Characterization of the cerebral cortical representation of heartburn in GERD patients

Although symptoms arising from the esophagus such as heartburn and pain can at times become challenging clinical problems, esophageal viscerosensation, especially with regard to chemical stimulation in humans, is incompletely understood. Our aims were 1) to characterize and ascertain the reproducibility of cerebral cortical registration of heartburn and 2) to elucidate the differences between these findings and those of esophageal subliminal acid stimulation in asymptomatic controls. We studied 11 gastroesophageal reflux disease (GERD) patients (9 males, 30-55 yr) and 15 healthy controls (8 males, 21-49 yr). Cerebral cortical functional magnetic resonance imaging (fMRI) activity was recorded twice in each subject, during two 5-min intervals of 0.1 N HCl, separated by 5 min of NaCl perfusion. Time from onset of acid perfusion to instant of fMRI signal increase and first report of heartburn averaged 1.60 +/- 0.80 and 1.85 +/- 0.60 min, respectively. Average maximum percent signal increase in the GERD patients (16.3 +/- 3.5%) was significantly greater than that of healthy controls (3.8 +/- 0.9%; P < 0.01). Temporal fMRI signal characteristics during heartburn were significantly different from those of subliminal acid stimulation in controls (P < 0.01). Activated cortical regions included sensory/motor, parieto-occipital, cingulate and prefrontal regions, and the insula. There was 92% concordance between the activated Brodmann areas in repeated studies of GERD patients. Cortical activity associated with perceived and unperceived esophageal acid exposure in GERD patients and healthy controls, respectively, involves multiple brain regions but occurs more rapidly and with greater intensity in GERD patients than the activity in response to subliminal acid exposure in healthy controls. The cortical pain-processing pathway seems to be involved in perception of esophageal acid exposure and could explain the variations encountered in clinical practice defining this sensation.     

Central neural mechanisms mediating human visceral hypersensitivity

Although visceral hypersensitivity is thought to be important in generating symptoms in functional gastrointestinal disorders, the neural mechanisms involved are poorly understood. We recently showed that central sensitization (hyperexcitability of spinal cord sensory neurones) may play an important role. In this study, we demonstrate that after a 30-min infusion of 0.15 M HCl acid into the healthy human distal esophagus, we see a reduction in the pain threshold to electrical stimulation of the non-acid-exposed proximal esophagus (9.6 +/- 2.4 mA) and a concurrent reduction in the latency of the N1 and P2 components of the esophageal evoked potentials (EEP) from this region (10.4 +/- 2.3 and 15.8 +/- 5.3 ms, respectively). This reduced EEP latency indicates a central increase in afferent pathway velocity and therefore suggests that hyperexcitability within the central visceral pain pathway contributes to the hypersensitivity within the proximal, non-acid-exposed esophagus (secondary hyperalgesia/allodynia). These findings provide the first electrophysiological evidence that central sensitization contributes to human visceral hypersensitivity.     

Cingulate cortex: a closer look at its gut-related functional topography

Earlier studies have documented activation of the cingulate cortex during gut related sensory-motor function. However, topography of the cingulate cortex in relationship to various levels of visceromotor sensory stimuli and gender is not completely elucidated. The aim was to characterize and compare the activation topography of the cingulate cortex in response to 1) subliminal, 2) perceived rectal distensions, and 3) external anal sphincter contraction (EASC) in males and females. We studied 18 healthy volunteers (ages 18-35 yr; 10 women, 8 men) using functional MRI blood-oxygenation-level-dependent technique. We obtained 11 axial slices (voxel vol. 2.5-6.0 x 2.5 x 2.5 mm(3)) through the cingulate cortex during barostat-controlled subliminal, liminal, and supraliminal nonpainful rectal distensions as well as EASC. Overall, for viscerosensation, the anterior cingulate cortex exhibited significantly more numbers of activated cortical voxels for all levels of stimulations compared with the posterior cingulate cortex (P < 0.05). In contrast, during EASC, activity in the posterior cingulate was larger than in the anterior cingulate cortex (P < 0.05). Cingulate activation was similar during EASC in males and females (P = 0.58), whereas there was a gender difference in anterior cingulate activation during liminal and supraliminal stimulations (P < 0.05). In females, viscerosensory cortical activity response was stimulus-intensity dependent. Intestinal viscerosensation and EASC induce different patterns of cingulate cortical activation. There may be gender differences in cingulate cortical activation during viscerosensation. In contrast to male subjects, females exhibit increased activity in response to liminal nonpainful stimulation compared with subliminal stimulation suggesting differences in cognition-related recruitment.     

