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Biomedical subjects

E A Mayer

Publications and source records attributed to E A Mayer.

At least 73 records · Page 4Linked to original sources
PubMed1999

Substance P release in the dorsal horn assessed by receptor internalization: NMDA receptors counteract a tonic inhibition by GABA(B) receptors.

Inhibitory amino acids have antinociceptive actions in the spinal cord that may involve inhibition of neurotransmitter release from primary afferents. Rat spinal cord slices with dorsal roots were used to study the effect of GABA and glycine on substance P release, assessed by the internalization of neurokinin 1 receptors. After electrical stimulation of the dorsal root at 100 Hz, about half of neurokinin 1 receptor-immunoreactive neurons in laminae I-IIo showed internalization. This internalization was inhibited by GABA (100 microM) and the GABA(B) agonist R-baclofen (10 microM), but not by the GABA(A) agonist muscimol (20 microM) or glycine (100 microM). The GABA(B) antagonist 2-hydroxysaclofen (100 microM) reversed the inhibitory effect of GABA, but not the GABA(A) antagonist bicuculline (100 microM). These findings demonstrate that GABA(B) receptors, but not GABA(A) or glycine receptors, inhibit substance P release induced by dorsal root stimulation. In contrast, R-baclofen did not inhibit the internalization produced by NMDA (100 microM), indicating that the stimulatory effect of NMDA receptors on substance P release is able to surmount the inhibitory effect of GABA(B) receptors. In the presence of the GABA(B) antagonist 2-hydroxysaclofen (100 microM), but not in its absence, stimulation of the dorsal root at 1 or 10 Hz was able to elicit internalization, which was not inhibited by the NMDA receptor antagonist AP-5 (50 microM) or the channel blocker MK-801 (10 microM). Therefore, inhibition of substance P release by GABA(B) receptors is tonic, and in its absence SP release no longer requires NMDA receptor activation.

Animals↗
PubMed1999

Evolving concepts in irritable bowel syndrome.

Converging evidence from investigations of the peripheral and central aspects of bidirectional brain-gut interactions is beginning to shape a pathophysiological model of irritable bowel syndrome (IBS) and related functional gastrointestinal (GI) disorders. This neurobiological model includes alterations in autonomic, neuroendocrine, and pain modulatory mechanisms. The frequent association of IBS and other functional GI disorders with co-morbid affective disorders and temporal association of symptom exacerbation with psychosocial or physical stressors are consistent with alterations in the neurobiological mechanisms underlying the central stress response. Renewed interest in drug development for IBS has resulted in development of instruments for the better assessment of the impact of global symptoms on quality of life and in the development of candidate compounds undergoing clinical evaluation.

Journal Article↗
PubMed1999

Symptoms and physiology in severe chronic constipation.

OBJECTIVE: Symptoms of constipation have been attributed to slow colon transit, irritable bowel syndrome (IBS), or pelvic floor dysfunction (PFD). Our aim was to determine the existence of symptom-based constipation subgroups and whether these correspond to differences in colonic transit and anorectal sensorimotor function. METHODS: Constipated patients (n = 108) completed questionnaires, and underwent colon transit studies, anorectal manometry, and rectal sensory testing. Factor analysis of symptoms was performed. Factor-based symptom scores were correlated with physiological findings. RESULTS: Three symptom factors were identified as compatible with slow colonic transit, IBS, and PFD. There was a significant correlation between the symptoms of slow transit and total and rectosigmoid colon transit. There were also significant correlations between both the IBS symptom score and the number of Manning criteria with measures of rectal hypersensitivity typical of IBS. Neither PFD symptom scores nor symptoms of straining correlated with any electromyographic or manometric measure of anal defecatory function or with rectosigmoid colon transit. Based on physiological testing patients were classified as slow transit, visceral hypersensitivity (typical of IBS), PFD, or no abnormalities found. As expected, slow-transit patients had symptoms of infrequent stools and patients with visceral hypersensitivity had an increased number of Manning criteria for IBS. Patients with PFD physiology and those with no detectable abnormalities had no specific symptoms. CONCLUSIONS: Three symptom-based subgroups for constipation were confirmed: slow transit, IBS, and PFD. Slow transit and IBS symptoms correlated with expected physiology. Conversely, PFD symptoms and physiology did not correlate.

