Although the idea that gastric problems are in some way related to mental activity dates back to the beginning of the last century, until now it has received scant attention by physiologists, general practitioners and gastroenterologists. The major breakthrough in understanding the interactions between the central nervous system and the gut was the discovery of the enteric nervous system (ENS) in the 19th century. ENS (also called ‘little brain') plays a crucial role in the regulation of the physiological gut functions. Furthermore, the identification of corticotropin-releasing factor (CRF) and the development of specific CRF receptor antagonists have permitted to characterize the neurochemical basis of the stress response. The neurobiological response to stress in mammals involves three key mechanisms: (1) stress is perceived and processed by higher brain centers; (2) the brain mounts a neuroendocrine response by way of the hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system (ANS), and (3) the brain triggers feedback mechanisms by HPA and ANS stimulation to restore homeostasis. Various stressors such as anger, fear, painful stimuli, as well as life or social learning experiences affect both the individual's physiologic and gastric function, revealing a two-way interaction between brain and stomach. There is overwhelming experimental and clinical evidence that stress influences gastric function, thereby outlining the pathogenesis of gastric diseases such as functional dyspepsia, gastroesophageal reflux disease and peptic ulcer disease. A better understanding of the role of pathological stressors in the modulation of disease activity may have important pathogenetic and therapeutic implications.

1.
Beaumont W: Experiments and Observations on the Gastric Juice and the Physiology of Digestion. Plattsburgh, FP Allen, 1833.
2.
Pavlov I: The Work of the Digestive Glands. English translation by W.H. Thompson. London, C Griffin and Co, 1910.
3.
James W: What is an emotion? Mind 1884;9:188-205.
4.
Lange C: The mechanism of the emotions; in Dunlap E (ed): The Emotions. Baltimore, Williams and Wilkins, 1885, pp 33-90.
5.
Cannon WB: The James-Lange theory of emotions: a critical examination and an alternative theory. Am J Psychol 1927;39:106-124.
6.
Bard P: A diencephalic mechanism for the expression of rage with special reference to the central nervous system. Am J Physiol 1928;84:490-513.
7.
Selye H: A syndrome produced by diverse nocuous agents. 1936. J Neuropsychiatry Clin Neurosci 1998;10:230-231.
8.
Laranjeira C, Pachnis V: Enteric nervous system development: recent progress and future challenges. Auton Neurosci 2009;151:61-69.
9.
Mayer EA: The neurobiology of stress and gastrointestinal disease. Gut 2000;47:861-869.
10.
Jones MP, Crowell MD, Olden KW, Creed F: Functional gastrointestinal disorders: an update for the psychiatrist. Psychosomatics 2007;48:93-102.
11.
Taché Y, Martinez V, Million M, Wang L: Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 2001;280:G173-G177.
12.
Zorrilla EP, Koob GF: Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today 2010;15:371-383.
13.
Zoumakis E, Chrousos GP: Corticotropin-releasing hormone receptor antagonists: an update. Endocr Dev 2010;17:36-43.
14.
Fink G: Stress controversies: post-traumatic stress disorder, hippocampal volume, gastroduodenal ulceration. J Neuroendocrinol 2011;23:107-117.
15.
Maras PM, Baram TZ: Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci 2012;35:315-324.
16.
Bonfiglio JJ, Inda C, Refojo D, Holsboer F, Arzt E, Silberstein S: The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved. Neuroendocrinology 2011;94:12-20.
17.
Aguilera G: HPA axis responsiveness to stress: implications for healthy aging. Exp Gerontol 2011;46:90-95.
18.
Refojo D, Holsboer F: CRH signaling. Molecular specificity for drug targeting in the CNS. Ann N Y Acad Sci 2009;1179:106-119.
19.
Holsboer F, Ising M: Stress hormone regulation: biological role and translation into therapy. Annu Rev Psychol 2010;61:81-109.
20.
Yarushkina NI: The role of hypothalamo-hypophyseal-adrenocortical system hormones in controlling pain sensitivity. Neurosci Behav Physiol 2008;38:759-766.
21.
Yuan PQ, Wu SV, Taché Y: Urocortins and CRF type 2 receptor isoforms expression in the rat stomach are regulated by endotoxin: role in the modulation of delayed gastric emptying. Am J Physiol Gastrointest Liver Physiol 2012;303:G20-G31.
22.
Hillhouse EW, Grammatopoulos DK: The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev 2006;27:260-286.
23.
Richard D, Lin Q, Timofeeva E: The corticotropin-releasing factor family of peptides and CRF receptors: their roles in the regulation of energy balance. Eur J Pharmacol 2002;440:189-197.
24.
Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, Gold PW: Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci USA 2000;97:6079-6084.
25.
Elenkov IJ: Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem Int 2008;52:40-51.
26.
Taché Y, Martinez V, Million M, Rivier J: Corticotropin-releasing factor and the brain-gut motor response to stress. Can J Gastroenterol 1999;13(suppl A):18-25.
27.
Miampamba M, Maillot C, Million M, Taché Y: Peripheral CRF activates myenteric neurons in the proximal colon through CRF(1) receptor in conscious rats. Am J Physiol Gastrointest Liver Physiol 2002;282:G857-G865.
28.
Maillot C, Million M, Wei JY, Gauthier A, Taché Y: Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology 2000;119:1569-1579.
29.
Nemeroff CB, Vale WW: The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry 2005;66(suppl 7):5-13.
30.
Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000;23:477-501.
31.
Holsboer F, Ising M: Central CRH system in depression and anxiety-evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol 2008;583:350-357.
