Effects of lidocaine on esophageal secondary peristalsis in humans

Background Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. Lidocaine has been used to evaluate the role of mucosa‐mediating pathways of esophageal reflexes in animal model, but its effects on esophageal secondary peristalsis are yet unclear in humans. We aimed to investigate whether esophageal secondary peristalsis can be affected by intraluminal infusion of lidocaine into the esophagus. Methods After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 13 healthy subjects. Two separate sessions with saline and lidocaine were randomly performed to test their effects on esophageal secondary peristalsis by mid‐esophageal air distension. Key Results Secondary peristalsis can be induced by slow or rapid air infusion. Secondary peristalsis was triggered less frequently in response to rapid air distension after lidocaine infusion (P = 0.001). After lidocaine infusion, the threshold volume to generate secondary peristalsis was significantly increased during rapid (P = 0.001), but not slow air infusions (P = NS). Infusion of lidocaine or saline did not affect pressure wave amplitude or duration during rapid and slow air infusions (P = NS). Conclusions & Inferences We have demonstrated selectively inhibitory effect of lidocaine on the triggering of esophageal secondary peristalsis during acute gaseous esophageal distension. The data suggest that part of the activation of secondary peristalsis is probably mediated by lidocaine‐sensitive mechanoreceptors; however, the infusion of lidocaine does not lead to any motility change in secondary peristalsis induced by either slow or rapid air infusions.     

Effects of mosapride on esophageal secondary peristalsis in humans

Background Secondary peristalsis is important for the clearance of refluxate or retained food bolus from the esophagus. Mosapride is a prokinetic agent that enhances GI motility by stimulating 5‐hydroxytrypatamine₄ (5‐HT₄) receptors, but its effects on secondary peristalsis are yet unclear in humans. We aimed to investigate the effect of a 5‐HT₄ agonist mosapride on esophageal distension‐induced secondary peristalsis in normal subjects. Methods After a baseline recording esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 15 healthy subjects. Two separate sessions with 40 mg oral mosapride or placebo were randomly performed to test their effects on esophageal secondary peristalsis. Key Results Mosapride decreased the threshold volume for triggering secondary peristalsis during rapid air distension (4.5 ± 0.3 vs 5.3 ± 0.4 mL; P = 0.04) but not slow air distension (14.3 ± 1.2 vs 13.3 ± 1.3 mL; P = 0.41). Secondary peristalsis was triggered more frequently in response to rapid air distension after application of mosapride [100% (90–100%) vs 90% (80–100%); P = 0.02]. Mosapride significantly increased pressure wave amplitudes of secondary peristalsis during slow (135.4 ± 13.8 vs 105.0 ± 12.9 mmHg; P = 0.001) and rapid air distensions (124.0 ± 11.6 vs 95.9 ± 14.0 mmHg; P = 0.002). Conclusions & Inferences Mosapride enhances sensitivity to distension‐induced secondary peristalsis and facilitates secondary peristaltic contractility. These data provide an evidence for modulation of esophageal secondary peristalsis by the 5‐HT₄ agonist mosapride, as well support for its clinical utility.     

Control of esophageal distension‐induced secondary peristalsis by the GABAB agonist baclofen in humans

Background Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. The effects of the gamma aminobutyric acid receptor type B (GABA_B) agonist on secondary peristalsis remain unclear in humans. We aimed to investigate the effect of a GABA_B agonist baclofen on esophageal secondary peristalsis. Methods After a baseline recording of esophageal motility, secondary peristalsis was generated by slow and rapid mid‐esophageal injections of air in 15 healthy subjects. Two separate sessions with 40 mg oral baclofen or placebo were randomly performed to test their effects on secondary peristalsis. Key Results Baclofen increased the threshold volume for triggering secondary peristalsis during slow air distension (P = 0.003) and rapid air distension (P = 0.002). Baclofen reduced the rate of secondary peristalsis by rapid air distension from 90% to 30% (P = 0.0002). Baclofen increased basal lower esophageal sphincter pressure (P = 0.03). Baclofen did not affect any of peristaltic parameters during primary or secondary peristalsis. Conclusions & Inferences This study provides an evidence for inhibitory modulation of esophageal secondary peristalsis by the GABA_B agonist baclofen. Activation of secondary peristalsis is probably modulated by GABA_B receptors; however, baclofen does not lead to any motility change in secondary peristalsis.     

