Opioid-Induced Foregut Dysfunction.

The impact of opioid use on the lower gastrointestinal tract is well described, but recent opioid crisis has caused increased awareness of the detrimental effects of these drugs on esophageal and gastroduodenal motility. Opioid use has been associated with increased incidence of spastic esophageal motility disorders and gastroduodenal dysfunction. Opioid receptors are present with high abundance in the myenteric and submucosal plexus of the enteric nervous system. Activation of these receptors leads to suppressed excitability of the inhibitory musculomotor neurons and unchecked tonic contraction of the autogenic musculature (such as the lower esophageal sphincter and the pylorus).

Ameliorating Effects of Transcutaneous Electrical Acustimulation Combined With Deep Breathing Training on Refractory Gastroesophageal Reflux Disease Mediated via the Autonomic Pathway.

AIMS: To investigate the effects and possible mechanisms of transcutaneous electrical acustimulation (TEA) combined with deep breathing training (DBT) on refractory gastroesophageal reflux disease (rGERD). METHODS: Twenty-one patients with rGERD were recruited and randomly assigned to receive either only esomeprazole (ESO, 20 mg bid) (group A, n = 7), TEA + DBT + ESO (group B, n = 7), or sham-TEA + DBT + ESO (group C, n = 7) in a four-week study. The reflux diagnostic questionnaire (RDQ) score and heart rate variability (HRV) were recorded and evaluated at baseline and at the end of each treatment. Blood samples were collected for the measurement of serum acetylcholine (Ach) and nitric oxide (NO). Esophageal manometry and 24-hour pH monitoring were performed before and after the treatment. RESULTS: After treatment, 1) the participants in group B had significantly lower scores of RDQ and DeMeester and increased lower esophageal sphincter pressure (LESP) than those in group C (all p < 0.05), suggesting the role of TEA; 2) low frequency band (LF)/(LF + HF) ratio in groups B and C was decreased, compared with group A (p = 0.010, p = 0.042, respectively); high frequency band (HF)/(LF + HF) ratio in B and C groups was significantly increased, compared with group A (p = 0.010, p = 0.042, respectively); 3) The serum Ach in groups B and C was significantly higher than group A (p = 0.022, p = 0.046, respectively); the serum NO in groups B and C was significantly lower than group A (p = 0.010, p = 0.027, respectively). CONCLUSIONS: TEA combined with the DBT can effectively improve the reflux symptoms in rGERD patients by increasing LESP and reducing gastroesophageal reflux, which may be mediated via the autonomic and enteric mechanisms.

Management of Gastroesophageal Reflux Disease.

Management of gastroesophageal reflux disease (GERD) commonly starts with an empiric trial of proton pump inhibitor (PPI) therapy and complementary lifestyle measures, for patients without alarm symptoms. Optimization of therapy (improving compliance and timing of PPI doses), or increasing PPI dosage to twice daily in select circumstances, can reduce persistent symptoms. Patients with continued symptoms can be evaluated with endoscopy and tests of esophageal physiology, to better determine their disease phenotype and optimize treatment. Laparoscopic fundoplication, magnetic sphincter augmentation, and endoscopic therapies can benefit patients with well-characterized GERD. Patients with functional diseases that overlap with or mimic GERD can also be treated with neuromodulators (primarily antidepressants), or psychological interventions (psychotherapy, hypnotherapy, cognitive and behavioral therapy). Future approaches to treatment of GERD include potassium-competitive acid blockers, reflux-reducing agents, bile acid binders, injection of inert substances into the esophagogastric junction, and electrical stimulation of the lower esophageal sphincter.

Pathophysiology of Gastroesophageal Reflux Disease.