Absence of increasing cortical fMRI activity volume in response to increasing visceral stimulation in IBS patients

Cerebral cortical activity associated with perceived visceral sensation represents registration of afferent transduction and cognitive processes related to perception. Abnormalities of gut sensory function can involve either or both of these processes. Cortical registration of subliminal viscerosensory signals represents cerebral cortical activity induced by stimulation of intestinal sensory neurocircuitry without the influence of perception-related cortical activity, whereas those associated with perception represent both neural circuitry and cognitive processes. Our aims were to determine and compare quantitatively cerebral cortical functional magnetic resonance imaging (fMRI) activity in response to subliminal, liminal, and nonpainful supraliminal rectal distension between a group of irritable bowel syndrome (IBS) patients and age/gender-matched controls. Eight female IBS patients and eight age-matched healthy female control subjects were studied using brain fMRI techniques. Three barostat-controlled distension levels were tested: 1) 10 mmHg below perception (subliminal), 2) at perception (liminal), and 3) 10 mmHg above perception (supraliminal). In control subjects, there was a direct relationship between stimulus intensity and cortical activity volumes, ie., the volume of fMRI cortical activity in response to subliminal (3,226 +/- 335 microl), liminal (5,751 +/- 396 microl), and supraliminal nonpainful stimulation (8,246 +/- 624 microl) were significantly different (P < 0.05). In contrast, in IBS patients this relationship was absent and fMRI activity volumes for subliminal (2,985 +/- 332 microl), liminal (2,457 +/- 342 microl), and supraliminal nonpainful stimulation (2,493 +/- 351 microl) were similar. Additional recruitment of cortical fMRI activity volume in response to increasing stimulation from subliminal to liminal and supraliminal domains is absent in IBS patients, suggesting a difference in the processing of perceived stimulation compared with controls.     

Effects of the concentration and frequency of acid infusion on the development and maintenance of esophageal hyperalgesia in a human volunteer model

Previous studies have demonstrated that a single 30-min distal esophageal infusion of concentrated (0.15 M, pH 0.8) hydrochloric acid (HCl) induces hyperalgesia to an electrical stimulus in a human model. The aim of this study was to refine this model using physiological acid concentrations (pH 1.8-4) in repeated short exposures. Two different cohorts of 10 volunteers underwent two studies. Study 1: randomization to four 5-min distal esophageal infusions of acid (0.15 M) or saline, 1 h apart. Double-blind measurements of baseline and postexposure proximal esophageal and chest wall pain thresholds (PTs) were performed to electrical stimulation at 30-min intervals throughout the study. Study 2: randomization to four 15-min infusions of 0.15, 0.075, and 0.01 M HCl and saline. In study 1, with multiple acid infusions, a significant progressive drop in PTs was observed in both areas tested (P < or = 0.0001). In study 2, increasing acid concentrations had a significant effect over multiple time points, P < or = 0.0001. Similar initial reductions in PTs were observed for all acid concentrations compared with saline; however, hypersensitivity was shorter lasting with 0.01 M acid. In healthy subjects, esophageal hypersensitivity can be induced and maintained up to 4 h by repeated short-duration acid infusion and at physiological pH levels. This has implications for future model design and pathophysiological understanding of acid-related esophageal hypersensitivity.     

Alterations in N-methyl-D-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats

The excitatory amino acid glutamate plays an important role in the development of neuronal sensitization and the ionotropic N-methyl-d-aspartate receptor (NMDAR) is one of the major receptors involved. The objective of this study was to use a cat model of gastroesophageal reflux disease (GERD) to investigate the expression of the NR1 and NR2A subunits of NMDAR in the vagal and spinal afferent fibers innervating the esophagus. Two groups of cats (Acid-7D and PBS-7D) received 0.1 N HCl (pH 1.2) or 0.1 M PBS (pH 7.4) infusion in the esophagus (1 ml/min for 30 min/day for 7 days), respectively. NR1 splice variants (both NH(2) and COOH terminals) and NR2A in the thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophagus were evaluated by RT-PCR, Western blot, and immunohistochemistry. Acid produced marked inflammation and a significant increase in eosinophil peroxidase and myeloperoxidase contents compared with PBS-infused esophagus. The NR1-4 splice variant gene exhibited a significant upregulation in DRGs and esophagus after acid infusion. In DRGs, NGs, and esophagus, acid infusion resulted in significant upregulation of NR1 and downregulation of NR2A subunit gene expression. A significant increase in NR1 polypeptide expression was observed in DRGs and NGs from Acid-7D compared with control. In conclusion, long-term acid infusion in the cat esophagus resulted in ulcerative esophagitis and differential expressions of NR1 and NR2A subunits. It is possible that these changes may in part contribute to esophageal hypersensitivity observed in reflux esophagitis.     

