Sensory Nerves pp 227-257 | Cite as

Roles of Gastro-oesophageal Afferents in the Mechanisms and Symptoms of Reflux Disease

  • Amanda J. Page
  • L. Ashley BlackshawEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)


Oesophageal pain is one of the most common reasons for physician consultation and/or seeking medication. It is most often caused by acid reflux from the stomach, but can also result from contractions of the oesophageal muscle. Different forms of pain are evoked by oesophageal acid, including heartburn and non-cardiac chest pain, but the basic mechanisms and pathways by which these are generated remain to be elucidated. Both vagal and spinal afferent pathways are implicated by basic research. The sensitivity of afferent fibres within these pathways may become altered after acid-induced inflammation and damage, but the severity of symptoms in humans does not necessarily correlate with the degree of inflammation. Gastro-oesophageal reflux disease (GORD) is caused by transient relaxations of the lower oesophageal sphincter, which are triggered by activation of gastric vagal mechanoreceptors. Vagal afferents are therefore an emerging therapeutic target for GORD. Pain in the absence of excess acid reflux remains a major challenge for treatment.


Visceral pain Vagal afferents Gastro-oesophageal reflux Lower oesophageal sphincter 







Adenosine triphosphate




Calcitonin gene-related peptide






γ-Aminobutyric acid


Gastro-oesophageal reflux disease




Intraganglionic laminar endings


Ionotropic glutamate receptor


Intramuscular array


L-(+)-2-Amino-4-phosphonobutyric acid


NG-nitro-L-arginine methyl ester


α,β-Methylene ATP


Metabotropic glutamate receptor






Non-cardiac chest pain


N-Methyl d-aspartate


Transient lower oesophageal sphincter relaxation


Transient receptor potential vanilloid receptor 1



L.A.B. is supported by a National Health and Medical Research Council of Australia Senior Research fellowship.