The pathogenesis of gastroesophageal reflux disease (GERD) is complex and involves changes in reflux exposure, epithelial resistance, and visceral sensitivity. The gastric refluxate is a noxious material that injures the esophagus and elicits symptoms. Esophageal exposure to gastric refluxate is the primary determinant of disease severity. This exposure arises via compromise of the anti-reflux barrier and reduced ability of the esophagus to clear and buffer the refluxate, leading to reflux disease. However, complications and symptoms also occur in the context of normal reflux burden, when there is either poor epithelial resistance or increased visceral sensitivity. Reflux therefore develops via alterations in the balance of aggressive and defensive forces.

Achalasia: new perspectives on an old disease.

Achalasia is defined by esophageal outflow obstruction from abnormal relaxation of the lower esophageal sphincter (LES) due to deranged inhibitory control. In genetically predisposed individuals, an autoimmune response to an unknown inciting agent, perhaps a viral infection, results in inflammation and sometimes loss of myenteric plexus ganglia and neurons. The net result is varying degrees of inhibitory dysfunction, at times associated with imbalanced and exaggerated excitatory function, with manometrically distinct achalasia phenotypes on high resolution manometry. There is new evidence in the current issue of this Journal suggesting that type 1 achalasia, with esophageal outflow obstruction and absent esophageal body contractility, is an end-stage phenotype from progression of type 2 achalasia, which is characterized by panesophageal compartmentalization of pressure in the untreated patient, and partial recovery of peristalsis after treatment. Esophageal outflow obstruction with premature peristalsis (type 3 achalasia) or intact peristalsis may result from plexitis in the myenteric plexus but can also be encountered in other settings including chronic opioid medication usage and structural processes at the esophagogastric junction and distally. In most instances when idiopathic esophageal outflow obstruction is confirmed, some form of pharmacologic manipulation or disruption of the LES provides durable symptom relief. This review will focus on current understanding of pathophysiology, diagnosis, and principles of management of achalasia in light of emerging literature on the topic.

Gestational and postnatal modulation of esophageal sphincter reflexes in human premature neonates.

BACKGROUND: Effects of gestational age (GA) and postnatal maturation on upper and lower esophageal sphincter (UES and LES) reflex development remain unclear. We hypothesized very-preterm (VPT) born neonates (< 32 wk GA) have delayed maturation of UES contractile reflex (UESCR) and LES relaxation reflex (LESRR) vs. preterm (PT) born (32-37 wk GA) neonates. METHODS: Using provocative manometry, effects of 1,263 graded mid-esophageal stimuli (air, liquid) on sensory-motor characteristics of UESCR and LESRR were investigated in 24 VPT-born and 12 PT-born neonates (37.8 ± 0.6 vs. 38.9 ± 0.4 wk postmenstrual age respectively, P = 0.14). RESULTS: In response to liquid stimuli (vs. air), VPT-born neonates displayed prolonged UESCR and LESRR response latencies (P < 0.001) and prolonged UESCR and LESRR durations (P < 0.01); unlike PT-born neonates, who exhibit prolonged LESRR response latency (P < 0.01), but similar UESCR and LESRR durations (P = 0.2). Differences were noted in LESRR duration in VPT vs. PT neonates for air stimuli (P = 0.04). With liquid stimuli, increasing GA was associated with decreasing response onset latencies to UESCR and LESRR (P < 0.05), and increasing LESRR duration (P = 0.02). CONCLUSION: Using GA as categorical or continuous variable, vagus-mediated mechano-sensitive and liquid-sensitive reflex characteristics of UESCR and LESRR are distinct; LESRR differs with varying intrauterine maturation suggesting inhibitory modulation progresses with advancing maturation.

Circular and longitudinal muscles shortening indicates sliding patterns during peristalsis and transient lower esophageal sphincter relaxation.

