Upper Gastrointestinal Sensitization And Symptom Generation
Second Medical Department “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
Abstract
Functional gastrointestinal disorders (FGIDs) are a highly prevalent group of heterogeneous disorders, and their diagnostic criteria are symptom-based, with the absence of anatomical and biochemical abnormalities of the gastrointestinal tract. Chronic visceral symptoms are common both in patients with an identifiable organic disease but also in FGID patients. Patients suffering from upper gastrointestinal functional disorders typically present with various symptoms such as early satiety, postprandial fullness, bloating, nausea, vomiting, and epigastric pain. Considering their increasing prevalence, difficulties in diagnosis, and low quality of life, FGIDs have become an emerging problem in gastroenterology. We aimed to provide an updated summary of pathways involved in visceral sensitization. We examined the recent literature searching for evidence of the most important studies about the mechanisms underlying gastrointestinal symptom generation and sensitization.
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Keywords: Functional Gastrointestinal Disorders, FGID, Brain-Gut Interaction, Sensitization, Visceral Hypersensitivity
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Keywords: ASICs - Acid-sensing ion channels, CHS - Cannabinoid hyperemesis syndrome, CNS - Central nervous system, CNVS - Chronic nausea vomiting syndrome, CVS - Cyclic vomiting syndrome, EPS- Epigastric pain syndrome, FGID - Functional gastrointestinal disorders, GNB3 - G-protein-coupled receptor in the brain-gut axis, HPA - Hypothalamic-pituitary-adrenal, NMDA N-methyl-D-aspartate receptor, PDS - Postprandial distress syndrome, PTSD - Posttraumatic stress disorder, TRPV1 - The transient receptor potential vanilloid 1.
Article notes
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Received 2019 Oct 3; Accepted 2019 Nov 20.
Introduction
The increasing burden of visceral symptoms has generated a growing interest of researchers and clinicians in studying the origins of FGID symptoms, especially visceral pain. The mechanisms involved in the perception of gastrointestinal pain and discomfort are complex. FGID patients typically present with various symptoms such as early satiety, postprandial fullness, bloating, nausea, vomiting, and epigastric pain. Considering their increasing prevalence, difficulties in diagnosis, and low quality of life, FGIDs have become an emerging problem in gastroenterology.
Some primary visceral afferent fibers have a significant efferent function, but their role in the physiology and pathophysiology of the viscera has not been widely studied [2]. The most evaluated function of visceral receptors is to convey information from the viscera to the central nervous system. Accordingly, the first conscious sensations that arise from the viscera are discomfort and pain [3]. The cell bodies of primary visceral afferent neurons are contained in the nodose ganglia (vagal afferents) and dorsal root ganglia (spinal afferents) [4].
The viscera receive a dual innervation from vagal and spinal primary afferent neurons. The central terminals of vagal sensory neurons are in the brain stem. A large part of the literature, however, suggests that most primary visceral afferents are contributing to altered sensations from the viscera in pathophysiological conditions [1-3]. The terminals (receptors) of primary visceral afferent neurons are located in the mucosa, muscularis, and serosa (mesentery) of hollow tubular organs [3]. Visceral receptors have no end organs or morphological specialization. Visceral afferent neuron terminals are placed to respond to luminal and local chemical stimuli and mechanical ones. These altered sensations are considered to represent visceral hyperalgesia [4-6].
Chronic visceral symptoms are common both in patients with an identifiable organic disease and also in those without structural or biochemical abnormalities.
In the last two decades, most experts believe that FGID with abdominal or chest pain may be a consequence of one or more mechanisms. Those mechanisms include abnormal motility, visceral hypersensitivity [7-12], microscopic inflammation [13], disorders of the brain-gut interaction [10, 14], psycho-social factors [15, 16], genetic susceptibility [17-19] and postinfectious, neuromuscular and neurotransmitter dysfunction [20-24].The Rome IV Criteria classified upper gastrointestinal functional disorders (table 1) in esophageal disorders (functional chest pain, functional heartburn, reflux hypersensitivity, globus, functional dysphagia) and gastric disorders (functional dyspepsia, belching disorders, nausea and vomiting disorders, rumination syndrome) [1].