Proton Pump Inhibitors Decrease Eotaxin-3 Expression in the Proximal Esophagus of Children with Esophageal Eosinophilia

Objective

Besides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells.

Design

Among 264 children with esophageal eosinophilia seen at a tertiary pediatric hospital from 2008 through 2012, we identified 10 with esophageal biopsies before and after PPI treatment alone. We correlated epithelial cell eotaxin-3 immunostaining with eosinophil numbers in those biopsies. In vitro, we measured eotaxin-3 protein secretion by esophageal squamous cells stimulated with IL-13 and exposed to acid and/or bile salt media, with or without omeprazole.

Results

There was strong correlation between peak eosinophil numbers and peak eotaxin-3-positive epithelial cell numbers in esophageal biopsies. Eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus. In esophageal cells, exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions.

Conclusion

In children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI-induced reduction in acid reflux (an effect that could increase eotaxin-3 secretion induced by Th2 cytokines) might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokine-stimulated eotaxin-3 secretion.     

The role of the superior laryngeal nerve in esophageal reflexes

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats (N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only.     

Shared "Core" Areas between the Pain and Other Task-Related Networks

The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been challenged. Alternative views now propose that the activity of the primary and secondary somatosensory cortices (SI, SII), the insula and cingulate cortex may be related to a basic defensive system through which significant potentially dangerous events for the body's integrity are detected. By reviewing the role of the SI, SII, the cingulate and the insular cortices in the perception of nociceptive and tactile stimuli, in attentional, emotional and reward tasks, and in interoception and memory, we found that all these task-related networks overlap in the dorsal anterior cingulate cortex, the anterior insula and the dorsal medial thalamus. A thorough analysis revealed that the 'pain-related' network shares important functional similarities with both somatomotor-somatosensory networks and emotional-interoceptive ones. We suggest that these shared areas constitute the central part of an adaptive control system involved in the processing and integration of salient information coming both from external and internal sources. These areas are activated in almost all fMRI tasks and have been indicated to play a pivotal role in switching between externally directed and internally directed brain networks.     

Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise

Recent brain imaging studies using functional magnetic resonance imaging (fMRI) have implicated insula and anterior cingulate cortices in the empathic response to another's pain. However, virtually nothing is known about the impact of the voluntary generation of compassion on this network. To investigate these questions we assessed brain activity using fMRI while novice and expert meditation practitioners generated a loving-kindness-compassion meditation state. To probe affective reactivity, we presented emotional and neutral sounds during the meditation and comparison periods. Our main hypothesis was that the concern for others cultivated during this form of meditation enhances affective processing, in particular in response to sounds of distress, and that this response to emotional sounds is modulated by the degree of meditation training. The presentation of the emotional sounds was associated with increased pupil diameter and activation of limbic regions (insula and cingulate cortices) during meditation (versus rest). During meditation, activation in insula was greater during presentation of negative sounds than positive or neutral sounds in expert than it was in novice meditators. The strength of activation in insula was also associated with self-reported intensity of the meditation for both groups. These results support the role of the limbic circuitry in emotion sharing. The comparison between meditation vs. rest states between experts and novices also showed increased activation in amygdala, right temporo-parietal junction (TPJ), and right posterior superior temporal sulcus (pSTS) in response to all sounds, suggesting, greater detection of the emotional sounds, and enhanced mentation in response to emotional human vocalizations for experts than novices during meditation. Together these data indicate that the mental expertise to cultivate positive emotion alters the activation of circuitries previously linked to empathy and theory of mind in response to emotional stimuli.     