Esophageal axial shortening is caused by longitudinal muscle (LM) contraction, but circular muscle (CM) may also contribute to axial shortening because of its spiral morphology. The goal of our study was to show patterns of contraction of CM and LM layers during peristalsis and transient lower esophageal sphincter (LES) relaxation (TLESR). In rats, esophageal and LES morphology was assessed by histology and immunohistochemistry, and function with the use of piezo-electric crystals and manometry. Electrical stimulation of the vagus nerve was used to induce esophageal contractions. In 18 healthy subjects, manometry and high frequency intraluminal ultrasound imaging during swallow-induced esophageal contractions and TLESR were evaluated. CM and LM thicknesses were measured (40 swallows and 30 TLESRs) as markers of axial shortening, before and at peak contraction, as well as during TLESRs. Animal studies revealed muscular connections between the LM and CM layers of the LES but not in the esophagus. During vagal stimulated esophageal contraction there was relative movement between the LM and CM. Human studies show that LM-to-CM (LM/CM) thickness ratio at baseline was 1. At the peak of swallow-induced contraction LM/CM ratio decreased significantly (<1), whereas the reverse was the case during TLESR (>2). The pattern of contraction of CM and LM suggests sliding of the two muscles. Furthermore, the sliding patterns are in the opposite direction during peristalsis and TLESR.

Pantoprazole decreases gastroesophageal muscle tone in newborn rats via rho-kinase inhibition.

Proton pump inhibitors reduce gastric acid secretion and are commonly utilized in the management of gastroesophageal reflux disease across all ages. Yet a decrease in lower esophageal sphincter tone has been reported in vitro in rats through an unknown mechanism; however, their effect on the gastroesophageal muscle tone early in life was never studied. Hypothesizing that proton pump inhibitors also reduce gastroesophageal muscle contraction in newborn and juvenile rats, we evaluated the in vitro effect of pantoprazole on gastric and lower esophageal sphincter muscle tissue. Electrical field stimulation and carbachol-induced force were significantly (P < 0.01) reduced in the presence of pantoprazole, whereas the drug had no effect on the neuromuscular-dependent relaxation. When administered in vivo, pantoprazole (9 mg/kg) significantly (P < 0.01) reduced gastric emptying time at both ages. To ascertain the signal transduction pathway responsible for the reduction in muscle contraction, we evaluated the tissue ROCK-2 and CPI-17 activity. Pantoprazole reduced myosin light chain phosphatase MYPT-1, but not CPI-17 phosphorylation of gastric and lower esophageal sphincter tissue, strongly suggesting that it is a ROCK-2 inhibitor. To the extent that these findings can be extrapolated to human neonates, the use of pantoprazole may impair gastric and lower sphincter muscle tone and thus paradoxically exacerbate esophageal reflux. Further studies addressing the effect of proton pump inhibitors on gastroesophageal muscle contraction are warranted to justify its therapeutic use in gastroesophageal reflux disease.

Gastric and lower esophageal sphincter pressures during nausea: a study using visual motion-induced nausea and high-resolution manometry.

Nausea is the subjective unpleasant sensation that immediately precedes vomiting. Studies using barostats suggest that gastric fundus and lower esophageal sphincter (LES) relaxation precede vomiting. Unlike barostat, high-resolution manometry allows less invasive, detailed measurements of fundus pressure (FP) and axial movement of the gastroesophageal junction (GEJ). Nausea was induced in 12 healthy volunteers by a motion video and rated on a visual analog scale. FP was measured as the mean value of the five pressure channels that were clearly positioned below the LES. After intubation, a baseline (BL) recording of 15 min was obtained. This was followed by presentation of the motion video (at least 10 min, maximum 20 min) followed by 30 min recovery recording. Throughout the experiment we recorded autonomic nervous system (ANS) parameters [blood pressure, heart rate (HR), and cardiac vagal tone (CVT), which reflects efferent vagal activity]. Ten out of 12 subjects showed a drop in FP during peak nausea compared with BL (-4.0 ± 0.8 mmHg; P = 0.005), and 8/10 subjects showed a drop in LES pressure (-8.8 ± 2.5 mmHg; P = 0.04). Peak nausea preceded peak fundus and LES pressure drop. Nausea was associated with configuration changes at the GEJ such as LES shortening and esophageal lengthening. During nausea we observed a significantly increased HR and decreased CVT. In conclusion, nausea is associated with a drop in fundus and LES pressure, configuration changes at the GEJ as well as changes in the ANS activity such as an increased sympathetic tone (increased HR) and decreased parasympathetic tone (decreased CVT).

