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The digestive tract contains endogenous cannabinoids (anandamide and 2-arachidonylglycerol) and cannabinoid CB1 receptors can be found on myenteric and submucosal nerves. Activation of CB1 receptors inhibits gastrointestinal motility, intestinal secretion and gastric acid secretion. The enteric location of CB1 receptors could provide new strategies for the management of gut disorders.
BACKGROUND AND PURPOSE: The neuromedin U (NMU) receptors, NMU1 and NMU2, are expressed in the gut but their functions are unclear. This study explores the role of NMU in gastrointestinal motility. EXPERIMENTAL APPROACH: The effects of NMU were examined in the forestomach and colon isolated from NMU2R wild-type and NMU2R-/- (knockout) mice, looking for changes in muscle tension and in nerve-mediated responses evoked by electrical field stimulation (EFS), and in models of peristalsis in mouse colon and faecal pellet transit in guinea-pig colon. KEY RESULTS: In the mouse forestomach, NMU (1 nM-10 microM) concentration-dependently induced muscle contraction, in the presence of tetrodotoxin and atropine, in preparations from both wild-type and NMU2R-/- mice (pEC50: 7.9, 7.6, Emax: 0.26, 0.20g tension, respectively, n=8 each concentration). The same concentrations of NMU had no consistent effects on the responses to EFS (n=8). In the mouse colon, NMU (0.1 nM-1 microM) had no significant effect on baseline muscle tension (n=8), but concentration-dependently potentiated EFS-evoked contractions in preparations from both wild-type and NMU2R-/- mice, pEC50: 8.1, 7.8, Emax: 24%, 21%, respectively, n=6-11. NMU (0.01 nM-0.1 microM, n=5-7) concentration-dependently decreased the interval between waves of peristalsis in the mouse colon (pEC50: 8.8) and increased the rate at which a faecal pellet moved along the guinea-pig colon. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that NMU exerts colon-specific, nerve-mediated, prokinetic activity, via a pathway involving activation of NMU1 receptors. This suggests that this receptor may represent a molecular target for the treatment of intestinal motility disorders.
BACKGROUND: There is increasing evidence that autonomic neuropathies may adversely affect gastrointestinal motility by involving the extrinsic nerves of the gut. The authors' hypothesize that functional abdominal pain in children is associated with generalized autonomic dysfunction. METHODS: The authors performed detailed autonomic testing in eight patients with functional abdominal pain, including deep breathing, Valsalva, tilting (to assess parasympathetic and sympathetic adrenergic function), and axon-reflex function and thermoregulatory sweat testing to assess sympathetic cholinergic function. Patients also completed a questionnaire regarding other autonomic symptoms. RESULTS: Results of autonomic testing were abnormal in seven patients. Parasympathetic function was normal in all, and the abnormalities were restricted to sympathetic cardiac, vasomotor, and sudomotor function. Abnormal results of axon-reflex testing in six were consistent with peripheral nervous system dysfunction. Five had decreased sweating over the abdomen, determined by thermoregulatory sweat testing. Five eight had nongastrointestinal autonomic symptoms, primarily palpitations and flushing. CONCLUSIONS: Functional abdominal pain in the current patients is associated with generalized dysfunction of the autonomic nervous system. This dysfunction can be peripheral or central in different individuals but seems to be restricted to the sympathetic branch. The known function of the sympathetic nervous system as the motility "brake" suggests that pain could be a manifestation of unmodulated peristalsis, resulting in abdominal cramps.
We attempted to determine whether the administration of erythromycin shortens the period of postoperative ileus by a prospective, double-blind, placebo-controlled study. Seventy-seven patients were randomized and included in the statistical calculations. The patients were stratified according to the operation performed (cholecystectomy, celiotomy, or other major abdominal operations). Forty-one patients (group 1) received 250 mg erythromycin intravenously every 8 h for nine doses upon admission to the recovery room. Thirty-six patients (group 2) received placebo. The time (in hours) to first passage of flatus, first liquid meal, first bowel movement, and total length of hospital stay was recorded. There was no significant difference between group 1 and group 2 in time to first flatus (54.9 +/- 29 vs. 53.9 +/- 27 h, respectively), first meal (70.4 +/- 44 vs. 71.7 +/- 65), first bowel movement (81.8 +/- 32 vs. 80.1 +/- 28), or length of hospital stay (185.2 +/- 183 vs. 182.1 +/- 163). Erythromycin, in the dosage tested in this study, does not seem to alter clinical parameters of gastrointestinal motility after an abdominal operation. New prokinetic agents may deserve further studies.
