported to stimulate motilin release in human duodenal organoids. However, how FFAR1 regulates gastric motility in vivo is unclear. This study investigated the role of FFAR1 in the regulation of gastric contractions and its possible mechanism of action using Suncus murinus. Firstly, intragastric administration of oleic acid (C18:1, OA), a natural ligand for FFAR1, stimulated phase II-like contractions, followed by phase III-like contractions in the fasted state, and the gastric emptying rate was accelerated. The administration of GW1100, an FFAR1 antagonist, inhibited the effects of OA-induced gastric contractions. Intravenous infusion of a ghrelin receptor antagonist (DLS) or serotonin 4 (5-HT4) receptor antagonist (GR125487) inhibited phase II-like contractions and prolonged the onset of phase III-like contractions induced by OA. MA-2029, a motilin receptor antagonist, delayed the occurrence of phase III-like contractions. In vagotomized suncus, OA did not induce phase II-like contractions. In addition, OA promoted gastric emptying through a vagal pathway during the postprandial period. However, OA did not directly act on the gastric body to induce contractions in vitro. In summary, this study indicates that ghrelin, motilin, 5-HT, and the vagus nerve are involved in the role of FFAR1 regulating MMC. Our findings provide novel evidence for the involvement of nutritional factors in the regulation of gastric motility.

Motilin fluctuations in healthy volunteers determined by liquid chromatography mass spectrometry.

Motilin is a hormone secreted by specialised enteroendocrine cells in the small intestine, and is known to modulate gastrointestinal motility in humans, regulating the migratory motor complex. It is understudied at least in part due to the lack of commercially available immunoassays. A multiplexed liquid chromatography mass spectrometry (LC-MS/MS) method was optimised to measure motilin, insulin, C-peptide, GIP (1-42) and GIP (3-42). Corresponding active ghrelin concentrations were determined by immunoassay. Ten healthy volunteers with no prior history of gastroenterological or endocrine condition attended after overnight fast and had blood samples taken every 15 minutes for 4 hours whilst continuing to fast, and then further sampling for 2 hours following a liquid mixed meal. Hunger scores were taken at each time point using a visual analogue scale. Normal bowel habit was confirmed by 1 week stool diary. Motilin levels fluctuated in the fasting state with an average period between peaks of 109.5 mins (SD:30.0), but with no evidence of a relationship with either ghrelin levels or hunger scores. The mixed meal interrupted cyclical motilin fluctuations, increased concentrations of motilin, insulin, C-peptide, GIP(1-42) and GIP(3-42), and suppressed ghrelin levels. This study highlights the utility of LC-MS/MS for parallel measurement of motilin alongside other peptide hormones, and supports previous reports of the cyclical nature of motilin levels in the fasting state and interruption with feeding. This analytical method has utility for further clinical studies into motilin and gut hormone physiology in human volunteers.

Overview of the Enteric Nervous System.

Propulsion of contents in the gastrointestinal tract requires coordinated functions of the extrinsic nerves to the gut from the brain and spinal cord, as well as the neuromuscular apparatus within the gut. The latter includes excitatory and inhibitory neurons, pacemaker cells such as the interstitial cells of Cajal and fibroblast-like cells, and smooth muscle cells. Coordination between these extrinsic and enteric neurons results in propulsive functions which include peristaltic reflexes, migrating motor complexes in the small intestine which serve as the housekeeper propelling to the colon the residual content after digestion, and mass movements in the colon which lead to defecation.

Effect of cholecystokinin on small intestinal motility in suncus murinus

In a fasting gastrointestinal tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occur that comprises of three phases: I, II, and III. Among these, phase III contractions propagate from the stomach to the lower intestine in mammals, including humans, dogs, and Suncus murinus (suncus). Apart from the phase III of MMC propagating from the stomach, during the gastric phase II, small intestine-originated strong contractions propagate to the lower small intestine; however, the mechanism of contractions originating in the small intestine has not been clarified. In this study, we aimed to elucidate the role of cholecystokinin (CCK) in small intestinal motility. Administration of sulfated CCK-8 in phase I induced phase II-like contractions in the small intestine, which lasted for approximately 10–20 min and then returned to the baseline, while no change was observed in the stomach. Contractions of small intestine induced by CCK-8 were abolished by lorglumide, a CCK1 receptor antagonist. Gastrin, a ligand for the CCK2 receptor, evoked strong contractions in the stomach, but did not induce contractions in the small intestine. To examine the effect of endogenous CCK on contractions of small intestinal origin, lorglumide was administered during phase II. However, there was no change in the duodenal motility pattern, and strong contractions of small intestinal origin were not abolished by treatment with lorglumide. These results suggest that exogenous CCK stimulates contractions of small intestine via CCK1 receptors, whereas endogenous CCK is not involved in the strong contractions of small intestinal origin.