Morphological demonstration of a vagal inhibitory pathway to the lower esophageal sphincter via nitrergic neurons in the rat esophagus.

BACKGROUND: The involvement of vagal parasympathetic efferents in esophageal myenteric neurons in vagal inhibitory pathways to the lower esophageal sphincter (LES) is not clear. Thus, this study was performed to demonstrate morphologically the presence of vagal inhibitory pathways to the LES via esophageal neurons. METHODS: Fast Blue (FB) was injected into the LES of Wistar rats, and 3 days after injection, the animals were subjected to electrical stimulation of the vagus nerve. The esophagus was processed for immunohistochemistry for Fos that was an immediate-early gene as a marker of neuronal activity, nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP) and choline acetyltransferase (ChAT). The immunoreactivities were then compared with the FB labeling in esophageal neurons. KEY RESULTS: Fast Blue-labeled neurons were observed within an esophageal area of 30 mm oral to the LES, with the highest frequency in the esophagus just above the LES. Most of the FB-labeled neurons were positive for NOS and VIP, but a few for ChAT. Following vagal-electrical stimulation, one fourth of the FB-labeled neurons presented nuclei expressing Fos and most of these Fos/FB neurons were NOS-positive. CONCLUSIONS & INFERENCES: A majority of the FB-labeled esophageal neurons appeared to be descending motor neurons innervating the LES. Moreover, the colocalization of VIP and NOS in most of the LES-projecting neurons suggests that VIP and NO released from these neurons induce LES relaxation, and the innervation of the vagal efferents to the LES-projecting esophageal neurons in the distal esophagus implies a vagal inhibitory pathway responsible for LES relaxation.

Vagal afferent innervation of the lower esophageal sphincter.

To supply a fuller morphological characterization of the vagal afferents innervating the lower esophageal sphincter (LES), specifically to label vagal terminals in the tissues forming the LES in the gastroesophageal junction, the present experiment employed injections of dextran biotin into the nodose ganglia of rats. Four types of vagal afferents innervated the LES. Clasp and sling muscle fibers were directly and prominently innervated by intramuscular arrays (IMAs). Individual IMA terminals subtended about 16° of arc of the esophageal circumference, and, collectively, the terminal fields were distributed within the muscle ring to establish a 360° annulus of mechanoreceptors in the sphincter wall. 3D morphometry of the terminals established that, compared to sling muscle IMAs, clasp muscle IMAs had more extensive arbors and larger receptive fields. In addition, at the cardia, local myenteric ganglia between smooth muscle sheets and striated muscle bundles were innervated by intraganglionic laminar endings (IGLEs), in a pattern similar to the innervation of the myenteric plexus throughout the stomach and esophagus. Finally, as previously described, the principle bundle of sling muscle fibers that links LES sphincter tissue to the antropyloric region of the lesser curvature was innervated by exceptionally long IMAs as well as by unique web ending specializations at the distal attachment of the bundle. Overall, the specialized varieties of densely distributed vagal afferents innervating the LES underscore the conclusion that these sensory projections are critically involved in generating LES reflexes and may be promising targets for managing esophageal dysfunctions.

Circulating antimyenteric autoantibodies in Tunisian patients with idiopathic achalasia.