Anal Canal↗
PubMed1999

Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome.

OBJECTIVE: Abdominal pain is thought to be a hallmark of the irritable bowel syndrome (IBS), although currently used symptom criteria do not differentiate between abdominal pain and discomfort. By focusing on viscerosensory symptoms, we sought to determine: 1) which type of symptoms are most commonly reported by IBS patients, and 2) whether patients who report pain as their most bothersome symptom differ in clinical, psychological, and physiological characteristics. METHODS: A total of 443 consecutive new patient referrals to a tertiary referral center for functional gastrointestinal disorders who met symptom criteria for IBS were given validated, psychometric, health status, and bowel symptom questionnaires containing specific questions regarding the patients' predominant viscerosensory gastrointestinal symptom. Of these patients, 155 (35%) also met criteria for functional dyspepsia. A representative subset of the total IBS patient population (n = 58) underwent evaluation of perceptual responses to controlled rectal distension before and after a noxious sigmoid conditioning stimulus. RESULTS: Viscerosensory symptoms clustered into four groups: 1) abdominal pain, 2) bloating-type discomfort, 3) sensation of incomplete rectal evacuation, and 4) extraabdominal (chest pain or pressure and nausea). A total of 66% of patients reported gas as one of their viscerosensory symptoms, whereas 60% reported abdominal pain as one of their symptoms. Only 29% rated abdominal pain as their most bothersome symptom, whereas bloating-type symptoms were listed by 60% as most bothersome. Although pain predominance did not correlate with the severity of gastrointestinal or psychological symptoms, there was a significant correlation with the development of rectal hypersensitivity in response to the sigmoid conditioning stimulus. CONCLUSIONS: In a tertiary referral population of IBS patients: 1) abdominal pain is reported by only one third of patients as their most bothersome viscerosensory symptoms; and 2) pain-predominance correlates with development of rectal hypersensitivity after a noxious sigmoid stimulus.

Abdominal Pain↗
PubMed1999

Symptom differences in moderate to severe IBS patients based on predominant bowel habit.

OBJECTIVE: We sought to determine if irritable bowel syndrome (IBS) patients with different bowel habit predominance differ in self-reported viscerosensory symptoms related to the upper and lower gastrointestinal (GI) tract, somatosensory symptoms, and constitutional functions. METHODS: Six hundred and twenty-five Rome criteria-positive IBS patients completed a bowel symptom questionnaire (BSQ), psychological symptom checklist (SCL-90), and health status (SF-36). Bowel habit predominance for IBS patients was determined using the Rome criteria for functional constipation (IBS-C; n = 140) and functional diarrhea (IBS-D; n = 216). The BSQ included questions about viscerosensory symptoms of the upper (chest pressure, bloating, fullness, early satiety, nausea) and lower GI tract (bloating, pain, incomplete evacuation), somatosensory symptoms related to the musculoskeletal system (pain in neck/shoulders, lower back/hip, muscles/joints), and constitutional functions (sleep, appetite, libido). Analysis was further conducted between the IBS-C and IBS-D patients, controlling for gender and quality of sleep, and using the Bonferroni correction to control for multiple comparisons. RESULTS: Female gender was more prevalent among IBS-C than IBS-D (77% vs 56.1%, p < 0.01), whereas age did not differ (40.2 +/- 1.2 yr vs 39.5 +/- 1.0 yr). Symptoms referred to the upper GI were more prevalent in IBS-C than IBS-D: early satiety (56.7% vs 33.9%, p < 0.004), fullness (63.2% vs 38.5%, p < 0.05), and a trend for upper bloating (80.3 vs 62.6%). IBS-C patients reported higher severity ratings for lower GI bloating (p < 0.001). IBS-C more commonly reported musculoskeletal symptoms (92.2% vs 75.4%, p < 0.001), as well as impairment in sleep (31.3 vs 17.5%, p < 0.009), appetite (35.0% vs 18.4%, p < 0.015) and sexual function (45.2% vs 33.1%, p < 0.0021). There were no differences in SCL-90 and SF-36 scores. CONCLUSIONS: Compared with the IBS-D group, the IBS-C patients show greater prevalence of a wide range of symptoms referred to the upper and lower abdomen, musculoskeletal, and constitutional functions. These findings may be related to differences in autonomic or perceptual responses to visceral and somatic stimuli, and are likely to have implications for treatment responses in the two subgroups.