Clinical Utility of Ileal Motility in Children With Defecation Disorders and Children With Chronic Intestinal Pseudo-Obstruction.

Little is known about ileal motility patterns and their utility in children. Here, we present our experience with children undergoing ileal manometry (IM). A retrospective review of children with ileostomy comparing IM between 2 groups: A [chronic intestinal pseudo-obstruction (CIPO)] and B (feasibility of ileostomy closure in children with defecation disorders). We also compared the IM findings with those from antroduodenal manometry (ADM), and evaluated the joint effect of age, sex, and study indication group on IM results. A total of 27 children (median age 5.8 years old, range 0.5-16.74 years, 16 were female) were included (12 in group A and 15 in group B). There was no association between IM interpretation and sex; however younger age was associated with abnormal IM ( P = 0.021). We found a significantly higher proportion of patients with presence of phase III of the migrating motor complex (MMC) during fasting and normal postprandial response in group B than in group A ( P < 0.001). Logistic regression analysis revealed that only Group B was associated with normal IM ( P < 0.001). We found a moderate agreement for the presence of phase III MMC and postprandial response between IM and ADM (kappa = 0.698, P = 0.008 and kappa = 0.683, P = 0.009, respectively). IM is abnormal in patients with CIPO and normal in patients with defecation disorders, suggesting that IM may be not needed for ostomy closure in those with defecation disorders. IM has a moderate agreement with ADM and could be used as a surrogate for small bowel motility.

Prokinetic Activity of Mulberry Fruit, Morus alba L.

The fruit of Morus alba L. (MAF) has been consumed as a food worldwide. MAF has also been widely used in traditional medicine for thousands of years in East Asia, and its diverse bioactivities have been reported in numerous publications. However, no prokinetic activity has been reported for MAF or its components. In the present study, therefore, we investigated the effects of MAF on gastrointestinal motor function by measuring the intestinal transit rate (ITR) of Evans blue in mice in vivo. The ITR values accelerated by MAF were significantly higher than those accelerated by cisapride or metoclopramide, suggesting that MAF has potential as a new prokinetic agent to replace cisapride and metoclopramide. We also investigated the effects of MAF on myogenic and neurogenic contractions in human intestinal smooth muscles by measuring spontaneous contractions of smooth muscle strips, smooth muscle contractions induced by neural stimulation, and migrating motor complexes from intestinal segments in the human ileum and sigmoid colon in situ. MAF increased both myogenic and neurogenic contractions to enhance ileal and colonic motility in the human intestine. Taken together, these results indicate that MAF enhanced intestinal motility by increasing both myogenic and neurogenic contractions, thereby accelerating the ITR.

Numerical simulation of peristalsis to study co-localization and intestinal distribution of a macromolecular drug and permeation enhancer

In this work, simulations of intestinal peristalsis are performed to investigate the intraluminal transport of macromolecules (MMs) and permeation enhancers (PEs). Properties of insulin and sodium caprate (C10) are used to represent the general class of MM and PE molecules. Nuclear magnetic resonance spectroscopy was used to obtain the diffusivity of C10, and coarse-grain molecular dynamics simulations were carried out to estimate the concentration-dependent diffusivity of C10. A segment of the small intestine with the length of 29.75 cm was modeled. Peristaltic speed, pocket size, release location, and occlusion ratio of the peristaltic wave were varied to study the effect on drug transport. It was observed that the maximum concentration at the epithelial surface for the PE and the MM increased by 397 % and 380 %, respectively, when the peristaltic wave speed was decreased from 1.5 to 0.5 cm s−1. At this wave speed, physiologically relevant concentrations of PE were found at the epithelial surface. However, when the occlusion ratio is increased from 0.3 to 0.7, the concentration approaches zero. These results suggest that a slower-moving and more contracted peristaltic wave leads to higher efficiency in transporting mass to the epithelial wall during the peristalsis phases of the migrating motor complex.

The regulatory effects of fucoidan and laminarin on functional dyspepsia mice induced by loperamide.