  1. Addex-Pharmaceuticals (2007) ADX10059 may be a potential treatment for patients with gastro-esophageal reflux. Inpharma 1:10–10Google Scholar
  2. Agrawal A, Hila A, Tutuian R, Mainie I, Castell DO (2006) Clinical relevance of the nutcracker esophagus: suggested revision of criteria for diagnosis. J Clin Gastroenterol 40:504–509PubMedGoogle Scholar
  3. Baccaglini PI, Hogan PG (1983) Some rat sensory neurons in culture express characteristics of differentiated pain sensory cells. Proc Natl Acad Sci USA 80:594–598PubMedGoogle Scholar
  4. Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN (2007) Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil 19:681–691PubMedGoogle Scholar
  5. Bautista J, Fullerton H, Briseno M, Cui H, Fass R (2004) The effect of an empirical trial of high-dose lansoprazole on symptom response of patients with non-cardiac chest pain – a randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 19:1123–1130PubMedGoogle Scholar
  6. Berthoud HR, Powley TL (1992) Vagal afferent innervation of the rat fundic stomach: morphological characterization of the gastric tension receptor. J Comp Neurol 319:261–276PubMedGoogle Scholar
  7. Berthoud HR, Patterson LM, Neumann F, Neuhuber WL (1997) Distribution and structure of vagal afferent intraganglionic laminar endings (IGLEs) in the rat gastrointestinal tract. Anat Embryol (Berl) 195:183–191Google Scholar
  8. Beyak MJ, Vanner S (2005) Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterol Motil 17:175–186PubMedGoogle Scholar
  9. Bielefeldt K (2000) Differential effects of capsaicin on rat visceral sensory neurons. Neuroscience 101:727–736PubMedGoogle Scholar
  10. Bielefeldt K, Davis BM (2008) Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice. Am J Physiol Gastrointest Liver Physiol 294:G130–G138PubMedGoogle Scholar
  11. Blackshaw LA, Dent J (1997) Lower oesophageal sphincter responses to noxious oesophageal chemical stimuli in the ferret: involvement of tachykinin receptors. J Auton Nerv Syst 66:189–200PubMedGoogle Scholar
  12. Blackshaw LA, Grundy D (1990) Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre. J Auton Nerv Syst 31:191–201PubMedGoogle Scholar
  13. Blackshaw LA, Grundy D (1993a) Effects of 5-hydroxytryptamine (5-HT) on the discharge of vagal mechanoreceptors and motility in the upper gastrointestinal tract of the ferret. J Auton Nerv Syst 45:51–59PubMedGoogle Scholar
  14. Blackshaw LA, Grundy D (1993b) Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Auton Nerv Syst 45:41–50PubMedGoogle Scholar
  15. Blackshaw LA, Grundy D, Scratcherd T (1987) Vagal afferent discharge from gastric mechanoreceptors during contraction and relaxation of the ferret corpus. J Auton Nerv Syst 18:19–24PubMedGoogle Scholar
  16. Blackshaw LA, Staunton E, Lehmann A, Dent J (1999) Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am J Physiol 277:G867–G874PubMedGoogle Scholar
  17. Blackshaw LA, Page AJ, Partosoedarso ER (2000a) Acute effects of capsaicin on gastrointestinal vagal afferents. Neuroscience 96:407–416PubMedGoogle Scholar
  18. Blackshaw LA, Smid SD, O'Donnell TA, Dent J (2000b) GABA(B) receptor-mediated effects on vagal pathways to the lower oesophageal sphincter and heart. Br J Pharmacol 130:279–288PubMedGoogle Scholar
  19. Boeckxstaens GE, Hirsch DP, Fakhry N, Holloway RH, D'Amato M, Tytgat GN (1998) Involvement of cholecystokininA receptors in transient lower esophageal sphincter relaxations triggered by gastric distension. Am J Gastroenterol 93:1823–1828PubMedGoogle Scholar
  20. Booth CE, Kirkup AJ, Hicks GA, Humphrey PP, Grundy D (2001) Somatostatin sst(2) receptor-mediated inhibition of mesenteric afferent nerves of the jejunum in the anesthetized rat. Gastroenterology 121:358–369PubMedGoogle Scholar
  21. Boulant J, Fioramonti J, Dapoigny M, Bommelaer G, Bueno L (1994) Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs. Gastroenterology 107:1059–1066PubMedGoogle Scholar
  22. Boulant J, Mathieu S, D'Amato M, Abergel A, Dapoigny M, Bommelaer G (1997) Cholecystokinin in transient lower oesophageal sphincter relaxation due to gastric distension in humans. Gut 40:575–581PubMedGoogle Scholar