Adult↗
PubMed1999

Chemical signaling from colonic smooth muscle cells to DRG neurons in culture.

Transduction mechanisms between target cells within the intestinal wall and peripheral terminals of extrinsic primary afferent neurons are poorly understood. The purpose of this study was to characterize the interactions between smooth muscle cells from the rat distal colon and lumbar dorsal root ganglion (DRG) neurons in coculture. DRG neurons visually appeared to make contact with several myocytes. We show that brief mechanical stimulation of these myocytes resulted in intracellular Ca2+ concentration ([Ca2+]i) transients that propagated into 57% of the contacting neurites. Direct mechanical stimulation of DRG neurites cultured without smooth muscle had no effect. We also show that colonic smooth muscle cells express multiple connexin mRNAs and that these connexins formed functional gap junctions, as evidenced by the intercellular transfer of Lucifer yellow. Furthermore, thapsigargin pretreatment and neuronal heparin injection abolished the increase in neurite [Ca2+]i, indicating that the neuronal Ca2+ signal was triggered by inositol 1,4, 5-trisphosphate-mediated Ca2+ release from intracellular stores. Our results provide evidence for intercellular chemical communication between DRG neurites and intestinal smooth muscle cells that mediates the exchange of second messenger molecules between different cell types.

Animals↗
PubMed1999

Calcium waves in colonic myocytes produced by mechanical and receptor-mediated stimulation.

The mechanisms underlying intracellular Ca2+ waves induced by either mechanical or receptor-mediated stimulation of myocytes isolated from the longitudinal muscle layer of the rabbit distal colon were compared using fura 2 and fluorescence videomicroscopy. Light focal mechanical deformation of the plasma membrane or focal application of substance P resulted in localized intracellular Ca2+ concentration ([Ca2+]i) transients that propagated throughout the cell. In both cases, the Ca2+ response consisted of a transient peak response followed by a delayed-phase response. Substance P-mediated [Ca2+]i responses involved generation of inositol 1,4, 5-trisphosphate and release of Ca2+ from thapsigargin-sensitive stores, whereas mechanically induced responses were partially (29%) dependent on La3+-sensitive influx of extracellular Ca2+ and partially on release of intracellular Ca2+ from thapsigargin-insensitive stores gated by ryanodine receptors. The delayed-phase response in both cases was dependent on extracellular Ca2+. However, although the response to substance P was sensitive to La3+, that after mechanical stimulation was not. In the later case, the underlying mechanism may involve capacitative Ca2+ entry channels that are activated after mechanical stimulation but not by substance P.

Animals↗
PubMed1999

Approaches to the modulation of abdominal pain.