Physical exercise is probably both beneficial and harmful for the gastrointestinal tract, depending partly on the training intensity. On the one hand, gastrointestinal symptoms such as heartburn, chest pain, nausea, vomiting, abdominal cramps, side ache and diarrhoea are common during heavy exercise. On the other hand, physical activity seems to protect from colon cancer, cholelithiasis and diverticular disease. Constipation has been shown to be related to inactivity. Despite this, no overwhelming evidence exists for a positive effect of physical exercise as a treatment option for chronic constipation. The reasons behind these somewhat discrepant effects are not understood fully. Altered gastrointestinal blood flow, effects on gastrointestinal motor function, neuroendocrine changes and mechanical effects are probably involved. Conflicting results exist regarding the effects of physical activity on gastrointestinal motility. Modern technologies now make motility studies in various parts of the gastrointestinal tract possible. More studies are needed to understand better the effects of physical exercise on the gastrointestinal tract. In particular, the relationship between the training intensity and duration and positive and negative alterations in gastrointestinal physiology needs to be addressed further.
Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by abdominal pain and change in defecation pattern. This review addresses the topic of possible sex (genetic, biological) and gender (experiential, perceptual) differences in individuals with and without IBS. Several observations make the topic important. First, there is a predominance of women as compared to men who seek health care services for IBS in the United States and other industrialized societies. Second, menstrual cycle-linked differences are observed in IBS symptom reports. Third, women with IBS tend to report greater problems with constipation and nongastrointestinal complaints associated with IBS. Fourth, serotonin (5-HT3) receptor antagonist and 5-HT4 partial agonist drugs appear to more effectively diminish reports of bowel pattern disruption in women with IBS as compared to men. This review examines sex and gender modulation of gastrointestinal motility and transit, visceral pain sensitivity, autonomic nervous system function, serotonin biochemistry, and differences in health care-seeking behavior for IBS.
Opiate peptides, encephalins and endorphins, originally isolated from the brain, have been detected by the immunocytochemistry and radioimmunoassay in the digestive system and localized in the distinctive endocrine-paracrine cells of APUD series of the gastrointestinal mucosa and the nerve fibers of the myenteric plexus. The physiological role of endogenous opiates is unknown but the spectrum of biological action on the digestive system resembles that of morphine and related drugs. They strongly affect gastrointestinal motility such as gastric and intestinal contractions, gastric emptying, intestinal transit, biliary pressure and defecation. They also increase gastric secretory activity and raise gastric mucosal microcirculation without affecting gastrin release. They inhibit pancreatic bicarbonate and enzyme secretion probably via suppressing the release of intestinal hormones, secretin and cholecystokinin. The actions of opiates on the motility and secretion can be reversed by specific opiate receptor antagonists, e.g. naloxone, indicating that opiate receptors may be involved in these actions.
Several pharmacologic studies were carried out with an aqueous extract of Rhigiocarya racemifera after phytochemical tests revealed the main constituents to be glycosides, saponins and tannins. Studies on intact mice showed that the extract has an intraperitoneal LD50 of 142 mg/kg and that 50 mg/kg of the extract reduced gastrointestinal motility comparable to 10 mg/kg of atropine. In rats, 28 mg/kg of extract showed significant anti-ulcer activity against indomethacin-induced ulcer and this effect was equivalent to 100 mg/kg of cimetidine. Studies on isolated tissue revealed that it may have musculotropic antispasmotic effects. These preliminary investigations seem to support its use by herbalists to treat various gastrointestinal disorders.