| A. Esophageal Disorders | B. Gastroduodenal disorders |
|---|---|
| Functional chest pain | I. Functional dyspepsia |
| Functional heartburn | Postprandial distress syndrome(PDS) |
| Reflux hypersensitivity | Epigastric pain syndrome (EPS) |
| Globus | II. Belching disorders |
| Functional dysphagia | Excessive supragastric belching |
| Excessive gastric belching | |
| III. Nausea and vomiting disorders | |
| Chronic nausea vomiting syndrome(CNVS) | |
| Cyclic vomiting syndrome (CVS) | |
| Cannabinoid hyperemesis syndrome (CHS) | |
| Rumination Syndrome |
We examined journal entries in PubMed from 2009 to 2019, focused on sensitization, symptom generation and visceral hyperalgesia in upper gastrointestinal functional disorders, providing an updated summary of the pathways involved in visceral sensitization.
Keywords of the search were: functional disorder, gastrointestinal, FGID, Brain-Gut Axis, Sensitization, Visceral hypersensitivity. We included in this narrative review original papers, reviews and meta-analyses.
Symptoms and mechanism of production
Typically, patients that are suffering from upper gastrointestinal (GI) disorders present with various symptoms such as early satiety, postprandial fullness, bloating, nausea, vomiting, and epigastric pain (Figure 1) [25]. Upper GI disorders have become an emerging problem in gastroenterology considering their increasing prevalence, difficulties in diagnosis, and patients’ low quality of life.
Individuals with functional gastrointestinal disorders report having experienced psychological trauma (e.g., sexual and/or physical abuse or assault) more often than patients with organic gastrointestinal diseases or healthy individuals [26-28].
Multiple psychosocial and biological mechanisms have incriminated for the occurrence of FGID (Figure 2) in individuals exposed to interpersonal trauma. Traumatic events have their role in symptoms expression, enhancing reliance on maladaptive coping styles, and by triggering the onset of psychiatric conditions known to impact pain sensitivity.
The most frequent example is posttraumatic stress disorder (PTSD) or major depressive disorder [29]. Individuals exposed to trauma tend to exhibit heightened autonomic and hypothalamic-pituitary-adrenal (HPA) responses to physical and psychological stressors. The experience of psychological trauma may impact risk for FGIDs by altering corticolimbic pain modulation [30], as well as visceral and central sensitization [31].
Central GI sensitization
Some researchers observed heightened central sensitization in patients with FGIDs [32], which is characterized by increased responsiveness to painful stimuli resulting from alterations within the central nervous system (CNS) and represents one possible mechanism linking FGIDs and trauma.
Central sensitization can be indexed through a pattern of increased perceived pain intensity in response to repetitive stimulation administered at a constant intensity, termed temporal summation [33]. Based on current scientific research, some hypotheses have been proposed to explain the mechanism of visceral hypersensitivity:
- •peripheral sensitization represented by sensitization of GI afferent nerves,
- •central sensitization represented by sensitization of spinal cord dorsal horn neurons,
- •misinterpretation of non-noxious sensation as noxious due to hypervigilance
- •altered descending excitatory or inhibitory influences on the spinal cord nociceptive neurons [6].
In the periphery, inflammatory mediators activate and sensitize nociceptive afferent nerves by reducing their transduction thresholds and by inducing the expression and recruitment of hitherto silent nociceptors culminating in an increase in pain sensitivity at the site of injury known as primary hyperalgesia.
The main mechanisms underlying maladjusted sensitization include changes in peripheral neuroimmune interactions, nerve injury, peripheral inflammation, and dysfunctions of acid-sensing ion channels (ASICs), ATP-gated ion channels (P2X, P2Y) voltage-gated sodium channels (VGSC) [30-35]. Central mechanisms of sensitization are modulated by substance P, N-methyl-D-aspartate (NMDA) receptor, neurokinin B, PGE2, psychological factors, hypervigilance, and endogenous pain modulation [9, 10, 23]. Centrally, secondary hyperalgesia, defined as an increase in pain sensitivity in anatomically distinct sites, occurs at the level of the spinal dorsal horn.