Oxytocin reduces satiety scores without affecting the volume of nutrient intake or gastric emptying rate in healthy subjects

Background Oxytocin is expressed throughout the gastrointestinal tract and is released in response to a fatty meal. Administration of an oxytocin receptor antagonist prolongs the gastric emptying rate. The aim of this study was to examine the effect of oxytocin on gastric accommodation, gastric emptying time, and satiety after food intake. Methods Ten healthy subjects participated in a slow satiety drinking test with a liquid meal. Every 5 min the subjects scored their sensation of satiety using a visual analogue scale (VAS) until maximum satiety was reached and the amount of liquid intake was determined. Twelve subjects participated in a gastric emptying test. They were given a standardized meal containing 20 radio‐opaque markers, after which fluoroscopy was performed and VAS was scored every hour. Both tests were performed four times during infusions of saline and three different oxytocin concentrations. Blood was collected for oxytocin concentration measurements. Key Results There were no differences in the volume of nutrient intake at maximum satiety between the three doses of oxytocin and saline. However, lower satiety scores at maximum satiety were seen after oxytocin infusion (P = 0.031), with 40 mU min^?1 being the most effective dosage (P = 0.013), and this was also true 30 min after finishing the meal (P = 0.032). There was no difference in gastric emptying time between saline and oxytocin. The oxytocin concentration in plasma was increased proportional to the oxytocin infusions. Conclusions & Inferences Infusion of oxytocin reduces satiety without affecting the volume of nutrient intake or gastric emptying in healthy subjects.     

The impact of primary peristalsis,contractile reserve,and secondary peristalsis on esophageal clearance measured by timed barium esophagogram

Background

Primary and secondary peristalsis facilitate esophageal bolus transport; however, their relative impact for bolus clearance remains unclear. We aimed to compare primary peristalsis and contractile reserve on high-resolution manometry (HRM) and secondary peristalsis on functional lumen imaging probe (FLIP) Panometry with emptying on timed barium esophagogram (TBE) and incorporate findings into a comprehensive model of esophageal function.

Methods

Adult patients who completed HRM with multiple rapid swallows (MRS), FLIP, and TBE for esophageal motility evaluation and without abnormal esophagogastric junction outflow/opening or spasm were included. An abnormal TBE was defined as a 1-min column height >5 cm. Primary peristalsis and contractile reserve after MRS were combined into an HRM–MRS model. Secondary peristalsis was combined with primary peristalsis assessment to describe a complementary neuromyogenic model.

Key Results

Of 89 included patients, differences in rates of abnormal TBEs were observed with primary peristalsis classification (normal: 14.3%; ineffective esophageal motility: 20.0%; absent peristalsis: 54.5%; p = 0.009), contractile reserve (present: 12.5%; absent: 29.3%; p = 0.05), and secondary peristalsis (normal: 9.7%; borderline: 17.6%; impaired/disordered: 28.6%; absent contractile response: 50%; p = 0.039). Logistic regression analysis (akaike information criteria, area under the receiver operating curve) demonstrated that the neuromyogenic model (80.8, 0.83) had a stronger relationship predicting abnormal TBE compared to primary peristalsis (81.5, 0.82), contractile reserve (86.8, 0.75), or secondary peristalsis (89.0, 0.78).

Conclusions and Inferences

Primary peristalsis, contractile reserve, and secondary peristalsis were associated with abnormal esophageal retention as measured by TBE. Added benefit was observed when applying comprehensive models to incorporate primary and secondary peristalsis supporting their complementary application.     