Despite their high prevalence and significant economic impact on the health care system, functional gastrointestinal disorders have evaded successful therapy. Conventional medical therapies are based on inadequate disease models, and the great majority of published treatment trials are flawed in their design, permitting no conclusions to be drawn about the true efficacy of any particular treatment. During the past several years, a new, comprehensive disease model based on alterations in brain-gut interactions has rapidly evolved. Even though the precise mechanisms and sites underlying these alterations remain incompletely understood, plausible targets for the development of effective pharmacological treatments are receptors on peripheral terminals of visceral afferent nerves (opioids and serotonin), ion channels and receptors on dorsal horn neurons within the spinal cord (opioids, glutamate, calcitonin gene-related peptide and neurokinin-1), and supraspinal targets in the brainstem within the limbic system and in the prefrontal cortex (serotonin, catecholamines, dopamine and acetylcholine). Regardless of the primary pathophysiology underlying functional gastrointestinal disorders (ie, central versus peripheral), different pharmacological strategies targeted at different sites in the periphery or within the central nervous system may become effective therapies in the future.

Abdominal Pain↗
PubMed1998

Substance P induces brief, localized increase in [Ca2+]i in dorsal horn neurons.

We determined the spatial and temporal dynamics of the increase in intracellular Ca2+ levels [Ca2+]i produced by substance P (SP) in dorsal horn neurons. A microinjection technique was used to apply minute amounts of SP to small areas of cultured neurons loaded with the Ca2+ indicator fura-2. Five successive applications of SP to the soma produced short-lasting (< 50 s) increases in [Ca2+]i that became gradually smaller, indicating receptor desensitization. Focal application of SP to a distal locus in a neurite produced a brief (12 s) increase in [Ca2+]i that travelled down the dendrite but did not spread into cell soma. Prolonged application of SP to these neurons caused the appearance of varicosities in their dendrites.

Animals↗
PubMed1998

Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.

BACKGROUND & AIMS: Chronic tissue injury in the esophagus associated with gastroesophageal reflux disease may result in sensitization of afferent pathways mediating mechanosensitivity and chemosensitivity. The aim of this study was to evaluate the sensitivity to intraluminal acid and to distention of the esophagus in patients with mild-to-moderate gastroesophageal reflux disease. METHODS: Perceptual responses to intraluminal acid perfusion and to esophageal distention and pressure volume relationships were evaluated in 10 healthy volunteers and in 11 patients. Mechanosensitivity was evaluated with a barostat using unbiased distention protocols and verbal descriptor ratings of sensations. Chemosensitivity to acid was determined at baseline and after a 1-month treatment of acid suppression. RESULTS: Patients showed enhanced perception of acid perfusion but not of esophageal distension. Chemosensitivity but not mechanosensitivity was correlated with reflux symptoms and with the degree of endoscopically shown tissue injury at baseline. Tissue injury was not associated with altered compliance. CONCLUSIONS: Mild-to-moderate chronic tissue injury in gastroesophageal reflux disease differentially affects mechanosensitive and chemosensitive afferent pathways. Chronic acid reflux by itself is not likely to play a role in reported esophageal hypersensitivity to distention in patients with noncardiac chest pain.

Adult↗
PubMed1998

Gastrointestinal sensory abnormalities in functional dyspepsia.

Symptoms of functional dyspepsia, such as epigastric pain, bloating or early satiety and nausea, are non-specific and are likely to arise from different mechanisms. Current evidence suggests the presence of at least two subgroups: patients who respond to a prolonged course of acid suppression and patients who show a significant overlap of symptoms with other functional gastrointestinal disorders such as irritable bowel syndrome. An enhanced sensitivity of visceral afferent pathways with or without associated autonomic dysregulation appears to play an important role in the aetiology of symptoms in the second group. In the absence of visceral hypersensitivity, neither the slowing of gastric emptying nor the presence of chronic gastritis appears to be sufficient to cause symptoms of functional dyspepsia. The mechanisms and aetiology of visceral hypersensitivity are incompletely understood. An alteration in the interplay between vagal and spinal afferents, and the inadequate activation of antinociceptive systems in response to tissue irritation, may play a role in symptom generation.

Dyspepsia↗
PubMed1998

Involvement of chloride channels in the receptormediated activation of longitudinal colonic muscle.

