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The accommodation response to meal ingestion is a robust, vagally mediated reflex in health. It results in a reduction in gastric tone and an increase in compliance, thereby facilitating the ingestion of large volumes of solids or liquids without inducing postprandial symptoms such as pain or bloating or the vomiting reflex. In health, the mechanisms involved in development of postprandial symptoms are incompletely understood. In several conditions,1–4 a reduced accommodation response appears to contribute to postprandial symptoms such as early satiety, distention and weight loss.4, 5 One mechanism proposed is that increased wall tension6 results in food/air stimulation of visceral afferents or alteration of cerebral perception and development of gastric hypersensitivity postprandially. These findings suggest that measurement of gastric accommodation or the change in gastric volume after a meal may facilitate our understanding of the mechanical factors that may result in upper gastrointestinal symptoms in the postprandial period. Symptoms in these patients may reflect either a lack of accommodation, visceral (mechanical or chemical) hypersensitivity, or a change in the gastric emptying rate. Correction of impaired accommodation might reduce postprandial symptoms in dyspepsia.7–9
Serotonergic type 3 receptors modulate intrinsic cholinergic neurones in the gut myenteric plexus.10 5-HT3 receptors have been located on vagal afferent neurones, dorsal root ganglion cells11 and in the vomiting centre in the brainstem.
Recently, alosetron was reported to reduce dyspepsia symptoms,12 an effect that was independent of gastric emptying. However, the physiological basis for this reduction in dyspepsia is unclear, and may reflect either gastric relaxation or reduced visceral sensitivity due to mechanical or chemical stimulation of visceral afferents. The gold standard to measure accommodation involved the placement of a polyethylene balloon into the proximal stomach and measurement of intragastric volumes in the fasting and postprandial periods under barostatic conditions.1 More recently, three-dimensional imaging with ultrasound, MRI and SPECT has been introduced13–15 to measure gastric volume noninvasively.
Previous studies had shown the feasibility of pertechnetate imaging of the gastric mucosa, identifying gastric wall motion under dynamic scintigraphy,16 and measuring gastric volume15, 17 by a three-dimensional (tomographic acquisition) single photon emission computed tomography (SPECT)-AnalyseAVW system.15
In parallel with these novel imaging studies to measure gastric volume, standardized meal tests4, 18 and questionnaires quantify postprandial symptoms in health, disease states and in response to pharmacological agents. These tests appear to partially assess the sensory and motor functions of the proximal stomach.19
In this study, the noninvasive methods were used to assess the physiological basis of the reduction in dyspepsia in response to the 5-HT3 antagonist, alosetron. Our hypothesis was that the measured postprandial change in gastric volume and the volume of liquid nutrient required to induce maximum tolerated symptoms would be dose-dependently increased by antagonism of 5-HT3 receptors in healthy humans. Our aims were to compare the effects of two doses of the 5-HT3 antagonist, alosetron, and placebo on fasting and postprandial gastric volumes and symptoms induced by ingestion of a liquid nutrient drink to the point of maximum tolerance in healthy volunteers.
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Our study has shown that a 5-HT3 antagonist, alosetron, reduces aggregate symptoms after a meal intended to induce maximum tolerable symptoms in healthy human subjects. The effect of alosetron is unrelated to any change in the volume of nutrient drink tolerated or the measured fasting or postprandial gastric volume. Although the precise mechanism of the effect of alosetron on symptoms is not completely elucidated, these data suggest a role for 5-HT3 mechanisms in visceral afferent sensation and provide the potential rationale for further study of 5-HT3 antagonists in patients with dyspepsia. The potential benefit of alosetron in dyspepsia was demonstrated in a recently published phase II clinical trial.12
Postprandial symptoms may arise from mechanical stimulation of afferents by the meal or from a change in sensitivity of afferents by chemical stimulation in the stomach or proximal small intestine. Our study also suggests that gastric relaxation is not always necessary for reduction of postprandial symptoms, because we observed a reduction in symptom scores without a significant increase in the postprandial relaxation of the stomach. The observed reduction in symptom scores may more likely be related to effects of the drug on chemosensitive afferents, as previously suggested by Feinle and Read.26
The lack of effect of alosetron on gastric volumes with reduced postprandial symptoms is consistent with a preliminary report which showed that another 5-HT3 antagonist, ondansetron,27 reduced symptoms in response to distension without altering tone, accommodation or compliance. In the latter study, the gastric volumes were measured with an intraluminal barostatically controlled balloon. Zerbib et al.28 and Bjornsson et al.29 also reported that two different 5-HT3 antagonists (alosetron and granisetron, respectively) did not alter fasting tone or compliance when tested with an intraluminal barostatically controlled balloon. The beneficial effects of the 5-HT3 antagonist may be mediated at the level of extrinsic afferents or centrally. There are central effects of alosetron in the dog,30 however human studies suggest that it has no significant anxiolytic activity.31 These data suggest that any central effects of the drug are more likely to be directed at centres such as the vomiting centre, rather than the limbic system.