Multiple rapid swallow responses segregate achalasia subtypes on high‐resolution manometry

Background Multiple rapid swallows (MRS) inhibit esophageal peristalsis and lower esophageal sphincter (LES) tone; a rebound excitatory response then results in an exaggerated peristaltic sequence. Multiple rapid swallows responses are dependent on intact inhibitory and excitatory neural function and could vary by subtype in achalasia spectrum disorders. Methods Consecutive subjects with incomplete LES relaxation on high‐resolution manometry (HRM) (Sierra Scientific, Los Angeles, CA, USA) in the absence of mechanical obstruction were prospectively identified. Achalasia spectrum disorders were classified and HRM plots reviewed according to Chicago criteria. Esophageal peristaltic performance and LES function were assessed after 10 wet swallows and MRS (five 2 mL water swallows 2–3 s apart). Findings were compared with 18 healthy controls (28.5 ± 0.6 years, 44% women). Key Results A total of 46 subjects (57.1 ± 2.1 years, 52.2% women) met inclusion criteria. There was complete failure of peristalsis with MRS in all subjects with achalasia subtypes 1 and 2. In contrast, 80% of achalasia subtype 3 and incomplete LES relaxation (EGJ outflow obstruction) with preserved esophageal body peristalsis had a contractile response to MRS (P < 0.001 compared with subtypes 1 and 2); controls demonstrated 94.4% peristalsis. Percent decrease in LES residual pressure during MRS (compared to wet swallows) segregated achalasia subtypes; those with aperistalsis (subtypes 1 and 2) had a lesser decline (22.6%) compared to those with retained esophageal body peristalsis (40.5%) and controls (51.3%, P < 0.001 across groups). Conclusions & Inferences Multiple rapid swallow responses segregate achalasia spectrum disorders into two patterns differentiated by presence or absence of esophageal body contraction response to wet swallows. These findings support subtyping of achalasia, with pathophysiologic implications.     

Upregulation of the esophago‐UES relaxation response: a possible pathophysiological mechanism in suspected reflux laryngitis

Background Inappropriate or excessive, non‐swallow related, reflexive relaxation of the upper esophageal sphincter (UES) in response to esophageal distension may be the principal mechanism permitting retrograde trans‐sphincteric flow during acid regurgitation. The neural pathways mediating reflexive UES relaxation in the human have received little attention. Patients with laryngitis demonstrate an increased acid reflux in the proximal esophagus. Such events, combined with an increased tendency for UES relaxation, might precipitate regurgitation into the pharynx. The aim was to determine whether the esophago‐UES relaxation reflex induced by rapid esophageal distension is upregulated in patients with posterior laryngitis. Methods In 21 healthy volunteers and 14 patients with posterior laryngitis, UES responses to rapid air insufflation were examined. UES responses were monitored with perfused manometry catheter with a oval sleeve sensor. Key Results The probability of triggering UES relaxation in response to the rapid esophageal air distension, for all volumes of insufflation, was higher in laryngitis (45%) than in health (17%). The minimum distension volume required to elicit an UES relaxation response was significantly lower in laryngitis patients when compared with controls. Patients who demonstrated a laryngoscopic response to a trial of omeprazole, were less likely to generate a distension‐induced UES contractile response (5%) than patients who did not respond (23%). Conclusions & Inferences The threshold for esophageal distension‐induced UES relaxation is reduced in patients with laryngitis when compared with controls. This finding supports the hypothesis that in this population, a hypersensitive belch‐like response may be one contributory mechanism of regurgitation when triggered by an abrupt spontaneous gastro‐esophageal reflux event.     

Pudendal afferent innervation of the guinea pig external anal sphincter

Background Sensory nerves to the external anal sphincter (EAS) contribute to mechanisms promoting continence and defecation, yet we know little about their function. We investigated the function of pudendal mechanoreceptors to the guinea pig EAS. Methods Extracellular recordings from pudendal nerve branches to 14 EAS preparations, in vitro, were used to characterize extrinsic primary afferent nerve endings activated by circumferential distension. Key Results All 42 pudendal nerve afferents were silent under non‐distended conditions. Thirty‐three of 42 afferents had slowly adapting, low‐threshold responses to circumferential stretch that correlated with stretch length (R² = 0.40, P < 0.001). Twenty of 20 slowly adapting afferents reduced firing when stretch was maintained for 60 s (P < 0.0001). They had low thresholds to von Frey hairs (0.1–0.5 mN). Firing frequency correlated with degree of compression (R² = 0.40, P < 0.0001). Nine of 42 afferents had rapidly adapting responses at the onset/offset of isometric stretch. During ramp stretch, small vibrations from the stepper motor evoked rapid bursts of firing at frequencies up to 200 Hz. Instantaneous frequency was unrelated to either the rate or degree of stretch. Rapidly adapting units had low thresholds (0.1–0.2 mN) to von Frey hairs and small punctate mechanotransduction sites. Responses to von Frey hair compression were also rapidly adapting, and instantaneous frequency was unrelated to the degree of compression. Conclusions & Inferences The EAS has two functional classes of mechanoreceptors: slowly adapting low‐threshold and rapidly adapting low‐threshold mechanoreceptors. These two classes of afferents are likely to be involved in the maintenance of continence, and the process of defecation.     

