Dysaccommodation of the stomach: therapeutic nirvana?

Functional dyspepsia (FD) is a highly prevalent gastrointestinal disorder and has a complex pathophysiology. Impaired fundic relaxation in response to a meal is present in 40% of patients with FD. This review focuses on impaired gastric accommodation of the stomach as a pathophysiological mechanism and the possible therapeutic targets that can be derived from the current knowledge of the neuroregulation of the accommodation reflex. First the different means of gastric accommodation assessment are described and the relationship between symptoms and impaired gastric accommodation. The different therapeutic options are subsequently discussed in view of their molecular target, based on the different receptor subtypes involved in the accommodation reflex. Although impaired gastric accommodation is highly prevalent in dyspeptic patients and basic knowledge about the accommodation reflex enables to develop pathophysiologically targeted therapies, it is unlikely that therapies aimed at dysaccommodation of the stomach will lead to symptom relief in all dyspeptic patients. A major challenge is the development of methods that readily identify impaired accommodation in clinical practice.     

Sumatriptan is an agonist at 5-HT1P receptors on myenteric neurones in the guinea-pig gastric antrum

Sumatriptan, a 5-hydroxytryptamine(1D) (5-HT(1D))-receptor agonist used in the treatment in migraine, inhibits gastric motility via the enteric nervous system. As no studies have reported enteric neuronal 5-HT(1D) receptors, we used conventional intracellular recordings to characterize the actions of sumatriptan on 145 guinea-pig antral myenteric neurones. In 24 of 29 neurones with a 5-HT(1P) receptor-mediated depolarizing response to 5-HT, application of sumatriptan caused a dose-dependent depolarization, accompanied by increased membrane resistance and enhanced excitability. Depolarizing responses to sumatriptan occurred both in cholinergic and in nitrergic neurones. Sumatriptan did not mimic the 5-HT(3) receptor-mediated fast-depolarizing responses or 5-HT(1A) receptor-mediated inhibitory responses to 5-HT. Sumatriptan had no effect on neurones not responding to 5-HT. The depolarizing response to sumatriptan was inhibited by renzapride, but not by 5-HT(1-7) receptor antagonists. We conclude that sumatriptan behaves as an agonist at the 5-HT(1P) receptor on myenteric neurones in the guinea-pig gastric antrum. The actions of sumatriptan on gastric motility seem to be attributable to a direct action on enteric neurones.     

Multiple rapid swallowing: a complementary test during standard oesophageal manometry

Abstract  Multiple rapid swallowing (MRS) stimulates neural inhibition resulting in abolition of contractions in the oesophageal body (OB) and complete lower oesophageal sphincter (LOS) relaxation which is followed by peristalsis and LOS contraction. The aim of this study was to evaluate the yield of MRS to detect abnormalities in inhibitory or excitatory oesophageal mechanisms in patients with oesophageal symptoms and either normal standard manometry or ineffective oesophageal motility (IOM). MRS (five water swallows, 2 mL, separated by 2–3 s) was evaluated in 23 healthy subjects, 109 symptomatic patients with normal standard sleeve manometry and in 48 patients with IOM. Healthy subjects had complete inhibition of OB motility during MRS and a strong motor response after MRS, i.e. amplitude of OB contractions in the oesophageal body and LOS tone being higher than after single swallows. Almost 70% of patients with oesophageal symptoms and normal manometry had abnormal MRS, mainly consistent on inability to increase amplitude of OB contractions after MRS. Nearly, half of the patients with IOM were able to normalize OB contractions after MRS. MRS is a simple complementary test that can be added to standard oesophageal manometry. Two-thirds of patients with normal manometry show abnormal MRS that could potentially underlie their symptoms. A normal response to MRS in patients with severe IOM might be used to predict response to prokinetic treatment.     