Symptom hypersensitivity to acid infusion is associated with hypersensitivity of esophageal contractility

Several investigators have observed that repeated acid infusions induce stronger symptoms (symptom hypersensitivity). The goal of our study was to determine whether symptom hypersensitivity is associated with esophageal contractile hypersensitivity. Subjects with chronic heartburn symptoms underwent simultaneous pressure and ultrasound imaging of esophagus. Normal saline and 0.1 N HCl were sequentially infused into the esophagus, and subjects scored heartburn symptoms on a 1-10 scale. Saline and HCl infusions were repeated in 10 subjects with a positive Bernstein test. Esophageal contraction amplitude and duration and muscularis propria thickness were measured using a computerized method during recording. Acid infusion induced heartburn. Esophageal contractions had higher amplitudes (pressure 114.2 +/- 7.0%) and longer duration (116.8 +/- 4.4%) during acid infusion compared with saline infusion. Average muscle thickness was greater during acid infusion than saline infusion (107.0 +/- 2.0%). Sustained esophageal contractions (SECs) were identified during acid infusion. A second acid infusion (acid-2) induced heartburn with shorter latency (93.0 +/- 15.0 vs. 317.0 +/- 43.0 s) and stronger severity (8.5 +/- 0.5 vs. 5.3 +/- 0.8) than the first acid infusion (acid-1). Contraction amplitudes (140.2 +/- 13.0%), average muscle thickness (118.0 +/- 3.3%), and contraction duration (148.5 +/- 5.6 vs. 116.8 +/- 4.4%) were higher during acid-2 than acid-1. Also, numbers of SECs were greater during acid-2 than acid-1 (31 in 8 subjects vs. 11 in 6 subjects). Our data show that acid infusion into esophagus induces esophageal hypersensitivity and that a close temporal correlation exists between symptom hypersensitivity and contractility hypersensitivity.     

A novel pattern of longitudinal muscle contraction with subthreshold pharyngeal stimulus: a possible mechanism of lower esophageal sphincter relaxation

A subthreshold pharyngeal stimulus induces lower esophageal sphincter (LES) relaxation and inhibits progression of ongoing peristaltic contraction in the esophagus. Recent studies show that longitudinal muscle contraction of the esophagus may play a role in LES relaxation. Our goal was to determine whether a subthreshold pharyngeal stimulus induces contraction of the longitudinal muscle of the esophagus and to determine the nature of this contraction. Studies were conducted in 16 healthy subjects. High resolution manometry (HRM) recorded pressures, and high frequency intraluminal ultrasound (HFIUS) images recorded longitudinal muscle contraction at various locations in the esophagus. Subthreshold pharyngeal stimulation was induced by injection of minute amounts of water in the pharynx. A subthreshold pharyngeal stimulus induced strong contraction and caudal descent of the upper esophageal sphincter (UES) along with relaxation of the LES. HFIUS identified longitudinal muscle contraction of the proximal (3-5 cm below the UES) but not the distal esophagus. Pharyngeal stimulus, following a dry swallow, blocked the progression of dry swallow-induced peristalsis; this was also associated with UES contraction and descent along with the contraction of longitudinal muscle of the proximal esophagus. We identify a unique pattern of longitudinal muscle contraction of the proximal esophagus in response to subthreshold pharyngeal stimulus, which we propose may be responsible for relaxation of the distal esophagus and LES through the stretch sensitive activation of myenteric inhibitory motor neurons.     

Central Projection of Pain Arising from Delayed Onset Muscle Soreness (DOMS) in Human Subjects

Delayed onset muscle soreness (DOMS) is a subacute pain state arising 24–48 hours after a bout of unaccustomed eccentric muscle contractions. Functional magnetic resonance imaging (fMRI) was used to examine the patterns of cortical activation arising during DOMS-related pain in the quadriceps muscle of healthy volunteers evoked by either voluntary contraction or physical stimulation. The painful movement or physical stimulation of the DOMS-affected thigh disclosed widespread activation in the primary somatosensory and motor (S1, M1) cortices, stretching far beyond the corresponding areas somatotopically related to contraction or physical stimulation of the thigh; activation also included a large area within the cingulate cortex encompassing posteroanterior regions and the cingulate motor area. Pain-related activations were also found in premotor (M2) areas, bilateral in the insular cortex and the thalamic nuclei. In contrast, movement of a DOMS-affected limb led also to activation in the ipsilateral anterior cerebellum, while DOMS-related pain evoked by physical stimulation devoid of limb movement did not.     