5-hydroxyindalpine, an agonist at the putative 5-HT1P receptor, has no activity on human recombinant monoamine receptors but accelerates distension-induced peristalsis in mouse isolated colon

Abstract Although the putative 5‐HT_1P receptor has been implicated to have a role in peristalsis, experiments which suggest this function are preliminary or have measured only components of the reflex. We have, therefore, further characterized a reported agonist at this receptor (5‐hydroxyindalpine; 5‐OHIP) and investigated the effects of 5‐OHIP and 5‐hydroxytrytophan‐dipeptide (5‐HTP‐DP), a reported 5‐HT_1P receptor antagonist, on distension‐induced peristalsis in mouse colon. The effects of 5‐OHIP on intracellular calcium, cyclic adenosine monophosphate concentrations or GTPγS binding were measured in cell lines expressing human recombinant 5‐HT_{1A, 1B, 1D, 2A, 2B, 2C, 3, 4, 6, 7} and α_1A, α_1B, D₁, D₂, D₃, H₁, H₃ receptors. The effects of 5‐OHIP and 5‐HTP‐DP on peristalsis were assessed by measuring changes in frequency and times to reach threshold of peristaltic contractions, as well as the threshold and maximum pressures of each peristaltic stroke. 5‐hydroxyindalpine (1 nmol L^?1–10 μmol L^?1) had no significant activity at any of the receptors studied. However, 5‐OHIP (0.1 nmol L^?1–1 μmol L^?1) concentration‐dependently increased the frequency of peristalsis (EC₅₀ = 4.4 nmol L^?1) and reduced the time taken to reach threshold and threshold pressure, without altering maximum pressures. The maximum effect of 5‐OHIP was at 1 μmol L^?1 (68.0 ± 14.5% increase in frequency); 10 μmol L^?1 decreased peristalsis. 5‐hydroxytrytophan‐dipeptide (1–300 nmol L^?1) also increased the frequency of peristalsis and prevented the actions of 5‐OHIP. The higher concentration (1 μmol L^?1) transiently inhibited peristalsis and after recovery, prevented the actions of 5‐OHIP but not the excitatory activity of the cholinesterase inhibitor neostigmine. In summary, the present data demonstrate an interaction of ‘5‐HT_1P‐ligands’ with the peristaltic reflex. However, the absence of an effect of 5‐OHIP on a range of different monoamine receptors continues to highlight the need to investigate the identity of the putative 5‐HT_1P receptor.     

Neonatal cystitis‐induced colonic hypersensitivity in adult rats: a model of viscero‐visceral convergence

Background The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms. Methods Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days [(postnatal (PN) days 14–16)]. The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissues. CRD‐ or urinary bladder distension (UBD)‐sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N‐methyl‐d ‐aspartic acid (NMDA)‐NR1 subunit in the lumbo‐sacral (L6‐S1) spinal cord was examined using Western blot. Key Results The VMR to CRD (≥10 mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD‐sensitive PNAs from the zymosan‐treated rats was significantly higher than the saline‐treated control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (P > 0.05). The expression of spinal NR1 subunit was significantly higher in zymosan‐treated rats compared with saline‐treated rats (P < 0.05). Conclusions & Inferences Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD‐sensitive PNAs. Neonatal cystitis does result in overexpression of spinal NR1 subunit in adult rats.     