Current evidence suggests that impaired intestinal motility may facilitate gallstone formation by influencing biliary deoxycholate levels or by modulating interdigestive gall bladder motility (fig 2), although a primary intestinal defect in gallstone pathogenesis has not yet been demonstrated. In the cold war period, most interesting events, from a political point of view, occurred at the border between capitalist and communist systems, near the iron curtain. Similarly, the gall bladder and biliary tract can be viewed as the border between liver and intestinal tract, where many interesting things occur with profound impact on both systems. Combined efforts by researchers in the field of hepatology and gastrointestinal motility should brake down the Berlin wall of ignorance of one of the most common diseases in the Western world.
A small animal model has been developed to study simultaneous mechanical and electrical activity of the gastrointestinal tract in the conscious unrestrained animal. Mechanical activity is detected using miniaturized half-bridge metal foil strain-gauge force transducers. The conventional lead-wire arrangement has been modified, thereby extending the useful life of the gauge. The electrical activity is monitored by silver/silver chloride bipolar electrodes. The lead wires from the recording units are encased in a metal compression spring and are permanently joined to a ball connector positioned on top of a modified cage. This allows the animal free access to all parts of the cage. The results are monitored using a polygraph chart recorder and stored on magnetic tape for subsequent modified replay or computer analysis. This model provides an inexpensive and reliable method for monitoring gastrointestinal motility in the unrestrained small laboratory animal, enabling more comprehensive studies than have hitherto been possible only with larger species.
BACKGROUND/AIMS: Although antidepressants have been used for decades in treating patients with functional abdominal syndromes, how they influence gastrointestinal motility remains unclear. We aimed to assess the role of depression in functional dyspepsia, and the effect of antidepressants on the functional dyspepsia patients' symptoms and gastric myoelectrical activity. METHODOLOGY: We conducted an open clinical trial with 40 functional dyspepsia patients. Zung self-rating depression scale was used in evaluating the patients' depression. Cutaneous electrogastrography and evaluation of upper gastrointestinal symptoms were performed before and after administration of a one-month course of fluoxetine. RESULTS: In the baseline study, the depressed functional dyspepsia patients had higher symptom scores than non-depressed patients (P < 0.05). The depressed functional dyspepsia patients had higher percentages of tachygastria than healthy controls (P < 0.05), but the electrogastrography parameters of depressed and non-depressed functional dyspepsia patients were not different. After one-month fluoxetine treatment, the symptom scores improved significantly in the depressed functional dyspepsia patients (P < 0.05), but not in the non-depressed patients. Electrogastrography did not improve in either group. CONCLUSIONS: Depressive functional dyspepsia patients had higher symptom scores and responded well to fluoxetine treatment. However, electrogastrography did not improve after the treatment. These findings suggest that depression is significant in the presentation of functional dyspepsia symptoms, but not correlated with gastric myoelectrical activity.
Several dystrophin isoforms are known. The full-length isoform is present in striated and smooth muscles and neurons and its lack causes Duchenne Muscular Dystrophy, a progressive myopathy accompanied by mild cognitive deficits and gastrointestinal dismotility. An ultrastructural study was undertaken in the colon of mice lacking full-length dystrophin and maintaining shorter isoforms (mdx mice) to ascertain whether myenteric neurons have an altered morphology. Results showed a significant increase in the size of synaptic vesicle and in the number of recycling vesicles. An enlargement of endoplasmic reticulum cisternae in a subpopulation of neurons was also seen. Immunohistochemistry confirmed that the shorter isoforms were expressed in mdx mice myenteric neurons. These findings indicate the presence of a neuropathy at the myenteric plexus which might justify the defective neuronal control of gastrointestinal motility reported for these animals and which might be correlated with full-length dystrophin loss, since the shorter isoforms are present.
1. The kinetics of inactivation of delayed rectifier K+ current in murine colonic myocytes differed in amphotericin-permeabilized patch and conventional patch clamp. The difference was accounted for by Ca2+ buffering. 2. Calcium-calmodulin-dependent protein kinase II (CaMKII) inhibitors increased the rate of inactivation and slowed recovery from inactivation of the outward current. This was seen in single steps and in the envelope of the current tails. The effect was largely on the TEA-insensitive component of current. 3. Dialysis of myocytes with autothiophosphorylated CaMKII slowed inactivation. This effect was reversed by addition of CaMKII inhibitor. 4. Antibodies revealed CaMKII-like immunoreactivity in murine colonic myocytes and other cells. Immunoblots identified a small protein with CaMKII-like immunoreactivity in homogenates of colonic muscle. 5. We conclude that CaMKII regulates delayed rectifier K+ currents in murine colonic myocytes. The changes in the delayed rectifier current may participate in the Ca2+-dependent regulation of gastrointestinal motility.