Source modeling of esophageal evoked potentials

Evoked potentials can be recorded from the scalp after stimulation of the esophagus by balloon distension. The purpose of this study was to estimate the number and localization of sources contributing to the esophageal evoked potential (EEP). The EEP was recorded from 32 scalp electrodes in 5 healthy subjects. Spatio-temporal dipole modeling was performed in the time interval from 185 msec to 525 msec after stimulation (mean values). The EEP was best explained by the combined activity of 1 dipole located relatively high in the midline and 2 lateral dipoles. Given the anatomical projection of esophageal sensory fibers and the location of these dipoles, the sources were probably located in the cingulate gyri and insular cortex. There was no evidence that sources in the lower brain-stem contributed to the scalp recorded EEP.     

Differences in activity and phosphorylation of MAPK enzymes in esophageal squamous cells of GERD patients with and without Barrett's esophagus

We hypothesized that, in esophageal squamous epithelial cells, there are differences among individuals in the signal transduction pathways activated by acid reflux that might underlie the development of Barrett's esophagus. To explore that hypothesis, we immortalized nonneoplastic, esophageal squamous cells from patients with gastroesophageal reflux disease (GERD) with (NES-B3T) and without (NES-G2T) Barrett's esophagus and used those cells to study acid effects on MAPK proteins. During endoscopy in patients with GERD with and without Barrett's esophagus, we took biopsy specimens from the distal squamous esophagus to study MAPK proteins before and after esophageal perfusion with 0.1 N HCl. We used immunoblotting and Western blotting to study MEK1/2 phosphorylation at two activating sites (serines 217/221), MEK1 phosphorylation at an inhibitory site (threonine 286), and MEK1/2 activity. After acid exposure, both cell lines exhibited increased MEK1/2 phosphorylation at the activating sites; the NES-B3T cells had higher levels of MEK1 phosphorylation at the inhibitory site, however, and only the NES-G2T cells showed an acid-induced increase in MEK1/2 activity. Similarly, in the squamous epithelium of patients with GERD with and without Barrett's esophagus, acid perfusion increased MEK1/2 phosphorylation at the activating sites in both patient groups; the Barrett's patients had higher levels of MEK1 phosphorylation at the inhibitory site, however, and only the patients without Barrett's demonstrated an acid-induced increase in ERK1/2 phosphorylation. In esophageal squamous cell lines and biopsies from patients with GERD with and without Barrett's esophagus, we have found differences in MAPK pathways activated by acid exposure. We speculate that these differences might underlie the development of Barrett's metaplasia.     

Cerebral cortical representation of external anal sphincter contraction: effect of effort

The external anal sphincter (EAS) plays a critical role in maintaining fecal continence; however, cerebral cortical control of voluntary EAS contraction is not completely understood. Our aims were to determine the cortical areas associated with voluntary EAS contraction and to determine the effect of two levels of sphincter contraction effort on brain activity. Seventeen asymptomatic adults (ages 21-48, 9 male) were studied using functional magnetic resonance imaging (fMRI) to detect brain activity. Studies were done in two stages. In stage 1 (10 subjects, 5 male), anal sphincter pressure was monitored from a catheter-affixed bag. Subjects performed maximal and submaximal EAS contractions during two fMRI scanning sessions consisting of alternating 10-s intervals of sustained contraction and rest. In stage 2 studies, seven subjects (4 male) performed only maximum effort sphincter contractions without a catheter. EAS contraction was associated with multifocal fMRI activity in sensory/motor, anterior cingulate, prefrontal, parietal, occipital, and insular regions. Total cortical activity volume was significantly larger (P < 0.05) for maximal (5,175 +/- 720 microl) compared with submaximal effort contractions (2,558 +/- 306 microl). Similarly, percent fMRI signal change was significantly higher (P < 0.05) for maximal (4.8 +/- 0.1%) compared with submaximal effort contractions (2.2 +/- 0.1%). Cortical region-of-interest analysis showed the incidence of insular activation to be more common in women compared with men. Other cortical regions showed no such gender differences. fMRI activity detected in stage 2 showed similar regions of cortical activation to those of the stage 1 study. Willful contraction of the EAS is associated with multifocal cerebral cortical activity. The volume and intensity of cerebral cortical activation is commensurate with the level of contractile effort.     