Swallow induces a peristaltic wave of distension that marches in front of the peristaltic wave of contraction

Background Current understanding is that swallow induces simultaneous inhibition of the entire esophagus followed by a sequential wave of contraction (peristalsis). We observed a pattern of luminal distension preceding contraction which suggested that inhibition may also traverses in a peristaltic fashion. Our aim is to determine the relationship between contraction and luminal distension during bolus transport. Methods Eight subjects using two solid‐state pressure and two ultrasound (US) transducers were studied. Synchronous pressure and US images were obtained with wet swallows and after edrophonium and atropine. Luminal cross‐sectional area (CSA) at 2 cm and 12 cm above the lower esophageal sphincter (LES) were recorded. Relationship between pressure and CSA at each site, propagation velocity of peak pressure and peak distension waves were determined. Fluoroscopy coupled with manometry was also performed in five normal subjects. Key Results Esophageal distension precedes contraction wave at both‐recorded sites. During distension, esophageal pressure remains constant while luminal CSA increases significantly. The onset and the peak of distension wave traverses in a peristaltic fashion between both sites. A tight coupling exists between the peak distension and peak contraction waves with similar velocities (3.7 cm s^?1 and 3.6 cm s^?1) of propagation. The degree of distension is greater at 2 cm compared to 12 cm. Atropine and edrophonium reduced and increased the contraction pressure respectively, without affecting the distension wave. Fluoroscopic study confirmed that the wave of distension traverses the esophagus in a peristaltic fashion. Conclusions & Inferences Distension and contraction waves are tightly coupled to each other and both traverse in a peristaltic fashion.     

Manometric features of eosinophilic esophagitis in esophageal pressure topography

Background Although most of the patients with eosinophilic esophagitis (EoE) have mucosal and structural changes that could potentially explain their symptoms, it is unclear whether EoE is associated with abnormal esophageal motor function. The aims of this study were to evaluate the esophageal pressure topography (EPT) findings in EoE and to compare them with controls and patients with gastro‐esophageal disease (GERD). Methods Esophageal pressure topography studies in 48 EoE patients, 48 GERD patients, and 50 controls were compared. The esophageal contractile pattern was described for ten 5‐mL swallows for each subject and each swallow was secondarily characterized based on the bolus pressurization pattern: absent, pan‐esophageal pressurization, or compartmentalized distal pressurization. Key Results Thirty‐seven percent of EoE patients were classified as having abnormal esophageal motility. The most frequent diagnoses were of weak peristalsis and frequent failed peristalsis. Although motility disorders were more frequent in EoE patients than in controls, the prevalence and type were similar to those observed in GERD patients (P = 0.61, chi‐square test). Pan‐esophageal pressurization was present in 17% of EoE and 2% of GERD patients while compartmentalized pressurization was present in 19% of EoE and 10% of GERD patients. These patterns were not seen in control subjects. Conclusions & Inferences The prevalence of abnormal esophageal motility in EoE was approximately 37% and was similar in frequency and type to motor patterns observed in GERD. Eosinophilic esophagitis patients were more likely to have abnormal bolus pressurization patterns during swallowing and we hypothesize that this may be a manifestation of reduced esophageal compliance.     

The autonomic response to human esophageal acidification and the development of hyperalgesia

Background Distal esophageal acidification induces variable hyperalgesia in the non‐acid exposed proximal esophagus. As the autonomic nervous system (ANS) modulates nociception, the aim was to determine whether autonomic reactivity to acid infusion predicted inter‐individual differences in hyperalgesia. Methods In 25 healthy volunteers (18 women, age range 22–58, mean 36.5 years), using a double‐blind, placebo‐controlled crossover design, pain thresholds to electrical stimulation were determined in the proximal esophagus and foot (control) pre and post a 30‐min distal esophageal infusion of 0.15 mol L^?1 HCl or saline with autonomic monitoring. Sympathetic Cardiac Sympathetic Index and Skin Conductance Response and parasympathetic Cardiac Vagal Tone and Cardiac Sensitivity to Baroreflex measures were derived. Plasma cortisol was measured pre and post infusion as were anxiety and unpleasantness. Key Results Acid infusion reduced group pain threshold in the proximal esophagus (adjusted mean change ?5.0 mA vs saline +3.4 mA, P < 0.001), and raised sympathetic measures (Cardiac Sympathetic Index, Skin Conduction Response) and cortisol levels, but reduced parasympathetic measures (cardiac vagal tone and cardiac sensitivity to Baroreflex) (all P < 0.05). Acid infusion also increased anxiety and unpleasantness scores (both P < 0.05). In 16 acid‐sensitizers, the degree of hyperalgesia correlated with increasing heart rate (r = ?0.66, P = 0.005), and fall in cardiac vagal tone (r = 0.54, P = 0.03) and Cardiac Sensitivity to Baroreflex (r = 0.54, P = 0.03). Conclusions & Inferences Acid‐induced esophageal hyperalgesia correlated with reduced parasympathetic tone, suggesting that the parasympathetic nervous system may have anti hyperalgesic properties. Additional studies on the autonomic modulation of esophageal hyperalgesia are required.     