We considered the possibility that the lack of effect of alosetron on gastric accommodation measured by SPECT may have been a technical failure. Thus, in contrast to the barostat, which imposes a continuous distending drive, it is conceivable that the already appropriate accommodation in healthy subjects could not be enhanced without the isobaric pressure load in the presence of alosetron. We cannot completely exclude this possibility and, hence, it is still possible that the drug may enhance accommodation in dyspeptics with reduced relaxation responses. However, reduced gastric volume postprandially has been observed in dyspeptics using the SPECT technique,32 and our data with alosetron confirm those of other investigators who studied the effects of 5-HT3 antagonists with the barostat device.27–29
An alternative hypothesis for the genesis of dyspeptic symptoms is the ‘chemical’ sensitivity of the small intestinal mucosa, which is abnormal in response to acid perfusion33 in dyspeptics. This mechanism of dyspepsia may be influenced by alosetron. Further studies are needed to specifically address the effect of 5-HT3 antagonists on duodenal sensitivity to chemical stimulation with acid or nutrients in health and disease.
Alosetron did not affect ‘satiety’ sensations during the actual ingestion of the nutrient drink or the symptom of fullness 30 min postprandially. Satiety is defined as the ‘condition of being full or gratified beyond the point of satisfaction’; we believe that the participants may equate the symptoms of ‘satiety’ and fullness. Our observation of nonsignificant differences in ‘fullness’ scores, maximum tolerable volumes and postprandial accommodation volumes are therefore internally consistent. We note that Tosetti et al. also reported virtually identical mean satiety and fullness scores 30 min after a volume load test in their preliminary report on dyspeptic patients.18 Because of the overlap in definition of symptoms of fullness and satiety, we elected to exclude the less familiar term ‘satiety’ when assessing the symptoms 30 min postprandially.
In view of the known location of 5-HT3 receptors at the vomiting centre, it was expected that alosetron would reduce the sensation of nausea. This was observed with both doses of alosetron, however it is important to note that bloating was significantly improved by the 1 mg dose. These data are consistent with the known location of 5-HT3 receptors on vagal10, 34 and visceral11, 35 afferents and that they may be blocked by the drug, thereby reducing meal-induced nausea and bloating.
Despite double-blinded and random allocation to treatment, the groups were unbalanced for gender, with significantly more females in the placebo group than the alosetron group. Previous studies suggest that alosetron is less effective in symptom relief among males with irritable bowel syndrome,36 therefore our study would have biased against finding a beneficial effect on symptoms in the 1 mg alosetron group.
In conclusion, our data suggest that alosetron reduces postprandial symptoms in health through effects on visceral afferents rather than by increasing postprandial gastric volume. These studies support the need for further clinical appraisal of 5-HT3 mechanisms in the development of postprandial symptoms. Antagonists to the 5-HT3 receptors show promise in the treatment of patients with functional dyspepsia. The lack of any significant inhibition of gastric emptying by 5-HT3 antagonists37 would suggest that this approach may also be beneficial among the dyspeptics with mild to moderate delay in gastric emptying of solids. Formal studies are required in dyspeptic patients to prove efficacy of 5-HT3 antagonism. The combination of noninvasive SPECT imaging to measure gastric volume and the nutrient drink test to assess postprandial symptoms appears to be an effective experimental medicine approach to evaluate the therapeutic potential of such medications in the future.