In gastrointestinal smooth muscle, intracellular Cl- is maintained at levels higher than its electrochemical equilibrium. Therefore, Cl- efflux through receptor-mediated opening of Cl- channels should result in membrane depolarization and may be sufficient to activate voltage-sensitive calcium channels (VSCCs). To determine the contribution of Cl- channels to receptor-mediated contraction of the longitudinal muscle layer of the rabbit distal colon, we studied the mechanical response of muscle strips to substance P, carbachol and potassium depolarization following the depletion of Cl- i, and in the presence of the Cl- channel blocker 5-nitro-2-(3-phenylpropyl-amino)-benzoate (NPPB). A 60-min incubation of tissues in a HEPES-buffered solution in which NaCl had been replaced by Na isethionate (or Na gluconate) in equimolar amounts resulted in disappearance of phasic contractions, and in a partially reversible reduction of the tonic response to substance P and carbachol, but not to KCl depolarization. When the agonist was applied to tissues in control solution, or to Cl-(-)depleted tissues in a solution in which Na+ was acutely replaced in equimolar amounts by N-methyl-D-glucosamine, the mechanical response to substance P and carbachol was almost abolished. Acute Na+ replacement alone without prior Cl- depletion did not abolish phasic contractions, but reduced the tonic response to substance P and carbachol. Similar to the effect of Cl- depletion, incubation of tissues in NPPB (6.6 x 10(-5) M) reduced the tonic response to substance P and carbachol, and abolished phasic contractions. These findings are consistent with a contribution of a Cl- channel to the receptor-mediated activation of colonic smooth muscle. In addition, the data suggest that transient Cl- channel mediated depolarizations may play a role in the generation of phasic contractions.

Animals↗
PubMed1998

Intestinal and extraintestinal symptoms in functional gastrointestinal disorders.

Functional gastrointestinal disorders such as irritable bowel syndrome or functional dyspepsia have traditionally been regarded as syndromes limited to the digestive system. However, both clinical experience and published evidence show that patients with such disorders also report a series of other symptoms of physical distress, such as fibromyalgia and irritable bladder and alterations in vital functions, such as sleep, libido, appetite and energy level. Some of these extraintestinal symptoms can be explained in the context of an evolving comprehensive disease model which views functional gastrointestinal disorders as manifestations of alterations in the interactions between the nervous system, the viscera and the musculoskeletal system. Alterations in central circuits concerned with arousal, attention and fear, cognitions about bodily symptoms and possible alterations in the hypothalamic pituitary adrenal (HPA) axis may all contribute to the wide range of symptoms reported by affected patients.

Colonic Diseases, Functional↗
PubMed1998

Psychosocial moderators of quality of life in irritable bowel syndrome.

Irritable Bowel Syndrome (IBS) is a chronic disorder with symptoms that range in intensity from mild and infrequent to severe and continuous. Similarly the impact of IBS on Quality of Life (QOL) measures can range from very small to disabling. In a very simple model one might expect a change in symptom intensity or frequency to be reflected in a similar change in QOL. However, a variety of other factors may alter this straightforward and unidirectional relationship between symptomatic treatment and QOL improvement. This paper presents several classes of these potential moderator variables in QOL outcome in IBS, as well as specific models of symptom, moderator, QOL relationships that can be investigated in future research. An illustrative example of a regression approach to analysis of psychosocial moderator variables indicates both psychosocial measures, and symptom severity, independently contribute to the prediction of QOL in IBS.

Age Factors↗
PubMed1998

Brain-gut interactions: implications for newer therapy.