Several neurotransmitters, such as N-methyl-d-aspartate [9], serotonin [22], and adenosine [23, 24], have been proposed as mediators for this symptom. Visceral hypersensitivity, either due to peripheral or central sensitization, has been postulated as a mechanism for functional gastrointestinal pain [8, 18].
Perifepheral sensitisation
Pain and gastrointestinal discomfort are the leading symptoms in the multitude of upper GI disorders. Generally, noxious stimuli are encoded by nociceptors located in the organs. When the nociceptor receives a noxious stimulus strong enough to cause a depolarization, an action potential is generated and transmitted along the first-order neuron to the dorsal horn of the spinal cord [34]. Most visceral nociceptors are nonspecific (polymodal) and respond to different mechanical, chemical, electrical, thermal, and ischemic stimuli [35]. Nerve fibers may respond to either phasic or tonic distension of the gut, and this has, to some degree, been confirmed in animal and human studies [36-41]. Some fibers, especially the mucosal fibers, are adapting to a given stimulus and give no response when the stimulus is maintained, whereas afferents in the muscular layers generally show less adaptation [38].
Potential mechanisms of dyspepsia that have been recently described include hypersensitivity to gastric distension, hypersensitivity to small intestinal fat, gut hormones, and hypersensitivity to acid.
The transient receptor potential vanilloid 1 (TRPV1) activation can be lowered by hydrogen ions and inflammatory mediators [42]. Acid-sensitive receptors in the gut consist mainly of three groups: TRPV1 (which is temperature, as well as acid-sensitive), acid-sensing ion channels (ASICs), and purine receptors [43]. All the afferent nerves projecting to the spinal cord terminate in the dorsal horn. From here, the stimulus transmits cephalad through the spinal cord pathways and synapses to the third-order neuron in the brain or brainstem [44].
There is a close interaction between GI afferents and those from the somatic, autonomic, and enteric nervous systems. The activity in the GI organs does not usually reach the higher brain centers, except for information due to the filling of the esophagus, stomach, and rectum. When the organs are potentially in danger, for example, due to diseases, symptoms such as discomfort and pain are sensed [45]. Furthermore, mechanisms involved in the occurrence of heartburn include esophageal hypersensitivity, peripheral or central sensitization, microscopic alteration of the esophageal mucosa, and dilated intercellular spaces. From the spinal cord, pain transmits to the brain through several distinct pathways but, most afferents travel in the spinothalamic tract to the thalamus and from the thalamus project to the insula, hypothalamus, and amygdala as well as to higher cortical levels such as cingulate and prefrontal cortices [44]. The anterior cingulate cortices and prefrontal cortices are a part of the medial pain system, which mediates the affective, emotional, and cognitive components of the pain experience [46]. Peripheral nociceptor sensitization underlies the hyperalgesia that develops around an injury site. Like in the cutaneous system, upper GI afferent fibers may become sensitized by endogenous chemicals, resulting in an increase in their responsiveness to a given stimulus and/or an increase in the spontaneous activity [47].
Various inflammatory mediators, including protons, prostaglandins, serotonin, and histamine, are released in case of local inflammation. This leads to increased afferent activity to the spinal cord and exacerbation of the pain [47].
Moreover, an upregulated expression of nociceptors such as sodium channels, TRPV1, ASICs, and purine receptors are seen during inflammation. As a consequence of all of these changes, the pain sensitivity at the site of inflammation is increased [48, 49].
Enhanced spinal input can activate intracellular signaling cascades within the spinal dorsal horn neurons. This results in increased synaptic efficacy and is known as central sensitization [50]. The input leads to the activation of the N-methyl-D-aspartic acid receptor and results in changes in the resting potential of the second-order neuron [44]. Blocking the N-methyl-D-aspartic acid receptor has been shown to prevent experimentally acid-induced central sensitization [51].
Discussion
The mechanisms involved in the perception of gastrointestinal pain and discomfort are complex. Apparently, visceral receptors have no end organs or morphological specialization.