Gastrointestinal dysmotility is a common cause of functional dyspepsia. As two kinds of polysaccharides derived from brown algae, fucoidan and laminarin possess many physiological properties; however, their relative abilities in regulating gastrointestinal motility have not been illustrated yet. In this study, we aimed to investigate the regulatory effect of fucoidan and laminarin on functional dyspepsia mice induced by loperamide. Mice with gastrointestinal dysmotility were treated with fucoidan (100 and 200 mg per kg bw) and laminarin (50 and 100 mg per kg bw). As a result, fucoidan and laminarin reversed the dysfunction mainly through regulating gastrointestinal hormones (motilin and ghrelin), the cholinergic pathway, the total bile acid level, c-kit protein expression, and gastric smooth muscle contraction-related gene expression (ANO1 and RYR3). Moreover, fucoidan and laminarin intervention modulated the gut microbiota profile including the altered richness of Muribaculaceae, Lachnospiraceae, and Streptococcus. The results indicated that fucoidan and laminarin may restore the rhythm of the migrating motor complex and regulate gut microecology. In conclusion, we provided evidence to support that fucoidan and laminarin might have potential abilities to regulate gastrointestinal motility.

In Vivo Evaluation of Anti-Nociceptive Effects of Silver Nanoparticles.

Silver nanoparticles (AgNPs) are widely used commercially due to their antimicrobial effects. Little is known about the effect of AgNPs on neural transmission and pain response. The aim of this study was to assess the anti-nociceptive activity of AgNPs. AgNPs were prepared at 16 ug/mL, white albino rats were injected with various doses of AgNPs, and challenged using a hot-plate test and paw withdrawal latency (PWL) was measured. The chronic constriction injury (CCI) model was utilized to evaluate the pedal withdrawal reflex and tail withdrawal reflex. An electrophysiological study was conducted utilizing colon longitudinal muscle strips. AgNPs increased the latency of PWL in a dose-dependent matter over the duration of 6 h. The paw withdrawal threshold in animals with CCI significantly increased after AgNPs administration. In isolated colon longitudinal muscle strips, AgNPs significantly reduced the colonic migrating motor complexes (MMCs) and contraction. This action was completely reversed after removing the AgNPs and adding acetylcholine to the preparation. In this study, AgNPs showed significant anti-nociception properties. To our knowledge, this is the first report to describe this pharmacological action of AgNPs.

Altered functional responses by PAR1 agonist in murine dextran sodium sulphate-treated colon

Protease-activated receptor-1 (PAR1) is highly expressed in murine colonic smooth muscles. Responses to PAR1 activation are complex and result from responses in multiple cell types. We investigated whether PAR1 responses are altered in inflamed colon induced by dextran sodium sulfate (DSS)-treatment. Colitis was induced in C57BL/6 mice by administration of 3% DSS in drinking water for 7 days. Measurements of isometric force, transmembrane potentials from impaled smooth muscle cells, quantitative PCR and Western blots were performed. Thrombin, an activator of PAR1, caused transient hyperpolarization and relaxation of untreated colons, but these responses decreased in DSS-treated colons. Apamin caused depolarization and increased contractions of muscles from untreated mice. This response was decreased in DSS-treated colons. Expression of Kcnn3 and Pdgfra also decreased in DSS-treated muscles. A second phase of thrombin responses is depolarization and increased contractions in untreated muscles. However, thrombin did cause depolarization in DSS-treated colon, yet it increased colonic contractions. The latter effect was associated with enhanced expression of MYPT1 and CPI-17. The propagation velocity and frequency of colonic migrating motor complexes in DSS-treated colon was significantly higher compared to control colons. In summary, DSS treatment causes loss of transient relaxations due to downregulation of SK3 channels in PDGFRα+ cells and may increase contractile responses due to increased Ca2+ sensitization of smooth muscle cells via PAR1 activation.

253. RABEPRAZOLE IS EFFECTIVE FOR BILE REFLUX ESOPHAGITIS AFTER TOTAL GASTRECTOMY IN A RAT MODEL

Abstract To evaluate the effect of PPI (Rabeprazole) on esophageal bile reflux in esophagitis after total gastrectomy. Twenty -one 8 week old male Wistar rats were studied. They were performed esophagoduodenostomy of total gastrectomy to induce esophageal reflux of biliary and pancreatic juice. Five rats were performed the sham operation (Sham) (n = 8). On the postoperative day 7, they were treated with saline (Control) (n = 8) or PPI (Rabeprazole 30 mg/kg per day, ip) (n = 8) for 2 weeks. On the postoperative 21 days, all rats were sacrificed and each esophagus was evaluated histologically. Esophageal injury was evaluated by macroscopic and microscopic findings as well as the expression of COX2. We measured bile acid in the esophageal lumen and common bile duct. The macroscopic ulcer score and microscopic ulcer length of the control group were significantly higher compared to those of the rabeprazole treated group. The expression of COX2 was significantly increased according to the immunostaing in the control group compared to rabeprazole treated group. Although there was no difference between the control and PPI groups in the total bile acids in the common bile duct, the bile acid in the esophageal lumen was significantly decreased in the rabeprazole treated group due to augmentation of the duodenal motor complex. With this model, rabeprazole is good effect for reflux esophagitis after total gastrectomy from bile reflux. Bile acid is an important factor in the mucosal lesion induced by duodenal reflux. PPI does not inhibit the secretion of bile acid from the common bile duct. Therefore, we speculate PPI accelerates duodenal phase III migrating motor complex, accelerating duodenal passage of duodenal contents (bile acids), which should reduce duodenoesophageal reflux.