  23. Brierley SM, Jones RC 3rd, Gebhart GF, Blackshaw LA (2004) Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127:166–178PubMedGoogle Scholar
  24. Brierley SM, Carter R, Jones W, Xu LJ, Robinson DR, Hicks GA, Gebhart GE, Blackshaw LA (2005) Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice. J Physiol (Lond) 567:267–281Google Scholar
  25. Brierley SM, Page AJ, Hughes PA, Adam B, Liebregts T, Cooper NJ, Holtmann G, Liedtke W, Blackshaw L (2008) A selective role for TRPV4 ion channels in visceral sensory pathways. Gastroenterology 134(7):2059–2069PubMedGoogle Scholar
  26. Broberger C, Farkas-Szallasi T, Szallasi A, Lundberg JM, Hokfelt T, Wiesenfeld-Hallin Z, Xu XJ (2000) Increased spinal cholecystokinin activity after systemic resiniferatoxin: electrophysiological and in situ hybridization studies. Pain 84:21–28PubMedGoogle Scholar
  27. Broberger C, Holmberg K, Shi TJ, Dockray G, Hokfelt T (2001) Expression and regulation of cholecystokinin and cholecystokinin receptors in rat nodose and dorsal root ganglia. Brain Res 903:128–140PubMedGoogle Scholar
  28. Brtva RD, Iwamoto GA, Longhurst JC (1989) Distribution of cell bodies for primary afferent fibers from the stomach of the cat. Neurosci Lett 105:287–293PubMedGoogle Scholar
  29. Brunsden AM, Grundy D (1999) Sensitization of visceral afferents to bradykinin in rat jejunum in vitro. J Physiol 521(Pt 2):517–527PubMedGoogle Scholar
  30. Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Ann Rev Neurosci 24:487–517PubMedGoogle Scholar
  31. Cervero F (1994) Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol Rev 74:95–138PubMedGoogle Scholar
  32. Chang HM, Liao WC, Lue JH, Wen CY, Shieh JY (2003) Upregulation of NMDA receptor and neuronal NADPH-d/NOS expression in the nodose ganglion of acute hypoxic rats. J Chem Neuroanat 25:137–147PubMedGoogle Scholar
  33. Clerc N (1983) Afferent innervation of the lower oesophageal sphincter of the cat. An HRP study. J Auton Nerv Syst 9:623–636Google Scholar
  34. Clerc N, Mazzia C (1994) Morphological relationships of choleragenoid horseradish peroxidase-labeled spinal primary afferents with myenteric ganglia and mucosal associated lymphoid tissue in the cat esophagogastric junction. J Comp Neurol 347:171–186PubMedGoogle Scholar
  35. Clouse RE, McCord GS, Lustman PJ, Edmundowicz SA (1991) Clinical correlates of abnormal sensitivity to intraesophageal balloon distension. Dig Dis Sci 36:1040–1045PubMedGoogle Scholar
  36. Collman PI, Tremblay L, Diamant NE (1992) The distribution of spinal and vagal sensory neurons that innervate the esophagus of the cat. Gastroenterology 103:817–822PubMedGoogle Scholar
  37. Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387:505–508PubMedGoogle Scholar
  38. Coutinho SV, Su X, Sengupta JN, Gebhart GF (2000) Role of sensitized pelvic nerve afferents from the inflamed rat colon in the maintenance of visceral hyperalgesia. Prog Brain Res 129:375–387PubMedGoogle Scholar
  39. Cox MR, Martin CJ, Dent J, Westmore M (1988) Effect of general anaesthesia on transient lower oesophageal sphincter relaxations in the dog. Aust N Z J Surg 58:825–830PubMedGoogle Scholar
  40. Dang K, Bielfeldt K, Lamb K, Gebhart GF (2005) Gastric ulcers evoke hyperexcitability and enhance P2X receptor function in rat gastric sensory neurons. J Neurophysiol 93:3112–3119PubMedGoogle Scholar
  41. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120–1128PubMedGoogle Scholar
  42. De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397PubMedGoogle Scholar
  43. Decktor DL, Allen ML, Robinson M (1990) Esophageal motility, heartburn, and gastroesophageal reflux: variations in clinical presentation of esophageal dysphagia. Dysphagia 5:211–215PubMedGoogle Scholar
  44. Dent J, Holloway RH, Toouli J, Dodds WJ (1988) Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux. Gut 29:1020–1028PubMedGoogle Scholar
  45. Dent J, El-Serag HB, Wallander MA, Johansson S (2005) Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54:710–717PubMedGoogle Scholar
  46. Dutsch M, Eichhorn U, Worl J, Wank M, Berthoud HR, Neuhuber WL (1998) Vagal and spinal afferent innervation of the rat esophagus: a combined retrograde tracing and immunocytochemical study with special emphasis on calcium-binding proteins. J Comp Neurol 398:289–307PubMedGoogle Scholar