The physiopathology of idiopathic achalasia is still unknown. The description of circulating antimyenteric autoantibodies (CAA), directed against enteric neurons in sera of patients, suggests an autoimmune process. Recent data showed controversies according to the existence and the significance of CAA. The aims of this study were to investigate whether CAA are detected in Tunisian patients with idiopathic achalasia and to look for associated clinical or manometrical factors with CAA positivity. Twenty-seven patients with idiopathic achalasia and 57 healthy controls were prospectively studied. CAA were assessed by indirect immunofluorescence on intestinal monkey tissue sections. Western blot on primate cerebellum protein extract and dot technique with highly purified recombinant neuronal antigens (Hu, Ri, and Yo) were further used to analyze target antigens of CAA. CAA were significantly increased in achalasia patients compared with controls when considering nuclear or cytoplasmic fluorescence patterns. (33% vs. 12%, P = 0.03 and 48% vs. 23%, P = 0.001 respectively). By immunoblot analysis, CAA did not target neuronal antigens, however 52/53 and 49 kDa bands were consistently detected. CAA positivity was not correlated to specific clinical features. The results are along with previous studies demonstrating high CAA prevalence in achalasia patients. When reviewing technical protocols and interpretation criteria, several discrepancies which could explain controversies between studies were noted.

Physical therapy management of entrapment of the superficial peroneal nerve in the lower leg: a case report.

This case report describes a 40-year-old male who presented with complaints of pain in the left lower lateral one-third of the leg. Tenderness was elicited 9.7 cm above the lateral malleoli with a positive Tinel's sign at the same site causing radiating pain into the foot (visual analog scale (VAS) score of 6.3 cm). Physical diagnosis for entrapment of the superficial peroneal nerve at the site of the peroneal tunnel was entertained based on clinical examination and three positive provocation tests. Conventionally, treatment for this type of entrapment has been surgical decompression by splitting the crural fascia, with successful outcomes. This is potentially a first-time report describing physical therapy management of entrapment mechanical interface with pain modalities, soft tissue mobilization, and neural mobilization. Reduction of pain was noted in this patient (VAS score of 0 cm by the sixth session) with complete pain resolution maintained at a six-month follow-up.

Physiology of the LES.

The purpose of this review is to consider the neuromuscular mechanism of LES contractility both by itself and in relation to the esophagogastric junction (EGJ) complex in order to appreciate the intricacies of EGJ valvular function.

Variability in the muscle composition of rat esophagus and neural pathway of lower esophageal sphincter relaxation.

Several studies from our laboratory show that axial stretch of the lower esophageal sphincter (LES) in an oral direction causes neurally mediated LES relaxation. Under physiological conditions, axial stretch of the LES is caused by longitudinal muscle contraction (LMC) of the esophagus. Because longitudinal muscle is composed of skeletal muscle in mice, vagal-induced LMC and LES relaxation are both blocked by pancuronium. We conducted studies in rats (thought to have skeletal muscle esophagus) to determine if vagus nerve-mediated LES relaxation is also blocked by pancuronium. LMC-mediated axial stretch on the LES was monitored using piezoelectric crystals. LES and esophageal pressures were monitored with a 2.5-Fr solid-state pressure transducer catheter. Following bilateral cervical vagotomy, the vagus nerve was stimulated electrically. LES, along with the esophagus, was harvested after in vivo experiments and immunostained for smooth muscle (smooth muscle α-actin) and skeletal muscle (fast myosin heavy chain). Vagus nerve-stimulated LES relaxation and esophageal LMC were reduced in a dose-dependent fashion and completely abolished by pancuronium (96 µg/kg) in six rats (group 1). On the other hand, in seven rats, LES relaxation and LMC were only blocked completely by a combination of pancuronium (group 2) and hexamethonium. Immunostaining revealed that the longitudinal muscle layer was composed of predominantly skeletal muscle in the group 1 rats. On the other hand, the longitudinal muscle layer of group 2 rats contained a significant amount of smooth muscle (P < 0.05). Our study shows tight coupling between axial stretch on the LES and relaxation of the LES, which suggests a cause and effect relationship between the two. We propose that the vagus nerve fibers that cause LMC induce LES relaxation through the stretch-sensitive activation of inhibitory motor neurons.