Influence of naloxone on rectal sensorimotor function in health

Abstract  Abnormal rectal motor physiology and visceral hypersensitivity are implicated in the pathogenesis of irritable bowel syndrome. Endogenous opioids are involved in both the regulation of gut motility and the processing of sensory information. Our aim was to study the effect of suppression of endogenous opioid function by naloxone on rectal sensorimotor function in health. Eighteen healthy subjects participated in a rectal barostat study. Sensorimotor function was evaluated during two consecutive stepwise distensions separated by 30 min of basal tone recording, and with perception scoring on a 0–6 graded scale. Naloxone was administered, after 15 min of basal tone measurements, as an intravenous bolus (0.4 mg), followed by continuous infusion (20 μg kg⁻¹ h⁻¹) in a placebo-controlled, single-blinded and randomized fashion. Naloxone did not alter rectal sensitivity. Comparison of visual analogue scale scores between naloxone and saline did not reveal altered intensities of pain or discomfort. Compared to the baseline distension, a significant adaptive increase in compliance occurred during the second distension after saline (7.8 ± 0.7 vs 11.0 ± 0.6 mL mmHg⁻¹, P  = 0.0016). This dynamic change in rectal compliance did not occur after naloxone administration (8.8 ± 0.7 vs 10.1 ± 0.8 mL mmHg⁻¹, ns). Low intensity tonic distension induced a rectal adaptive relaxation, which was absent after naloxone. Naloxone does not alter rectal sensitivity but abolishes rectal adaptation in response to repeated balloon distention. These observations suggest that the endogenous opioid system is involved in control of rectal tone rather than rectal sensitivity.     

A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia

Abstract  Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z-338) was well-tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double-blind, placebo-controlled study (14, 21 and 28 days, respectively, for run-in, study drug administration and follow-up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and ¹³C breath test, symptoms by daily diary cards and QOL by SF-36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation ( P  = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating ( P  = 0.001) and overall symptom score ( P  = 0.022), and at week 3 for bloating ( P  = 0.008) and heartburn ( P  = 0.041). 100 mg was also better than placebo for QOL (physical function) ( P  = 0.003). Acotiamide was safe and well-tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal-induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.     

ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice

Abstract  The importance of dynamic interactions between glia and neurons is increasingly recognized, both in the central and enteric nervous system. However, apart from their protective role, little is known about enteric neuro–glia interaction. The aim was to investigate neuro–glia intercellular communication in a mouse culture model using optical techniques. Complete embryonic (E13) guts were enzymatically dissociated, seeded on coverslips and studied with immunohistochemistry and Ca²⁺-imaging. Putative progenitor-like cells (expressing both PGP9.5 and S-100) differentiated over approximately 5 days into glia or neurons expressing typical cell-specific markers. The glia–neuron ratio could be manipulated by specific supplements (N2, G5). Neurons and glia were functionally identified both by their Ca²⁺-response to either depolarization (high K⁺) or lysophosphatidic acid and by the expression of typical markers. Neurons responded to ACh, DMPP, 5-HT, ATP and electrical stimulation, while glia responded to ATP and ADPβs. Inhibition of glial responses by MRS2179 suggests involvement of P2Y1 receptors. Neuronal stimulation also caused delayed glial responses, which were reduced by suramin and by exogenous apyrases that catalyse nucleotide breakdown. Conversely, glial responses were enhanced by ARL-67156, an ecto-ATPase inhibitor. In this mouse enteric co-culture, functional glia and neurons can be easily monitored using optical techniques. Glial cells can be activated directly by ATP or ADPβs. Activation of neuronal cells (DMPP, K⁺) causes secondary responses in glial cells, which can be modulated by tuning ATP and ADP breakdown. This strongly supports the involvement of paracrine purinergic communication between enteric neurons and glia.     

Relationship between symptom pattern, assessed by the PAGI-SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = ?0.27), bloating (r = ?0.23), heartburn/regurgitation (r = ?0.21), and upper abdominal pain (r = ?0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.     