  47. Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci 18:9471–9479PubMedGoogle Scholar
  48. Fass R (2007) Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure. Drugs 67:1521–1530PubMedGoogle Scholar
  49. Fass R, Tougas G (2002) Functional heartburn: the stimulus, the pain, and the brain. Gut 51: 885–892PubMedGoogle Scholar
  50. Fass R, Fennerty MB, Vakil N (2001) Nonerosive reflux disease – current concepts and dilemmas. Am J Gastroenterol 96:303–314PubMedGoogle Scholar
  51. Fong AY, Krstew EV, Barden J, Lawrence AJ (2002) Immunoreactive localisation of P2Y1 receptors within the rat and human nodose ganglia and rat brainstem: comparison with [alpha 33P]deoxyadenosine 5′-triphosphate autoradiography. Neuroscience 113:809–823PubMedGoogle Scholar
  52. Fox EA, Phillips RJ, Martinson FA, Baronowsky EA, Powley TL (2000) Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse: morphology and topography. J Comp Neurol 428:558–576PubMedGoogle Scholar
  53. Franzi SJ, Martin CJ, Cox MR, Dent J (1990) Response of canine lower esophageal sphincter to gastric distension. Am J Physiol 259:G380–G385PubMedGoogle Scholar
  54. Freidin N, Fisher MJ, Taylor W, Boyd D, Surratt P, McCallum RW, Mittal RK (1991) Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 32:1275–1279PubMedGoogle Scholar
  55. Frisby CL, Mattsson JP, Jensen JM, Lehmann A, Dent J, Blackshaw LA (2005) Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands. Gastroenterology 129:995–1004PubMedGoogle Scholar
  56. Fujino K, de la Fuente SG, Takami Y, Takahashi T, Mantyh CR (2006) Attenuation of acid induced oesophagitis in VR-1 deficient mice. Gut 55:34–40PubMedGoogle Scholar
  57. Furness JB, Koopmans HS, Robbins HL, Lin HC (2000) Identification of intestinofugal neurons projecting to the coeliac and superior mesenteric ganglia in the rat. Auton Neurosci 83:81–85PubMedGoogle Scholar
  58. Gold MS, Dastmalchi S, Levine JD (1996) Co-expression of nociceptor properties in dorsal root ganglion neurons from the adult rat in vitro. Neuroscience 71:265–275PubMedGoogle Scholar
  59. Green T, Dockray GJ (1987) Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett 76:151–156PubMedGoogle Scholar
  60. Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 11:946–958PubMedGoogle Scholar
  61. Hewson EG, Sinclair JW, Dalton CB, Wu WC, Castell DO, Richter JE (1989) Acid perfusion test: does it have a role in the assessment of non cardiac chest pain? Gut 30:305–310PubMedGoogle Scholar
  62. Hicks G, Clayton J, Gaskin P (2001) 5-HT4 receptor agonists stimulate small intestinal transit but do not have direct visceral antinociceptive effects in the rat. Gastroenterology 120:A6Google Scholar
  63. Hirsch DP, Holloway RH, Tytgat GN, Boeckxstaens GE (1998) Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis. Gastroenterology 115:1374–1380PubMedGoogle Scholar
  64. Hirsch DP, Tytgat GN, Boeckxstaens GE (2002) Is glutamate involved in transient lower esophageal sphincter relaxations? Dig Dis Sci 47:661–666PubMedGoogle Scholar
  65. Hobson AR, Furlong PL, Sarkar S, Matthews PJ, Willert RP, Worthen SF, Unsworth BJ, Aziz Q (2006) Neurophysiologic assessment of esophageal sensory processing in noncardiac chest pain. Gastroenterology 130:80–88PubMedGoogle Scholar
  66. Holloway RH, Penagini R, Ireland AC (1995) Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 268:G128–G133PubMedGoogle Scholar
  67. Hoyer D, Martin G (1997) 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 36:419–428PubMedGoogle Scholar
  68. Janssens J, Vantrappen G (1987) Angina-like chest pain of oesophageal origin. Baillieres Clin Gastroenterol 1:843–855PubMedGoogle Scholar
  69. Janssens J, Vantrappen G, Ghillebert G (1986) 24-Hour recording of esophageal pressure and pH in patients with noncardiac chest pain. Gastroenterology 90:1978–1984PubMedGoogle Scholar
  70. Jensen J, Lehmann A, Uvebrant A, Carlsson A, Jerndal G, Nilsson K, Frisby C, Blackshaw LA, Mattsson JP (2005) Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist. Eur J Pharmacol 519:154–157PubMedGoogle Scholar