Evidence for altered circular smooth muscle cell function in lower esophageal sphincter of W/Wv mutant mice.

Nitrergic neurotransmission to gut smooth muscle is impaired in W/W(v) mutant mice, which lack intramuscular interstitial cells of Cajal (ICC-IM). In addition, these mice have been reported to have smaller amplitude unitary potentials (UPs) and a more negative resting membrane potential (RMP) than control mice. These abnormalities have been attributed to absence of ICC-IM, but it remains possible that they are due to alterations at the level of the smooth muscle itself. Amphotericin-B-perforated patch-clamp recordings and Ca(2+) imaging (fura 2) were compared between freshly isolated single circular smooth muscle cells (CSM) from W/W(v) mutant and control mice lower esophageal sphincter (LES). There was no significant difference in seal resistance, capacitance, or input resistance in response to applied electrotonic current pulses between CSM cells from W/W(v) mutants and controls. Compared with control mice, RMP was more negative and UPs significantly smaller in CSM cells from mutant mice LES. Administration of caffeine induced an inward current in cells from both mutant and control mice, but the current density was significantly larger in cells from W/W(v) mutants. Membrane potential hyperpolarization induced by sodium nitroprusside was larger in cells from control mice vs. W/W(v) mutants. In addition, intracellular Ca(2+) transients induced by caffeine were significantly increased in cells from mutants. These findings indicate that LES CSM is abnormal in W/W(v) mutant mice. Thus some physiological functions attributed to ICC-IM based on experiments in smooth muscle of ICC deficient mice may need to be reconsidered.

[The efficiency of structural resonance electromagnetotherapy for the treatment of patients with gastroesophageal reflux disease].

The results of application of structural resonance electromagnetotherapy (SRT) for the treatment of patients presenting with gastroesophageal reflux disease (GERD) are presented. They show that SRT has positive influence on the neurohumoral regulation of the lower oesophageal sphincter, ensures psychocorrection, and optimizes the vegetative regulation. Taken together, these effects result in the marked clinical improvement in patients presenting with GERD. It is concluded that structural resonance electromagnetotherapy can be recommended as an efficacious and pathogenetically sound method for the treatment of patients with gastroesophageal reflux disease.

Effects of acetylcholine on sling and clasp fibers of the human lower esophageal sphincter.

BACKGROUND AND AIM: Manometric studies on the human lower esophageal sphincter (LES) have shown radial asymmetry of the high-pressure zone (HPZ). The aim of this study was to compare the functional properties of human LES clasp and sling muscles, and to look at their relationship with the expression of muscarinic receptors and intracellular Ca(2+) concentration. METHODS: Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing subtotal esophagectomy. Isometric tension responses of the strips to acetylcholine were studied. Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the expression of five subtypes of muscarinic receptors. Intracellular Ca(2+) ([Ca(2+) ]i) was measured using laser scanning confocal microscopy. RESULTS: Acetylcholine caused a concentration-dependent increase in the tension of sling and clasp strips, the sling strip being stronger than clasp (P=0.00). Messenger RNA and protein for the five muscarinic acetylcholine receptor (mAChRs) expressed in the sling and clasp muscles were highest for M2, and then in decreasing levels: M(3)>M(1)>M(4)>M(5) . Acetylcholine caused significant elevation of [Ca(2+) ]i in sling and clasp muscle cells in the presence of extracellular Ca2+ (1.5mmol/L), and Ach-induced [Ca(2+) ]i elevation was 1.6 times greater in sling cells than in clasp cells. CONCLUSION: Variation of intracellular concentrations of Ca(2+) may be the reason for differential responses to acetylcholine for sling versus clasp fibers. However, these differences are not associated with the distribution and the level of expression of the five mAChRs between the two muscle types. Further study should focus on the ligand affinity and signal transduction pathway.