The role of somatosensory cortical regions in the processing of painful gastric fundic distension: an update of brain imaging findings

Abstract  Painful gastric distension is processed in a network consisting of brainstem, thalamus, insula, anterior cingulate cortex, (lateral) orbitofrontal and prefrontal cortex, superior temporal cortex and cerebellum. However, the role of primary and secondary somatosensory cortical regions (SI/SII) in the processing of visceral sensation or pain in general and gastric sensation in particular remains unclear. The aim of this study was to localize activations in the SI/SII area from our previously published functional brain imaging studies on gastric distension more precisely, using newly available cytoarchitectonic probability maps of SI/SII, implemented in the SPM Anatomy toolbox. In healthy volunteers, we found two clusters to be overlapping with SII (mainly the OP4 subregion) and, to a lesser extent, SI, although this overlap was small in size. In functional dyspepsia patients, we found two clusters to be overlapping with SII (mainly OP4), of which the cluster in the right hemisphere also overlapped with SI. These findings were confirmed in a conjunction analysis of both groups. Activation in right SI/SII was significantly higher in healthy volunteers when formally compared to patients. These results provide more detailed information on the brain processing of gastric sensation, supporting the hypothesis that SI/SII are involved. This is in line with some previously published studies on visceral sensation, but at variance with some other studies. Methodological differences between the brain imaging studies on gastric distension may account for these somewhat discrepant findings.     

Acotiamide hydrochloride (Z-338), a novel prokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats

Abstract  Acotiamide hydrochloride (Z-338) is a member of new class prokinetic agents currently being developed for the treatment of functional dyspepsia (FD). DNA microarray analysis showed that acotiamide altered the expressions of stress-related genes such as γ -aminobutyric acid (GABA) receptors, GABA transporters and neuromedin U (NmU) in the medulla oblongata or hypothalamus after administration of acotiamide. Therefore, effects of acotiamide on stress-related symptoms, delayed gastric emptying and feeding inhibition, in rats were examined. Acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress-induced model, but did not affect both basal gastric emptying and feeding in intact rats, indicating that acotiamide exerted effects only on gastric emptying and feeding impaired by the stress. On the other hand, mosapride showed significant acceleration of gastric emptying in intact and restraint stress-induced model, and itopride showed no effect on restraint stress-induced delayed gastric emptying. In addition, gene expression of NmU increased by restraint stress was suppressed by administration of acotiamide, while acotiamide had no effect on delayed gastric emptying induced by an intracerebroventricular administration of NmU, suggesting that the suppressive effect of acotiamide on gene expression of NmU might be important to restore delayed gastric emptying or feeding inhibition induced by restraint stress. These findings suggest that acotiamide might play an important role in regulation of stress response. As stress is considered to be a major contributing factor in the development of FD, the observed effects may be relevant for symptom improvement in FD.     

Characterization of myenteric neuropathy in the jejunum of spontaneously diabetic BB-rats

Abstract  Decreased gastric expression and function of neuronal nitric oxide synthase (nNOS) has been proposed as a potential mechanism underlying diabetic gastroparesis. As gastric nNOS expression is vagally controlled, these changes might occur secondarily to vagal neuropathy. In addition, it is unclear whether other inhibitory neurotransmitters are also involved. We used the type 1 diabetic BioBreeding (BB)-rat model to study jejunal motor control and nNOS expression, which is independent of the vagus. Jejunal segments were used for in vitro contractility studies, and measurement of nNOS expression after 8 or 16 weeks of diabetes compared with age- and sex-matched controls. Unlike electrical field stimulation and acetylcholine (ACh)-induced contractions, non-adrenergic non-cholinergic (NANC) relaxations were significantly reduced in diabetic rats. In contrast to control rats, NANC relaxations in diabetic rats were N _ω-nitro- l -arginine methyl ester ( l -NAME) insensitive. Jejunal nNOS expression was significantly decreased in diabetic rats. Both in diabetic and in control animals, l -NAME resistant relaxations were sensitive to P₂-receptor antagonists. In the jejunum of spontaneously diabetic rats, decreased nitric oxide responsiveness and decreased nNOS protein expression occur while purinergic transmission is unaffected. These findings indicate that nitrergic enteric neuropathy may be a primary dysfunction in diabetes, independent from vagal dysfunction.