  71. Johnson DA, Winters C, Spurling TJ, Chobanian SJ, Cattau EL Jr (1987) Esophageal acid sensitivity in Barrett's esophagus. J Clin Gastroenterol 9:23–27PubMedGoogle Scholar
  72. Jones RC, 3rd, Xu L, Gebhart GF (2005) The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. J Neurosci 25:10981–10989PubMedGoogle Scholar
  73. Kahrilas PJ (2000) Esophageal motility disorders: current concepts of pathogenesis and treatment. Can J Gastroenterol 14:221–231PubMedGoogle Scholar
  74. Khurana RK, Petras JM (1991) Sensory innervation of the canine esophagus, stomach, and duodenum. Am J Anat 192:293–306PubMedGoogle Scholar
  75. Kirkup AJ, Eastwood C, Grundy D, Chessell IP, Humphrey PP (1998) Characterization of adenosine receptors evoking excitation of mesenteric afferents in the rat. Br J Pharmacol 125:1352–1360PubMedGoogle Scholar
  76. Kirkup AJ, Booth CE, Chessell IP, Humphrey PP, Grundy D (1999) Excitatory effect of P2X receptor activation on mesenteric afferent nerves in the anaesthetised rat. J Physiol 520(Pt 2):551–563PubMedGoogle Scholar
  77. Kjellen G, Tibbling L (1985) Oesophageal motility during acid-provoked heartburn and chest pain. Scand J Gastroenterol 20:937–940PubMedGoogle Scholar
  78. Kollarik M, Ru F, Undem BJ (2007) Acid-sensitive vagal sensory pathways and cough. Pulm Pharmacol Ther 20:402–411PubMedGoogle Scholar
  79. Kressel M, Berthoud HR, Neuhuber WL (1994) Vagal innervation of the rat pylorus: an anterograde tracing study using carbocyanine dyes and laser scanning confocal microscopy. Cell Tissue Res 275:109–123PubMedGoogle Scholar
  80. Lee KJ, Vos R, Janssens J, Tack J (2004) Differences in the sensorimotor response to distension between the proximal and distal stomach in humans. Gut 53:938–943PubMedGoogle Scholar
  81. Lehmann A, Branden L (2001) Effects of antagonism of NMDA receptors on transient lower esophageal sphincter relaxations in the dog. Eur J Pharmacol 431:253–258PubMedGoogle Scholar
  82. Lehmann A, Antonsson M, Bremner-Danielsen M, Flärdh M, Hansson-Branden L, Kärrberg L (1999) Activation of the GABAb receptor inhibits transient lower esophageal sphincter relaxations in dogs. Gastroenterology 117:1147–1154PubMedGoogle Scholar
  83. Lehmann A, Blackshaw LA, Branden L, Carlsson A, Jensen J, Nygren E, Smid SD (2002) Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs. Gastroenterology 123:1129–1134PubMedGoogle Scholar
  84. Lidums I, Lehmann A, Checklin H, Dent J, Holloway RH (2000) Control of transient lower esophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in normal subjects. Gastroenterology 118:7–13PubMedGoogle Scholar
  85. Lindh B, Aldskogius H, Hokfelt T (1989) Simultaneous immunohistochemical demonstration of intra-axonally transported markers and neuropeptides in the peripheral nervous system of the guinea pig. Histochemistry 92:367–376PubMedGoogle Scholar
  86. Lindstrom E, Brusberg M, Hughes PA, Martin CM, Brierley SM, Phillis BD, Martinsson R, Abrahamsson C, Larsson H, Martinez V, Blackshaw LA (2008) Involvement of metabotropic glutamate 5 receptor in visceral pain. Pain 137(2):295–305PubMedGoogle Scholar
  87. Longhurst JC, Kaufman MP, Ordway GA, Musch TI (1984) Effects of bradykinin and capsaicin on endings of afferent fibers from abdominal visceral organs. Am J Physiol 247:R552–R559PubMedGoogle Scholar
  88. Lynn PA, Blackshaw LA (1999) In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon. J Physiol 518(Pt 1):271–282PubMedGoogle Scholar
  89. Martin CJ, Patrikios J, Dent J (1986) Abolition of gas reflux and transient lower esophageal sphincter relaxation by vagal blockade in the dog. Gastroenterology 91:890–896PubMedGoogle Scholar
  90. Martin CJ, Dodds WJ, Liem HH, Dantas RO, layman RD, Dent J (1992) Diaphragmatic contribution to gastroesophageal competence and reflux in dogs. Am J Physiol 263:G551–G557PubMedGoogle Scholar
  91. Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P (2004) Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 16:897–902PubMedGoogle Scholar
  92. Mazzia C, Clerc N (1997) Ultrastructural relationships of spinal primary afferent fibres with neuronal and non-neuronal cells in the myenteric plexus of the cat oesophago-gastric junction. Neuroscience 80:925–937PubMedGoogle Scholar