The effects of immobilization stress on the pharmacokinetics of omeprazole were studied in rats. The immobilization stress for 30 or 60 min immediately after oral administration of the drug caused an increase in the time to reach the maximum concentration. However, such stress did not alter the area under the plasma concentration-time curve (AUC). When administered intravenously, the half-life during the elimination phase was significantly prolonged by 30 min of immobilization stress, but the AUC value remained unchanged. The intestinal propulsive activity was significantly decreased by immobilization stress. These findings suggest that immobilization stress reduces gastrointestinal motility. A resulting delay during the absorption phase of omeprazole occurs, although the degree of influence on overall pharmacokinetics is relatively insignificant.
A patient is described in whom gastric stasis and vomiting of 28-yr duration were successfully treated with behavior therapy. Failure of conventional medical treatment in the face of continued vomiting led to consideration for surgery. The need for surgery was obviated by the successful application of exposure and response prevention, which resulted in a complete elimination of vomiting. Changes were produced, not only in the overt behavioral manifestation (vomiting) but in gastrointestinal motility as well. Although there was a lag, gastric emptying returned to normal. The improvements were maintained at over 1-yr follow-up study.
Abnormal pupillary function and a severely depressed electroretinogram were found in four members of a family with neuronal intranuclear hyaline inclusion disease, an idiopathic degenerative disorder that involves the central and peripheral nervous systems. Symptoms were limited to the gastrointestinal system and consisted principally of abdominal pain, constipation, and severe weight loss. The discovery of light-fixed pupils in the propositus led to the first antemortem diagnosis by rectal biopsy in two generations of this family. Abnormalities of gastrointestinal motility and pupillary reactions constituted the only objective evidence of autonomic dysfunction; the abnormal electroretinogram was the only evidence of central nervous system dysfunction.
Myoelectric recordings of the opossum gastrointestinal tract were performed during continuous infusion of 16,16-dimethyl prostaglandin E2 at 0.1, 1, 2 and 5 micrograms/kg X h. Continuous administration of prostaglandin caused a dose-dependent reduction of the duration of the migrating myoelectric complex cycle and an increase in the velocity of phase III migration from the duodenum to the terminal ileum. The reduction of the migrating myoelectric complex cycle was due to a shortening of the duration of both phase I and II. Bolus administration of 16,16-dimethyl prostaglandin E2 caused intense spike activity for 2-4 min in all recording sites simultaneously. Administration of indomethacin did not change the myoelectric activity of the gastrointestinal tract. Infusion of prostaglandin E2 caused diarrhoea in eight of forty experiments. These changes in gastrointestinal motility may be important contributory factors in the pathogenesis of prostaglandin-induced diarrhoea.
The aim of our study was to determine whether the discrepancy in the data reported on the effect of atropine on food-induced intestinal hyperemia results from a difference in experimental materials and methods. In the first two series of experiments, atropine (0.5 mg/kg iv) was given before or during intraluminal perfusion of digested food plus bile through a long jejunal loop (62% of the total small intestine) at 4 ml/min for 60 min while measuring the portion of the blood flow through the superior mesenteric artery (SMA) that perfused the loop. Atropine per se had no effect on jejunal blood flow. Before atropine food increased flow 31.5 +/- 10.1% and after atropine flow increased 54.8 +/- 11.0 and 66.0 +/- 28.0% above controls in the first and second series, respectively. Atropine also increased net fluid volume absorption. In the third series, food alone and food plus bile were placed into the lumens of the two adjacent jejunal segments. Atropine had no effect on the increases in flow and oxygen uptake produced by food alone but enhanced the hyperemia produced by food plus bile without affecting the increase in oxygen uptake. Our results suggest that the previously reported inhibition of increased SMA flow by atropine is due to the inhibitory effect of atropine on gastrointestinal motility and inhibition of pancreatic blood flow. In conclusion, food-induced jejunal hyperemia does not result from a direct vasodilator action of the cholinergic nerves.