Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017168 (gastroesophageal reflux disease)
11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vagal afferents are extensively distributed in the digestive tract from the oesophagus to the colon. They are involved in the reflex control of normal gastrointestinal (GI) tract function (e.g. secretion and motility) as well as reflexes more characteristic of diseases such as functional dyspepsia and gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal sphincter relaxation and gastric accommodation). They are also implicated in signalling non-painful sensations (e.g. nausea and early satiety) associated with disease. A variety of receptors has been identified on vagal afferents, which can either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin, leptin, k-opioid and GABAB receptors) activity, offering a range of potential therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack an emetic reflex, and the implications of this for models of upper GI disorders have been explored in the light of expanding knowledge of the neuropharmacology of the emetic reflex implicating glutamate, prostanoids, cannabinoids and substance P. Additional pathophysiological roles for vagal afferents (e.g. in thermoregulation, arousal and fatigue) are being investigated, raising the intriguing possibility of the vagus as a target in non-GI disorders.
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PMID:Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. 1248 26

Transient lower esophageal sphincter relaxation is the major mechanism for gastroesophageal reflux. The present study was initiated to investigate the potential effect of the metabotropic glutamate 5 (mGlu5) receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on transient lower esophageal sphincter relaxations in the conscious dog. MPEP (1.4-8.7 micromol/kg i.v.) produced a dose-dependent inhibition of transient lower esophageal sphincter relaxations (59+/-11% inhibition at 8.7 micromol/kg). In addition, there was a reduction of the number of reflux episodes and an increase in latency time to the occurrence of the first transient lower esophageal sphincter relaxation. No effect was seen on basal lower esophageal sphincter pressure or on swallowing. It is concluded that the mGlu5 receptor antagonist MPEP potently inhibits transient lower esophageal sphincter relaxations and that the mGlu5 receptor is a potential target for treatment of gastroesophageal reflux disease.
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PMID:Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist. 1610 47

Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.
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PMID:Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications. 1617 34

Understanding the innervation of the esophagus is a prerequisite for successful treatment of a variety of disorders, e.g., dysphagia, achalasia, gastroesophageal reflux disease (GERD) and non-cardiac chest pain. Although, at first glance, functions of the esophagus are relatively simple, their neuronal control is considerably complex. Vagal motor neurons of the nucleus ambiguus and preganglionic neurons of the dorsal motor nucleus innervate striated and smooth muscle, respectively. Myenteric neurons represent the interface between the dorsal motor nucleus and smooth muscle but they are also involved in striated muscle innervation. Intraganglionic laminar endings (IGLEs) represent mechanosensory vagal afferent terminals. They also establish intricate connections with enteric neurons. Afferent information is implemented by the swallowing central pattern generator in the brainstem, which generates and coordinates deglutitive activity in both striated and smooth esophageal muscle and orchestrates esophageal sphincters as well as gastric adaptive relaxation. Disturbed excitation/inhibition balance in the lower esophageal sphincter results in motility disorders, e.g., achalasia and GERD. Loss of mechanosensory afferents disrupts adaptation of deglutitive motor programs to bolus variables, eventually leading to megaesophagus. Both spinal and vagal afferents appear to contribute to painful sensations, e.g., non-cardiac chest pain. Extrinsic and intrinsic neurons may be involved in intramural reflexes using acetylcholine, nitric oxide, substance P, CGRP and glutamate as main transmitters. In addition, other molecules, e.g., ATP, GABA and probably also inflammatory cytokines, may modulate these neuronal functions.
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PMID:Innervation of the mammalian esophagus. 1657 41

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
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PMID:Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5. 1705 58