  93. McDermott CM, Abrahams TP, Partosoedarso E, Hyland N, Ekstrand J, Monroe M, Hornby PJ (2001) Site of action of GABA(B) receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats. Gastroenterology 120:1749–1762PubMedGoogle Scholar
  94. McRoberts JA, Coutinho SV, Marvizon JC, Grady EF, Tognetto M, Sengupta JN, Ennes HS, Chaban VV, Amadesi S, Creminon C, Lanthorn T, Geppetti P, Bunnett NW, Mayer EA (2001) Role of peripheral N-methyl-d-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 120:1737–1748PubMedGoogle Scholar
  95. Medda BK, Sengupta JN, Lang IM, Shaker R (2005) Response properties of the brainstem neurons of the cat following intra-esophageal acid-pepsin infusion. Neuroscience 135:1285–1294PubMedGoogle Scholar
  96. Mittal RK, Balaban DH (1997) The esophagogastric junction. N Engl J Med 336:924–932PubMedGoogle Scholar
  97. Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J (1995) Transient lower esophageal sphincter relaxation. Gastroenterology 109:601–610PubMedGoogle Scholar
  98. Mittal RK, Liu J, Puckett JL, Bhalla V, Bhargava V, Tipnis N, Kassab G (2005) Sensory and motor function of the esophagus: lessons from ultrasound imaging. Gastroenterology 128:487–497PubMedGoogle Scholar
  99. Moriarty P, Dimaline R, Thompson DG, Dockray GJ (1997) Characterization of cholecystokininA and cholecystokininB receptors expressed by vagal afferent neurons. Neuroscience 79:905–913PubMedGoogle Scholar
  100. Neuhuber WL (1987) Sensory vagal innervation of the rat esophagus and cardia: a light and electron microscopic anterograde tracing study. J Auton Nerv Syst 20:243–255PubMedGoogle Scholar
  101. Neuhuber WL, Kressel M, Stark A, Berthoud HR (1998) Vagal efferent and afferent innervation of the rat esophagus as demonstrated by anterograde DiI and DiA tracing: focus on myenteric ganglia. J Auton Nerv Syst 70:92–102PubMedGoogle Scholar
  102. Nicol GD, Cui M (1994) Enhancement by prostaglandin E2 of bradykinin activation of embryonic rat sensory neurones. J Physiol 480(Pt 3):485–492PubMedGoogle Scholar
  103. Ozaki N, Gebhart GF (2001) Characterization of mechanosensitive splanchnic nerve afferent fibers innervating the rat stomach. Am J Physiol Gastrointest Liver Physiol 281:G1449–G1459PubMedGoogle Scholar
  104. Ozaki N, Sengupta JN, Gebhart GF (2000) Differential effects of mu-, delta-, and kappa-opioid receptor agonists on mechanosensitive gastric vagal afferent fibers in the rat. J Neurophysiol 83:2209–2216PubMedGoogle Scholar
  105. Page AJ, Blackshaw LA (1998) An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach. J Physiol 512(Pt 3):907–916PubMedGoogle Scholar
  106. Page AJ, Blackshaw LA (1999) GABA(B) receptors inhibit mechanosensitivity of primary afferent endings. J Neurosci 19:8597–8602PubMedGoogle Scholar
  107. Page AJ, O'Donnell TA, Blackshaw LA (2000) P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation. J Physiol 523(Pt 2):403–411PubMedGoogle Scholar
  108. Page AJ, Martin CM, Blackshaw LA (2002) Vagal mechanoreceptors and chemoreceptors in mouse stomach and esophagus. J Neurophysiol 87:2095–2103PubMedGoogle Scholar
  109. Page AJ, Brierley SM, Martin CM, Martinez-Salgado C, Wemmie JA, Brennan TJ, Symonds E, Omari T, Lewin GR, Welsh MJ, Blackshaw LA (2004) The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology 127:1739–1747PubMedGoogle Scholar
  110. Page AJ, Brierley SM, Martin CM, Price MP, Symonds E, Butler R, Wemmie JA, Blackshaw LA (2005a) Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 54:1408–1415PubMedGoogle Scholar
  111. Page AJ, Slattery JA, O'Donnell TA, Cooper NJ, Young RL, Blackshaw LA (2005b) Modulation of gastro-oesophageal vagal afferents by galanin in mouse and ferret. J Physiol 563:809–819PubMedGoogle Scholar
  112. Page AJ, Young RL, Martin CM, Umaerus M, O'Donnell TA, Cooper NJ, Coldwell JR, Hulander M, Mattsson JP, Lehmann A, Blackshaw LA (2005c) Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons. Gastroenterology 128:402–410PubMedGoogle Scholar
  113. Page AJ, Brierley SM, Martin CM, Hughes PA, Blackshaw LA (2007a) Acid sensing ion channels 2 and 3 are required for inhibition of visceral nociceptors by benzamil. Pain 133:150–160PubMedGoogle Scholar