32.
Legros JJ: Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying-yang neurohormones? Psychoneuroendocrinology 2001;26:649-655.
33.
Zheng J, Babygirija R, Bülbül M, Cerjak D, Ludwig K, Takahashi T: Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats. Am J Physiol Gastrointest Liver Physiol 2010;299:G946-G953.
34.
Yang H, Wu SV, Ishikawa T, Taché Y: Cold exposure elevates thyrotropin-releasing hormone gene expression in medullary raphe nuclei: relationship with vagally mediated gastric erosions. Neuroscience 1994;61:655-663.
35.
Martinez V, Wu SV, Taché Y: Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats. Endocrinology 1998;139:3730-3735.
36.
Feurle GE, Helmstaeter V, Weber U: Met- and leu-enkephalin immuno- and bio-reactivity in human stomach and pancreas. Life Sci 1982;31:2961-2969.
37.
Black PH, Garbutt LD: Stress, inflammation and cardiovascular disease. J Psychosom Res 2002;52:1-23.
38.
Kim CH, Hanson RB, Abell TL, Malagelada JR: Effect of inhibition of prostaglandin synthesis on epinephrine-induced gastroduodenal electromechanical changes in humans. MayoClin Proc 1989;64:149-157.
39.
Muth ER, Koch KL, Stern RN, Thayer JF: Effect of autonomic nervous system manipulations on gastric myoelectrical activity and emotional responses in healthy human subjects. Psychosom Med 1999;61:297-303.
40.
Chen TS, Lee YC, Chang FY, Wu HC, Lee SD: Psychosocial distress is associated with abnormal gastric myoelectrical activity in patients with functional dyspepsia. Scand J Gastroenterol 2006;41:791-796.
41.
You CH, Lee KY, Chey WY, Menguy R: Electrogastrographic study of patients with unexplained nausea, bloating, and vomiting. Gastroenterology 1980;79:311-314.
42.
Corazziari E: Definition and epidemiology of functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol 2004;18:613-631.
43.
Maxion-Bergemann S, Thielecke F, Abel F, Bergemann R: Costs of irritable bowel syndrome in the U.K. and U.S. Pharmacoeconomics 2006;24:21-37.
44.
Camilleri M, Malagelada JR, Kao PC, Zinsmeister AR: Gastric and autonomic responses to stress in functional dyspepsia. Dig Dis Sci 1986;31:1169-1177.
45.
Huerta-Franco MR, Vargas-Luna M, Montes-Frausto JB, Morales-Mata I, Ramirez-Padilla L: Effect of psychological stress on gastric motility assessed by electrical bio-impedance. World J Gastroenterol 2012;18:5027-5033.
46.
De Giorgi F, Sarnelli G, Cirillo C, Savino IG, Turco F, Nardone G, Rocco A, Cuomo R: Increased severity of dyspeptic symptoms related to mental stress is associated with sympathetic hyperactivity and enhanced endocrine response in patients with postprandial distress syndrome. Neurogastroenterol Motil 2013;25:31-38.
47.
Geeraerts B, Vandenberghe J, Van Oudenhove L, Gregory LJ, Aziz Q, Dupont P, Demyttenaere K, Janssens J, Tack J: Influence of experimentally induced anxiety on gastric sensorimotor function in humans. Gastroenterology 2005;129:1437-1444.
48.
Konturek PC, Brzozowski T, Konturek SJ: Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol 2011;62:591-599.
49.
Mittal RK, Shaffer HA, Parollisi S, Baggett L: Influence of breathing pattern on the esophagogastric junction pressure and esophageal transit. Am J Physiol 1995;269:G577-G583.
50.
Mizyed I, Fass SS, Fass R: Review article: gastrooesophageal reflux disease and psychological comorbidity. Aliment Pharmacol Ther 2009;29:351-358.
51.
Li J, Brackbill RM, Stellman SD, Farfel MR, Miller-Archie SA, Friedman S, Walker DJ, Thorpe LE, Cone J: Gastroesophageal reflux symptoms and comorbid asthma and posttraumatic stress disorder following the 9/11 terrorist attacks on World Trade Center in New York City. Am J Gastroenterol 2011;106:1933-1941.
52.
Perlman SE, Friedman S, Galea S, Nair HP, Eros-Sarnyai M, Stellman SD, Hon J, Greene CM: Short-term and medium-term health effects of 9/11. Lancet 2011;378:925-934.
53.
Ali T, Harty RF: Stress-induced ulcer bleeding in critically ill patients. Gastroenterol Clin North Am 2009;38:245-265.
54.
Konturek SJ, Bielański W, Płonka M, Pawlik T, Pepera J, Konturek PC, Czarnecki J, Penar A, Jedrychowski W: Helicobacter pylori, nonsteroidal anti-inflammatory drugs and smoking in risk pattern of gastroduodenal ulcers. Scand J Gastroenterol 2003;38:923-930.
55.
Konturek PC: Physiological, immunohistochemical and molecular aspects of gastric adaptation to stress, aspirin and to H. pylori-derived gastrotoxins. J Physiol Pharmacol 1997;48:3-42.
56.
Jones MP: The role of psychosocial factors in peptic ulcer disease: beyond Helicobacter pylori and NSAIDs. J Psychosom Res 2006;60:407-412.
57.
Konturek PC, Brzozowski T, Burnat G, Kwiecien S, Pawlik T, Hahn EG, Konturek SJ: Role of brain-gut axis in healing of gastric ulcers. J Physiol Pharmacol 2004;55:179-192.
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