Inhibition of sensory afferents activation and visceral pain by a brominated algal diterpene

Background In the search of new therapeutic options for the treatment of pain, isolation, and testing of secondary metabolites from plant extracts has raised significant attention. We have investigated the effects of the brominated diterpene O¹¹15‐ cyclo‐14‐bromo‐14,15‐dihydrorogiol‐3,11‐diol (that we have named VLC5), extracted from the Mediterranean red algae Laurencia glandulifera. Methods The pure extract was tested on primary afferent calcium signals induced by high concentration of KCl, transcient receptor potential vanilloid (TRPV)1 (capsaicin) or TRPV4 agonists, histamine, or protease‐activated receptor‐2 (PAR₂) agonist. It was also tested in mice in a model of mustard oil‐induced colonic hypersensitivity. Key Results VLC5 was inhibited PAR₂ agonist or histamine‐induced calcium mobilization in mouse primary afferents, but did not modify calcium signals induced by high concentrations of KCl, TRPV1 or TRPV4 agonists. The effect of VLC5 on histamine‐induced calcium signal in primary afferent was inhibited by pertussis toxin pretreatment and was dependent on the activation of mu‐ or kappa‐opioid receptor agonists, as it was inhibited by selective antagonists of those two receptors, but not by selective antagonist of the delta‐opioid receptor. Intraperitoneal treatment of mice with VLC5 (10 mg kg^?1) significantly reduced visceral pain behaviors induced by the intracolonic administration of mustard oil, in an opioid receptor‐dependent manner. Conclusions & Inferences We have demonstrated significant analgesic properties for the algal metabolite VLC5, which is able to signal directly to primary afferents, through a mechanism dependent on the activation of opioid receptors. This identifies a new natural compound capable of activating peripheral opioidergic systems, exerting analgesic properties.     

Sensation evoked by esophageal distension in functional chest pain patients depends on mechanical stress rather than on ischemia

Background Functional chest pain is commonly reproduced by bag distension in the esophageal body. It is unknown whether such pain is primarily associated with mechanical stress and strain (force‐deformation) or with changes in mucosal perfusion. Methods Fourteen patients (6M, 8F, average age 55.9 years) underwent ramp bag distension before and after injection of 20 mg butylscopolamine bromide (BS) using a novel bag catheter incorporating endosonography and laser Doppler perfusion monitoring. Healthy subjects served as controls. Mucosal perfusion was evaluated and stress and strain were computed and related to the sensation. Key Results The symptom score increased with bag volume (P < 0.001). Volume as a function of pressure was higher in patients than in controls (P < 0.001), both before and during BS. The stress–strain relationship was exponential and indicated a stiffer esophageal wall in patients especially before BS (P < 0.01). The stress–strain curves indicate increased muscle tone in the functional chest pain patients. The perfusion decreased with increasing symptom score from visual analog scale 1–7 during BS. The decrease was on average 18.9% in patients and 19.7% in controls (P = ns). Multiple regression analysis from distensions during BS showed that the discomfort/pain sensations depended on stress and strain (P < 0.001) and with stress as the largest contributor. Perfusion did not contribute. Conclusions & Inferences Pain evoked by bag distension in patients with functional chest pain is stress‐dependent rather than dependent on mucosal perfusion. Furthermore, the esophagus of the patients was characterized by more pronounced muscle tone during the distensions.     