  114. Page AJ, O'Donnell TA, Blackshaw LA (2007b) Role of nitric oxide in peripheral control of vagal afferent mechamosensitivity. Gastroenterology 132:A155–A155Google Scholar
  115. Page AJ, Slattery JA, Brierley SM, Jacoby AS, Blackshaw LA (2007c) Involvement of galanin receptors 1 and 2 in the modulation of mouse vagal afferent mechanosensitivity. J Physiol 583:675–684PubMedGoogle Scholar
  116. Page AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C, Brierley SM, Blackshaw LA (2007d) Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents. Am J Physiol Gastrointest Liver Physiol 292:G1376–G1384PubMedGoogle Scholar
  117. Partosoedarso ER, Blackshaw LA (1997) Vagal efferent fibre responses to gastric and oesophageal mechanical and chemical stimuli in the ferret. J Auton Nerv Syst 66:169–178PubMedGoogle Scholar
  118. Partosoedarso ER, Young RL, Blackshaw LA (2001) GABA(B) receptors on vagal afferent pathways: peripheral and central inhibition. Am J Physiol Gastrointest Liver Physiol 280:G658–G668PubMedGoogle Scholar
  119. Paterson WG, Selucky M, Hynna-Liepert TT (1991) Effect of intraesophageal location and muscarinic blockade on balloon distension-induced chest pain. Dig Dis Sci 36:282–288PubMedGoogle Scholar
  120. Patterson LM, Zheng H, Ward SM, Berthoud HR (2003) Vanilloid receptor (VR1) expression in vagal afferent neurons innervating the gastrointestinal tract. Cell Tissue Res 311:277–287PubMedGoogle Scholar
  121. Penagini R, Bianchi PA (1997) Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology 113:409–414PubMedGoogle Scholar
  122. Phillips RJ, Powley TL (2000) Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Res Brain Res Rev 34:1–26PubMedGoogle Scholar
  123. Pouderoux P, Verdier E, Kahrilas PJ (2003) Patterns of esophageal inhibition during swallowing, pharyngeal stimulation, and transient LES relaxation. Lower esophageal sphincter. Am J Physiol Gastrointest Liver Physiol 284:G242–G247Google Scholar
  124. Richards W, Hillsley K, Eastwood C, Grundy D (1996) Sensitivity of vagal mucosal afferents to cholecystokinin and its role in afferent signal transduction in the rat. J Physiol 497(Pt 2):473–481PubMedGoogle Scholar
  125. Richter JE (1991a) Gastroesophageal reflux disease as a cause of chest pain. Med Clin North Am 75:1065–1080PubMedGoogle Scholar
  126. Richter JE (1991b) Investigation and management of non-cardiac chest pain. Baillieres Clin Gastroenterol 5:281–306PubMedGoogle Scholar
  127. Richter JE, Barish CF, Castell DO (1986) Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 91:845–852PubMedGoogle Scholar
  128. Rodrigo J, Hernandez J, Vidal MA, Pedrosa JA (1975) Vegetative innervation of the esophagus. II. Intraganglionic laminar endings. Acta Anat (Basel) 92:79–100Google Scholar
  129. Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D (2004) Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol 560:867–881PubMedGoogle Scholar
  130. Rouzade ML, Fioramonti J, Bueno L (1996) Role of 5-HT3 receptors in the control by cholecystokinin of transient relaxations of the inferior esophageal sphincter in dogs. Gastroenterol Clin Biol 20:575–580PubMedGoogle Scholar
  131. Ruan HZ, Burnstock G (2003) Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochem Cell Biol 120:415–426PubMedGoogle Scholar
  132. Sarkar S, Hobson AR, Hughes A, Growcott J, Woolf CJ, Thompson DG, Aziz Q (2003) The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology 124:18–25PubMedGoogle Scholar
  133. Schicho R, Florian W, Liebmann I, Holzer P, Lippe IT (2004) Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa. Eur J Neurosci 19:1811–1818PubMedGoogle Scholar
  134. Schikowski A, Thewissen M, Mathis C, Ross HG, Enck P (2002) Serotonin type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum. Neurogastroenterol Motil 14:221–227PubMedGoogle Scholar
  135. Schoeman MN, Holloway RH (1994) Secondary oesophageal peristalsis in patients with non-obstructive dysphagia. Gut 35:1523–1528PubMedGoogle Scholar
  136. Schoeman MN, Holloway RH (1995) Integrity and characteristics of secondary oesophageal peristalsis in patients with gastro-oesophageal reflux disease. Gut 36:499–504PubMedGoogle Scholar