New method for quantitative evaluation of esophageal sensibility

A method for quantitating esophagus sensibility by an electric stimulation test is described. Square stimulus waveform at different voltages and durations were transmitted to the esophagus, three series of electric stimuli being used in successive durations (0.5, 1, 2, 4, 8 and 16 ms); in each series the voltage discharge was increased progressively from 0 mV, until the subject noted the first sensation. This procedure was carried out at all esophageal levels. The following parameters were analyzed: sensitive threshold along the esophagus; the relation of threshold sensibility (mV) duration of stimulus (ms), and reobase and cronaxia for each esophageal level. At all esophageal levels, the sensitive threshold was regular and coherent; in the middle esophagus a zone was found having higher sensitive threshold than the proximal and distal esophageal zones. The relationship between sensitive threshold and inverse of the stimulus duration indicated that esophageal sensibility follows the basic law of excitation of WEISS, at least with this type of stimulus, reobase and cronaxia being representative of the sensibility threshold along the esophagus. Quantitative esophageal sensibility, therefore is concluded to be particularly suited to evaluation by electric stimulation.     

Effects of feeding on luminal pH and morphology of the gastroesophageal junction of snakes

At the gastroesophageal junction, most vertebrates possess a functional lower esophageal sphincter (LES) which may serve to regulate the passage of liquids and food into the stomach and prevent the reflux of gastric contents into the esophagus. Snakes seemingly lack an LES and consume meals large enough to extend anteriorly from the stomach into the esophagus thereby providing the opportunity for the reflux of gastric juices. To explore whether snakes experience or can prevent gastric reflux, we examined post-feeding changes of luminal pH of the distal esophagus and stomach, the fine scale luminal pH profile at the gastroesophageal junction, and the morphology of the gastroesophageal junction for the Burmese python (Python molurus), the African brown house snake (Lamprophis fuliginosus), and the diamondback water snake (Nerodia rhombifer). For each species fasted, there was no distension of the gastroesophageal junction and only modest changes in luminal pH from the distal esophagus into the stomach. Feeding resulted in marked distension and changes in tissue morphology of the gastroesophageal junction. Simultaneously, there was a significant decrease in luminal pH of the distal esophagus for pythons and house snakes, and for all three species a steep gradient in luminal pH decreasing across a 3-cm span from the distal edge of the esophagus into the proximal edge of the stomach. The moderate acidification of the distalmost portion of the esophagus for pythons and house snakes suggests that there is some anterior movement of gastric juices across the gastroesophageal junction. Given that this modest reflux of gastric fluid is localized to the most distal region of the esophagus, snakes are apparently able to prevent and protect against acid reflux in the absence of a functional LES.     

Role of endogenous prostaglandins in regulating the tone of opossum lower esophageal sphincter in vivo.

The role of prostaglandins in maintenance of basal myogenic tone of the lower esophageal sphincter (LES) of opossum has been studied in vivo. Intra-arterial infusion of arachidonic acid decreased LES tone, and this was inhibited by intravenous indomethacin (IDM) or intra-arterial 5,8,11,14-eicosatetraynoic acid (ETA). Alone these drugs did not reduce LES tone except transiently. In addition they did not affect relaxation of the LES to distention of a balloon located proximal to it or inhibit the "off" contractions of esophageal body and LES pressure which followed balloon deflation. Spontaneous oscillations of LES pressure were increased with IDM. Thus prostaglandin synthesis plays no essential role in maintenance of resting LES tone or in functioning of non-adrenergic inhibitory nerves in the esophagus in vivo. Endogenous inhibitory prostaglandins might reduce LES tone if synthesized in increased amounts.     

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications V. Central nervous system processing of somatic and visceral sensory signals

Somatic and visceral sensation, including pain perception, can be studied noninvasively in humans with functional brain imaging techniques. Positron emission tomography and functional magnetic resonance imaging have identified a series of cerebral regions involved in the processing of somatic pain, including the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory, and primary motor and premotor cortices, the thalamus, hypothalamus, brain stem, and cerebellum. Experimental evidence supports possible specific roles for individual structures in processing the various dimensions of pain, such as encoding of affect in the anterior cingulate cortex. Visceral sensation has been examined in the setting of myocardial ischemia, distension of hollow viscera, and esophageal acidification. Although knowledge regarding somatic sensation is more extensive than the information available for visceral sensation, important similarities have emerged between cerebral representations of somatic and visceral pain.