Visceral afferent neuron terminals are placed to respond to luminal and local chemical stimuli and mechanical ones. These altered sensations are considered to represent visceral hyperalgesia.
Visceral hyperalgesia is a complex form of hypersensitivity involving complex mechanisms. Mechanisms involved in the occurrence of chest pain include gastroesophageal reflux, esophageal motility disorders, and esophageal hypersensitivity.
This phenomenon takes place between visceral organs that share their central afferent termination; that is why central sensitization plays an important role [51].
Besides changes at the spinal level, changes in the cortical processing of pain may be involved in these mechanisms [52]. Irritation of peripheral nerve trunks (neuritis) or direct damage (neuropathy) contributes with an altered input to the central nervous system. In animal models of somatic nerve mononeuropathy or neuritis, hyperalgesia is characteristically produced and is long-lasting [48-52]. Ligand and voltage-gated channels in sensory neurons may be altered subsequent to a nerve injury and thus contributes to the occurrence of pain. Candidate channels include voltage-gated sodium and calcium channels, acid-sensing and temperature-sensing ion channels, and ion channels gated by endogenous ligands such as serotonin or ATP [40-45].
Many ion channels have been cloned, opening the possibility of precise studying of molecular and pharmacological processes. A new promising research direction is represented by the genetic variation in GNB3 (G-protein-coupled receptor in the brain-gut axis) and ADRB2 (which is a mediator of the stress response) that can explain the abnormal effect and esophageal mucosal injury in patients with esophageal symptoms [53]. Current evidence for the relation between genetic, immunological, psychosocial, and infectious factors involved in the occurrence of FGID is insufficient because of the limited number of prospective studies with detailed analysis of patients and matched controls but also the limited data provided by experimental animal studies
Conclusions
FGIDs are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. Chronic visceral symptoms are common both in patients with an identifiable organic disease but also in those without structural or biochemical abnormalities. Visceral pain hypersensitivity induced by central sensitization results from increased central neuronal excitability.
Conflict of Interest
The authors confirm that there are no conflicts of interest.
References
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References
- 1.Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV. Gastroenterology. 2016;150:1262–1279. doi: 10.1053/j.gastro.2016.02.032.
- 2.Holzer P, Maggi CA. Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons. Neuroscience. 1998;86:389–398. doi: 10.1016/s0306-4522(98)00047-5.
- 3.Gebhart GF. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain. Am J Physiol Gastrointest Liver Physiol. 2000;278:G834–8. doi: 10.1152/ajpgi.2000.278.6.G834.
- 4.Farmer AD, Aziz Q. Visceral pain hypersensitivity in functional gastrointestinal disorders. British Medical Bulletin. 2009;91:123–136. doi: 10.1093/bmb/ldp026.
- 5.Mayer EM, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271–293. doi: 10.1016/0016-5085(94)90086-8.
- 6.Anand P, Aziz Q, Willert R, van Oudenhove L. Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil. 2007;19(1 Suppl):29–46. doi: 10.1111/j.1365-2982.2006.00873.x.
- 7.Rao SS, Gregersen H, Hayek B, Summers RW, Christensen J. Unexplained chest pain: The hypersensitive, hyperreactive, and poorly compliant esophagus. Ann Intern Med. 1996;124:950–958. doi: 10.7326/0003-4819-124-11-199606010-00002.
- 8.Rao SS, Hayek B, Summers RW. Functional chest pain of esophageal origin: Hyperalgesia or motor dysfunction. Am J Gastroenterol. 2001;96:2584–2589. doi: 10.1111/j.1572-0241.2001.04101.x.
- 9.Sarkar S, Aziz Q, Woolf CJ, Hobson AR, Thompson DG. Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet. 2000;356:1154–1159. doi: 10.1016/S0140-6736(00)02758-6.
- 10.Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000;118:842–848. doi: 10.1016/s0016-5085(00)70170-3.
- 11.Schmulson M, Chang L, Naliboff B, Lee OY, Mayer EA. Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients. Am J Gastroenterol. 2000;95:152–156. doi: 10.1111/j.1572-0241.2000.01677.x.