A placebo-controlled trial of an oral capsaicin load in patients with functional dyspepsia

Background The pathophysiology of functional dyspepsia is poorly understood. Visceral hypersensitivity may play a key role. We studied a previously validated test to assess chemical hypersensitivity in functional dyspepsia by applying an oral capsaicin load. Methods A total of 116 outpatients with upper gastrointestinal (GI) symptoms participated in this double‐blind, placebo‐controlled trial of which 73 patients received a final diagnosis of functional dyspepsia. Patients swallowed a capsule containing 0.75 mg capsaicin or placebo. A graded questionnaire evaluated the severity of nine upper GI symptoms before and after capsule ingestion and an aggregate symptom score was calculated. A final score of >9 was considered as a positive test. Key Results In functional dyspepsia, median perception scores were 10.8 (interquartile range: 4.5–18.8) after ingestion of capsaicin and 0.5 (0.0–2.5) after placebo (P < 0.001). Thirty‐seven functional dyspepsia patients (54%) had a positive test after capsaicin ingestion, whereas only four (11%) patients with upper GI symptoms but without functional dyspepsia were capsaicin positive [median perception score: 1.5 (0.0–5.0)]. After placebo, symptom scores were low and not significantly different among patient groups (P > 0.05). Clinical characteristics, age, and gender distribution was similar in capsaicin positive and capsaicin negative functional dyspepsia patients (P > 0.05). The value of patient blinding was good. Conclusions & Inferences Half of functional dyspepsia patients had chemical hypersensitivity, determined with an oral capsaicin load. Placebo response was negligible. The results of the capsaicin test were not associated with specific dyspepsia symptoms or Rome subgroups.     

Botulinum toxin injection in dysphagia syndromes with preserved esophageal peristalsis and incomplete lower esophageal sphincter relaxation

Background Botulinum toxin injection into the lower esophageal sphincter (LES) treats dysphagia syndromes with preserved peristalsis and incomplete LES relaxation (LESR). We evaluated clinical and esophageal motor characteristics predicting response, and compared duration of efficacy to similarly treated achalasia patients. Methods Thirty‐six subjects (59 ± 2.2 years, 19F/17M) with incomplete LESR on high resolution manometry (HRM) treated with botulinum toxin injection were identified. Individual and composite symptom indices were calculated, and HRM characteristics extracted. Symptom resolution for 6 months was a primary outcome measure, and repeat botulinum toxin injection, dysphagia recurrence or employment of alternate therapeutic approaches were secondary outcome measures. Duration of response was compared using Kaplan‐Meier survival curves to a historical cohort of similarly treated achalasia subjects. Key Results Response lasted a mean of 12.8 ± 2.3 months. Symptom relief for >6 months was seen in 58.3%; short (<6 months) response was associated with younger age, higher chest pain index, and esophageal body spastic features (P ≤ 0.04). On multivariate logistic regression, chest pain, younger age and contraction amplitudes >180 mmHg independently predicted <6 months relief (P < 0.05 for each). On survival analysis, relief with a single injection extended to 1 year in 54.8% and 1.5 years in 49.8%, statistically equivalent to that reported by 42 similarly treated achalasia subjects (59 ± 3.2 years, 24F/18M). Symptom relief was more prolonged compared to achalasia when repeat injections were performed on demand (P = 0.003). Conclusions & Inferences Botulinum toxin injections can provide lasting symptom relief in dysphagia syndromes with incomplete LESR. Prominent perceptive symptoms and non‐specific spastic features may predict shorter relief.     

Subdiaphragmatic vagal afferent innervation in activation of an opioidergic antinociceptive system in response to colorectal distension in rats.