Metabotropic glutamate receptors (mGluR) are classified into groups I (excitatory), II and III (inhibitory) mGluR. Activation of peripheral group III mGluR (mGluR4, mGluR6, mGluR7, mGluR8), particularly mGluR8, inhibits vagal afferent mechanosensitivity in vitro which translates into reduced triggering of transient lower oesophageal sphincter relaxations and gastroesophageal reflux in vivo. However, the expression and function of group III mGluR in central gastrointestinal vagal reflex pathways is not known. Here we assessed the expression of group III mGluR in identified gastric vagal afferents in the nodose ganglion (NG) and in the dorsal medulla. We also determined the central action of the mGluR8a agonist S-3,4-DCPG (DCPG) on nucleus tractus solitarius (NTS) neurons with gastric mechanosensory input in vivo. Labelling for mGluR4 and mGluR8 was abundant in gastric vagal afferents in the NG, at their termination site in the NTS (subnucleus gelatinosus) and in gastric vagal motorneurons, while labelling for mGluR6 and mGluR7 was weaker in these regions. DCPG (0.1 nmol or 0.001-10 nmol i.c.v.) inhibited or markedly attenuated responses of 8/10 NTS neurons excited by isobaric gastric distension with no effect on blood pressure or respiration; 2 NTS neurons were unaffected. The effects of DCPG were significantly reversed by the group III mGluR antagonist MAP4 (10 nmol, i.c.v.). In contrast, 4/4 NTS neurons inhibited by gastric distension were unaffected by DCPG. We conclude that group III mGluR are expressed in peripheral and central vagal pathways, and that mGluR8 within the NTS selectively reduce excitatory transmission along gastric vagal pathways.
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PMID:Anatomy and function of group III metabotropic glutamate receptors in gastric vagal pathways. 1837 91

Gastro-oesophageal reflux disease (GORD) is caused by disordered control of the gastro-oesophageal reflux barrier, comprised internally of the lower oesophageal sphincter (LOS) and externally the crural diaphragm (CD). Both relax briefly to allow bolus passage during oesophageal peristalsis. Brief relaxation also occurs prior to gastro-oesophageal reflux, known as transient LOS relaxation (TLOSR), normally allowing venting of gas. TLOSRs also account for up to 90% of acid reflux episodes. The development of GORD therefore depends upon the rate of TLOSR and the physical and chemical nature of refluxate. We established an animal model of reflux in ferrets, in which similar patterns of TLOSR are seen to humans. TLOSRs are mediated via a vago-vagal pathway initiated by tension receptors in the gastric musculature. They have central terminals in the brainstem which provide input to a central program generator. The program has 3 simultaneous outputs: 1. brief activation of vagal motor neurones to the LOS, which activate inhibitory enteric motorneurones, leading to smooth muscle relaxation: 2. suppression of oesophageal peristalsis: 3. suppression of motor output to the CD. We have investigated several aspects of the TLOSR pathway in ferrets, and determined that the optimal site for therapeutic pharmacological intervention is at gastric vagal tension receptor endings. Their responses to distension are potently inhibited by gamma-aminobutyric acid type B (GABAB) receptor agonists and metabotropic glutamate type 5 receptor (mGluR5) antagonists. These effects translate to inhibition of TLOSR and reflux in animal models and humans. Clinical studies indicate both types of drug may have potential in the treatment of GORD.
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PMID:New insights in the neural regulation of the lower oesophageal sphincter. 1892 42

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.
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PMID:Alterations in N-methyl-D-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats. 1897 10

Proton pump inhibitors are highly successful in treating gastroesophageal reflux disease, but a significant proportion of patients have persistent symptoms from weakly or nonacidic reflux. Transient lower esophageal sphincter relaxation (TLESR) represents the dominant mechanism of gastroesophageal reflux and has therefore become the most intensely investigated therapeutic target. The triggering of TLESR involve the vagal pathways and the gamma-aminobutyric type B (GABA(B)) and metabotropic glutamate type 5 (mGluR5) receptors. Baclofen is a GABA(B) receptor agonist that is effective in inhibiting TLESR and reducing the number of reflux episodes, but is associated with significant central nervous system (CNS) side effects. The newer GABA(B) agonists, such as AZD9343 and AZD3355, and mGluR5 antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), have been shown in small, randomized, controlled trials to have comparable efficacy to baclofen, but possibly a more favorable CNS side effect profile. Cannibinoid agonists, such as Delta(9)-THC, have also been demonstrated to reduce TLESRs and reflux events respectively. Macrolide antibiotics (eg, erythromycin) show early promise in a select group of patients with possible reflux associated post-lung transplant problems.
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PMID:Beyond acid suppression: new pharmacologic approaches for treatment of GERD. 2042 77

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson's disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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PMID:Metabotropic glutamate receptors: from the workbench to the bedside. 2103 82


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