- 12.Camilleri M, Talley NJ. Pathophysiology as a basis for understanding symptom complexes and therapeutic targets. Neurogastroenterol Motil. 2004;16:135–142. doi: 10.1111/j.1365-2982.2004.00516.x.
- 13.Spiller RC. Inflammation as a basis for functional GI disorders. Best Pract Res Clin Gastroenterol. 2004;18:641–661. doi: 10.1016/j.bpg.2004.04.002.
- 14.Kim DY, Camilleri M. Serotonin: A mediator of the brain-gut connection. Am J Gastroenterol. 2000;95:2698–2709. doi: 10.1111/j.1572-0241.2000.03177.x.
- 15.Popa SL, Chiarioni G, David L, Dumitrascu DL. The Efficacy of Hypnotherapy in the Treatment of Functional Dyspepsia. Am J Ther. 2019 Jul 9; doi: 10.1097/MJT.
- 16.Palsson OS, Drossman DA. Psychiatric and psychological dysfunction in irritable bowel syndrome and the role of psychological treatments. Gastroenterol Clin North Am. 2005;34:281–303. doi: 10.1016/j.gtc.2005.02.004.
- 17.Park MI, Camilleri M. Genetics and genotypes in irritable bowel syndrome: Implications for diagnosis and treatment. Gastroenterol Clin North Am. 2005;34:305–317. doi: 10.1016/j.gtc.2005.02.009.
- 18.Locke GR, 3rd, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ., 3rd Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc. 2000;75:907–912. doi: 10.4065/75.9.907.
- 19.Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: Heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799–804. doi: 10.1053/gast.2001.27995.
- 20.Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: Postal survey of patients. BMJ. 1997;314:779–782. doi: 10.1136/bmj.314.7083.779.
- 21.Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol. 2004;99:1774–1778. doi: 10.1111/j.1572-0241.2004.30435.x.
- 22.Varia I, Logue E, O’connor C, Newby K, Wagner HR, Davenport C, Rathey K, Krishnan KR. Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J. 2000;140:367–372. doi: 10.1067/mhj.2000.108514.
- 23.Remes-Troche JM, Chahal P, Mudipalli R, Rao SS. Adenosine modulates oesophageal sensorimotor function in humans. Gut. 2009;58:1049–55. doi: 10.1136/gut.2006.116699.
- 24.Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol. 1998;347:1–11. doi: 10.1016/s0014-2999(97)01605-1.
- 25.Tack J, Carbone F. Functional dyspepsia and gastroparesis. Curr Opin Gastroenterol. 2017;33:446–454. doi: 10.1097/MOG.0000000000000393.
- 26.Drossman DA, Leserman J, Nachman G, et al. Sexual and physical abuse in women with functional or organic gastrointestinal disorders. Ann Intern Med. 1990;113:828–833. doi: 10.7326/0003-4819-113-11-828.
- 27.Bradford K, Shih W, Videlock EJ, et al. Association between early adverse life events and irritable bowel syndrome. Clin Gastroenterol Hepatol. 2012;10:385–390. doi: 10.1016/j.cgh.2011.12.018.
- 28.Afari N, Ahumada SM, Wright LJ, et al. Psychological trauma and functional somatic syndromes: a systematic review and meta-analysis. Psychosom Med. 2014;76:2–11. doi: 10.1097/PSY.0000000000000010.
- 29.Levy RL, Olden KW, Naliboff BD, et al. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology. 2006;130:1447–1458. doi: 10.1053/j.gastro.2005.11.057.
- 30.Sherman AL, Morris MC, Bruehl S, Westbrook TD, Walker LS. Heightened Temporal Summation of Pain in Patients with Functional Gastrointestinal Disorders and History of Trauma. Ann Behav Med. 2015;49:785–92. doi: 10.1007/s12160-015-9712-5.
- 31.Leserman J, Drossman DA. Relationship of abuse history to functional gastrointestinal disorders and symptoms: some possible mediating mechanisms. Trauma Violence Abuse. 2007;8:331–343. doi: 10.1177/1524838007303240.
- 32.Bruehl S, France CR, France J, Harju A, al’Absi M. How accurate are parental chronic pain histories provided by offspring? Pain. 2005;115:390–397. doi: 10.1016/j.pain.2005.03.017.