Abstract In a number of different experimental paradigms of somatic pain, there is evidence for a vagally mediated antinociceptive system. This pathway probably involves opioid mechanisms. However, whether this pathway is activated in visceral pain or if it involves subdiaphragmatic vagal afferents is unclear. The aim of the present study was to determine whether subdiaphragmatic vagal afferents mediate antinociception in response to a visceral stimulus and whether this involves an opioid pathway. Colorectal distension was performed in fasted, conscious male Sprague-Dawley rats using a balloon catheter connected to an electronic distension device. The number of abdominal contractions (visceromotor response) in response to a tonic colorectal distension (60 mmHg for 10 min) was recorded. Experiments were performed in sham or subdiaphragmatically vagotomized, perineural vehicle- or capsaicin-treated rats (to functionally denervate vagal afferents) before and after administration of naloxone (25 mg kg(-1) bodyweight intraperitoneally). Vagotomy, capsaicin and naloxone pretreatments all significantly enhanced the visceromotor response to colorectal distension. The effect of naloxone in capsaicin-treated rats did not appear to be additive. These results suggest that activation of subdiaphragmatic afferents, which can be blocked by capsaicin, may play a role in opioid-dependent antinociceptive pathways activated by a noxious visceral stimulus.     

Luminal serotonin time‐dependently modulates vagal afferent driven antinociception in response to colorectal distention in rats

Background Compelling evidence shows that vagal afferents mediate antinociception in response to visceral insults. Our recent findings implied that luminal serotonin (5‐hydroxytryptamine, 5‐HT) might mediate chronic food allergen sensitized visceral hyperalgesia, in which vagal afferents might be implicated. Here, to test this hypothesis, we investigated the effects of luminal infused 5‐HT on visceral nociception and the involvement of vagal antinociceptive pathway. Methods The vagus‐intact or vagotomized rats were given acute intraluminally or intraperitoneally administered 5‐HT, or chronic luminal infusion of 5‐HT. The visceromotor response (VMR) to colorectal distension (CRD) was electrophysiologically recorded. Key Results Acute intraluminal infusion of 5‐HT (10 or 100 nmol) significantly attenuated VMR to CRD, while systemic administered 5‐HT at similar doses resulted in markedly augmented nociception. Pretreatment with luminal application of granisetron or lidocaine, or pharmacological depletion of endogenous 5‐HT with injection of p‐chlorophenylalanine, a 5‐HT synthesis inhibitor, and subdiaphragmatic vagotomy or functional deafferentation with capsaicin abolished the effect of luminal (but not systemic) 5‐HT. Chronic infusion of 5‐HT (10 nmol d^?1for 5 days) produced gradual augmentation of baseline VMR. And, the VMR to CRD after 5‐HT infusion decreased on day 1 and 2, then gradually increased from day 3. Surgical vagotomy or daily preperfusion with granisetron canceled these time‐dependent patterns. Conclusions & Inferences Luminal 5‐HT time‐dependently modulates vagal afferent driven antinociception. Acute infusion of 5‐HT attenuates visceral nociception via activation of vagal afferent 5‐HT type 3 receptors (5‐HT₃Rs)within intestinal mucosa; while chronic luminal 5‐HT caused gradually developed visceral hyperalgesia, which may also involve vagal 5‐HT₃Rs.     

Ghrelin augments afferent response to distension in rat isolated jejunum

Abstract Ghrelin has been shown to decrease firing of gastric vagal afferents at doses comparable with circulating levels in the fasted state. This raises the possibility that ghrelin may have a hormonal action on other vagal afferent populations. The aim of this study was to determine the effects of ghrelin on jejunal afferent activity; including responses to distension, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT) and cholecystokinin (CCK) in both naïve and vagotomized rats. Ghrelin significantly augmented the afferent response to distension. No effect was observed on baseline afferent discharge, or the response to 2‐methyl‐5‐HT and CCK. The effect of ghrelin was more pronounced at lower ramp distending pressures (0–30 mmHg). Similarly, ghrelin augmented the jejunal afferent responses to phasic distension at 10–30 mmHg, but had no effect at higher pressures. Chronic subdiaphragmatic vagotomy and administration of the growth hormone secretagogue receptor (GHS‐R) antagonist [d ‐Lys3]‐GHRP‐6 prevented the augmentation of the afferent responses to distension indicating ghrelin is acting through the GHS‐R on vagal afferent fibres. Ghrelin augments the mechanosensation of jejunal vagal afferents and hence may lead to increased perception of hunger contractions.