Role of cannabinoid receptor-2 in small intestinal fasted myoelectric activity of rats

Cannabinoid receptor-1 (CB1R) and cannabinoid receptor-2 (CB2R) have significant roles in the esophagus, small intestine, and colon motility in the postprandial period besides gastric emptying, secretion, and defecation in the gastrointestinal system. Furthermore, our previous study showed that activation of peripheral CB1R inhibited migrating myoelectric complex (MMC), forming the source of fasted small intestinal motility. However, the role of the central/peripheral CB2Rs on the MMC pattern is still unknown. The present study aimed to investigate the roles of peripheral and central CB2Rs in forming and regulating small intestine MMC patterns in rats. In this study, we used 42 adult male Sprague-Dawley rats (n:7). We implanted bipolar electrodes in three different jejunum sites of rats (J1, J2, J3) to record the MMC pattern. We placed a cannula in the right lateral ventricle to perform drug intracerebroventricularly (i.c.v.) and implanted a catheter in the right jugular vein to inject the drug intravenously (i.v). After the amelioration period, we conducted experiments following an 18-hour fasting period and later took at least a one-hour baseline recording of the MMC pattern. Then, we injected JWH 133, a CB2R agonist i.v. (1.25-10 mg/kg) or i.c.v. (2.5- 20 μg/rat) and also administered AM 630, a CB2R antagonist, i.v. (0.25-2 mg/kg) or i.c.v. (2.5-20 μg/rat). We compared the effects of JWH 133 or AM 630 on the MMC pattern to the vehicle group (10% dimethyl sulfoxide). Centrally or peripherally injected JWH 133 and AM 630 did not cause any change in the spike frequency and the number of the MMC cycle. The results of the present study propose that CB2Rs are involved in neither endogenous formation nor exogenous regulation of the fasting myoelectric activity in healthy fasted rats.

Neurotensin and xenin stimulates pancreatic exocrine secretion through the peripheral cholinergic nerves in conscious sheep

The present study aimed to clarify the effects of neurotensin and xenin on pancreatic exocrine secretion in conscious sheep and their mechanism of actions. The animals were equipped with two silastic cannulae in the common bile duct to separately collect pancreatic fluid and bile, and a silastic cannula in the proximal duodenum to continuously return the mixed fluids. NT and xenin were intravenously injected at range of 0.01–3.0 nmol/kg during the phase I of duodenal migrating motor complex. A single intravenous NT injection significantly and dose-dependently increased pancreatic fluid, protein, and bicarbonate outputs. The effect of NT at 1 nmol/kg was completely inhibited by a background intravenous infusion of atropine methyl nitrate at a dose of 10 nmol/kg/min, however, the effect was not altered by a prior injection of the neurotensin receptor subtype (NTR)-1 antagonist SR 48692 at 60 nmol/kg. Moreover, a single intravenous xenin-25 injection significantly and dose-dependently increased pancreatic fluid and protein output, whereas the effect of xenin-25 did not clearly show dose-dependence. The prior SR 48692 injection at 30 nmol/kg did not significantly alter the effects of xenin-25 at 0.3 nmol/kg, while the atropine infusion significantly inhibited the increase in fluid secretion. Under the atropine infusion, xenin-25 at 0.3 nmol/kg did not increase protein and bicarbonate outputs, whereas the inhibitory effect of the atropine was not significant compared to that of the single injection of xenin-25. A single intravenous injection of NTR-2 agonist levocabastine at 0.1–3 nmol/kg did not alter pancreatic exocrine secretion. These results suggest that both NT and xenin-25 effectively stimulates pancreatic exocrine secretion through the peripheral cholinergic system in sheep and that NTR-2 is not involved in the regulation of pancreatic exocrine secretion, however, we did not precisely determine the role of NTR-1 in the actions of both the peptides on pancreatic exocrine secretion.