- 33.Walker LS, Dengler-Crish CM, Rippel S, Bruehl S. Functional abdominal pain in childhood and adolescence increases risk for chronic pain in adulthood. Pain. 2010;150:568–572. doi: 10.1016/j.pain.2010.06.018.
- 34.Junquiera LC, Carneiro J. New York, NY, USA: McGraw- Hill, Medical Publishing Division; 2005. Basic Histology.
- 35.Su X, Gebhart GF. Mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat polymodal in character. Journal of Neurophysiology. 1998;5:2632–2644. doi: 10.1152/jn.1998.80.5.2632.
- 36.Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multimodal assessment of pain in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol. 2002;283:G95–103. doi: 10.1152/ajpgi.00496.2001.
- 37.Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multimodal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain. 2003;7:539–549. doi: 10.1016/s1090-3801(03)00053-3.
- 38.Sengupta JN, Gebhart GF. Gastrointestinal afferent fibers and sensation. In: Johnson L., editor. Physiology of the Gastrointestinal Tract. 3rd edition. New York, NY, USA: Raven Press; 1994.
- 39.Cervero F. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiological Reviews. 1994;1:95–138. doi: 10.1152/physrev.1994.74.1.95.
- 40.Lembo T, Munakata J, Mertz H, Niazi N, Kodner A, Nikas V. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology. 1994;6:1686–1696. doi: 10.1016/0016-5085(94)90809-5.
- 41.Popa SL, Leucuta DC, Dumitrascu DL. Pressure management as an occupational stress risk factor in irritable bowel syndrome: A cross-sectional study. Medicine (Baltimore) 2018 Dec;97(49):e13562. doi: 10.1097/MD.0000000000013562.
- 42.Luo J, Walters ET, Carlton SM, Hu H. Targeting Pain-evoking Transient Receptor Potential Channels for the Treatment of Pain. Curr Neuropharmacol. 2013 Dec;11(6):652–63. doi: 10.2174/1570159X113119990040.
- 43.Holzer P. Taste receptors in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2007;292:G699–705. doi: 10.1152/ajpgi.00517.2006.
- 44.Knowles CH, Aziz Q. Basic and clinical aspects of gastrointestinal pain. Pain. 2009;141:191–209. doi: 10.1016/j.pain.2008.12.011.
- 45.Lottrup C, Olesen SS, Drewes AM. The pain system in oesophageal disorders: mechanisms, clinical characteristics, and treatment. Gastroenterol Res Pract. 2011;2011:910420. doi: 10.1155/2011/910420.
- 46.Mayer EA, Aziz Q, Coen S, et al. Brain imaging approaches to the study of functional GI disorders: a Rome working team report. Neurogastroenterol Motil. 2009;21:579–96. doi: 10.1111/j.1365-2982.2009.01304.x.
- 47.Anand P, Aziz Q, Willert R, van Oudenhove L. Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil. 2007;19(1 Suppl):29–46. doi: 10.1111/j.1365-2982.2006.00873.x.
- 48.Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203–10. doi: 10.1038/35093019.
- 49.Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–9. doi: 10.1126/science.288.5472.1765.
- 50.Frøkjaer JB, Andersen SD, Gale J, Arendt-Nielsen L, Gregersen H, Drewes AM. An experimental study of viscero-visceral hyperalgesia using an ultrasound-based multimodalsensory testing approach. Pain. 2005;119:191–200. doi: 10.1016/j.pain.2005.09.031.
- 51.Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology. 2004;126:683–92. doi: 10.1053/j.gastro.2003.11.047.
- 52.Sami SA, Rössel P, Dimcevski G, et al. Cortical changes to experimental sensitization of the human esophagus. Neuroscience. 2006;140:269–79. doi: 10.1016/j.neuroscience.2006.02.031.
- 53.de Vries DR, ter Linde JJ, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal reflux disease is associated with C825T polymorphism in the G-protein β3 subunit gene (GNB3) Am J Gastroenterol. 2009;104:281–285. doi: 10.1038/ajg.2008.139.