Despite their high prevalence and significant economic impact on the healthcare system, functional GI disorders have evaded successful therapy. Conventional medical therapies are based on inadequate disease models, and the great majority of published treatment trials are flawed in their design, thus not permitting to draw any conclusions about true efficacy of any particular treatment. The past several years have seen the rapid evolution of a new, comprehensive disease model, based on alterations in brain-gut interactions. Even though the precise mechanisms and sites underlying these alterations remain incompletely understood, plausible targets for the development of effective pharmacologic treatment are receptors on peripheral terminals of visceral afferent nerves (opioids, serotonin), ion channels and receptors on dorsal horn neurons within the spinal cord (opioids, glutamate, CGRP, NK-1) and supraspinal targets in the brainstem, within the limbic system and in the prefrontal cortex (serotonin, catecholamines, dopamine, acetylcholine). Regardless of the primary pathophysiology underlying functional GI disorders (i.e. central vs. peripheral), different pharmacological strategies targeted at different sites in the periphery or within the central nervous system may be effective.

Brain↗
PubMed1998

Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia.

OBJECTIVE: Tricyclic antidepressants in low doses are widely used in the therapy of patients with functional gastrointestinal disorders, yet the mechanism(s) of action of these drugs in these disorders is not known. In the current study, we sought to determine in a group of patients with functional dyspepsia and associated poor sleep how amitryptiline affects digestive symptoms, perceptual responses to gastric distension, and subjective and objective measures of sleep. METHODS: Patients were randomized to 4 wk of amitryptiline 50 mg taken at bedtime versus placebo. There was a 3-wk washout phase, followed by a cross-over to the alternate treatment. Perceptual sensitivity to gastric distention and sleep EEG were recorded at the end of each treatment period. Diaries of symptoms were maintained throughout. RESULTS: Seven of seven patients reported significantly less severe gastrointestinal symptoms after 4 wk on amitryptiline compared to placebo. Five of seven patients had evidence for altered perception of gastric balloon distension during placebo. However, the subjective symptom improvement on amitryptiline was not associated with a normalization of the perceptual responses to gastric distension. Baseline sleep dysfunction in the form of reduced sleep efficiency, increased arousal, or abnormal amounts of REM sleep was found in all seven patients. Amitryptiline significantly reduced absolute and relative amounts of REM sleep, but had no effect on sleep parameters related to nonregenerative sleep. CONCLUSION: The beneficial effect of low dose amitryptiline seen in functional dyspepsia is not related to changes in perception of gastric distension, or to measures of arousal from sleep. An increased tolerance to aversive visceral sensations may play a role in the therapeutic effect.

Adult↗
PubMed1998

Audio and visual stimulation reduces patient discomfort during screening flexible sigmoidoscopy.

OBJECTIVE: Despite current recommendations calling for regular screening flexible sigmoidoscopies over the age of 50, only a small percentage of the population have regular examinations. Improving patient tolerance of flexible sigmoidoscopies could therefore increase patient compliance with these recommended guidelines. The aim of this study was to determine whether audio and visual stimulation reduces discomfort during flexible sigmoidoscopy and whether the effects of the stimulation are secondary to distraction. METHODS: A total of 37 patients undergoing routine screening flexible sigmoidoscopy were randomized to receive no intervention, audio stimulation alone, or audio and visual stimulation. Patient discomfort ratings and affect states were measured prior to and immediately following flexible sigmoidoscopy using a visual analogue scale and the Stress Symptom Ratings (SSR) ratings. RESULTS: Patients receiving audio and visual intervention had lower abdominal discomfort ratings (7.1 +/- 1.4) than patients receiving audio stimulation (9.5 +/- 1.3) or no intervention (10.8 +/- 1.6) (p < 0.05). Patients receiving audio and visual intervention also had higher arousal (7.3 +/- 0.4) and attention (9.2 +/- 0.2) ratings than patients receiving no intervention (6.1 +/- 0.4 and 6.2 +/- 0.7, respectively) (p < 0.05). Anxiety and anger ratings, on the other hand, were significantly lower in patients receiving audio and visual intervention (2.5 +/- 0.4, 1.4 +/- 0.3, respectively) than patients receiving no intervention (4.4 +/- 0.6, 3.6 +/- 0.7). CONCLUSION: Audio and visual stimulation reduces abdominal discomfort associated with flexible sigmoidoscopy. This effect appears to be due to distraction.

Abdominal Pain↗