  137. Schwetz I, Naliboff B, Munakata J, Lembo T, Chang L, Matin K, Ohning G, Mayer EA (2004) Anti-hyperalgesic effect of octreotide in patients with irritable bowel syndrome. Aliment Pharmacol Ther 19:123–131PubMedGoogle Scholar
  138. Sekizawa S, Ishikawa T, Sant'Ambrogio FB, Sant'Ambrogio G (1999) Vagal esophageal receptors in anesthetized dogs: mechanical and chemical responsiveness. J Appl Physiol 86:1231–1235PubMedGoogle Scholar
  139. Sengupta JN, Kauvar D, Goyal RK (1989) Characteristics of vagal esophageal tension-sensitive afferent fibers in the opossum. J Neurophysiol 61:1001–1010PubMedGoogle Scholar
  140. Sengupta JN, Saha JK, Goyal RK (1990) Stimulus-response function studies of esophageal mechanosensitive nociceptors in sympathetic afferents of opossum. J Neurophysiol 64:796–812PubMedGoogle Scholar
  141. Sengupta JN, Saha JK, Goyal RK (1992) Differential sensitivity to bradykinin of esophageal distension-sensitive mechanoreceptors in vagal and sympathetic afferents of the opossum. J Neurophysiol 68:1053–1067PubMedGoogle Scholar
  142. Sengupta JN, Su X, Gebhart GF (1996) Kappa, but not mu or delta, opioids attenuate responses to distention of afferent fibers innervating the rat colon. Gastroenterology 111:968–980PubMedGoogle Scholar
  143. Sengupta JN, Medda BK, Shaker R (2002) Effect of GABA(B) receptor agonist on distension-sensitive pelvic nerve afferent fibers innervating rat colon. Am J Physiol Gastrointest Liver Physiol 283:G1343–G1351PubMedGoogle Scholar
  144. Sengupta JN, Petersen J, Peles S, Shaker R (2004) Response properties of antral mechanosensitive afferent fibers and effects of ionotropic glutamate receptor antagonists. Neuroscience 125:711–723PubMedGoogle Scholar
  145. Shigemoto R, Ohishi H, Nakanishi S, Mizuno N (1992) Expression of the mRNA for the rat NMDA receptor (NMDAR1) in the sensory and autonomic ganglion neurons. Neurosci Lett 144:229–232PubMedGoogle Scholar
  146. Slattery JA, Page AJ, Dorian CL, Brierley SM, Blackshaw LA (2006) Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors. J Physiol 577:295–306PubMedGoogle Scholar
  147. Smid SD, Blackshaw LA (2000) Vagal neurotransmission to the ferret lower oesophageal sphincter: inhibition via GABA(B) receptors. Br J Pharmacol 131:624–630PubMedGoogle Scholar
  148. Smid SD, Lynn PA, Templeman R, Blackshaw LA (1998) Activation of non-adrenergic non-cholinergic inhibitory pathways by endogenous and exogenous tachykinins in the ferret lower oesophageal sphincter. Neurogastroenterol Motil 10:149–156PubMedGoogle Scholar
  149. Smid SD, Young RL, Cooper NJ, Blackshaw LA (2001) GABA(B)R expressed on vagal afferent neurones inhibit gastric mechanosensitivity in ferret proximal stomach. Am J Physiol Gastrointest Liver Physiol 281:G1494–G1501PubMedGoogle Scholar
  150. Smith JL, Opekun AR, Larkai E, Graham DY (1989) Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux disease. Gastroenterology 96:683–689PubMedGoogle Scholar
  151. Staunton E, Smid SD, Dent J, Blackshaw LA (2000) Triggering of transient LES relaxations in ferrets: role of sympathetic pathways and effects of baclofen. Am J Physiol Gastrointest Liver Physiol 279:G157–G162PubMedGoogle Scholar
  152. Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci USA 98:6951–6956PubMedGoogle Scholar
  153. Uddman R, Grunditz T, Luts A, Desai H, Fernstrom G, Sundler F (1995) Distribution and origin of the peripheral innervation of rat cervical esophagus. Dysphagia 10:203–212PubMedGoogle Scholar
  154. Wang FB, Powley TL (2000) Topographic inventories of vagal afferents in gastrointestinal muscle. J Comp Neurol 421:302–324PubMedGoogle Scholar
  155. Wank M, Neuhuber WL (2001) Local differences in vagal afferent innervation of the rat esophagus are reflected by neurochemical differences at the level of the sensory ganglia and by different brainstem projections. J Comp Neurol 435:41–59PubMedGoogle Scholar
  156. Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q (2004) The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-d-aspartate receptor. Gastroenterology 126:683–692PubMedGoogle Scholar
  157. Willert RP, Hobson AR, Delaney C, Hicks KJ, Dewit OE, Aziz Q (2007) Neurokinin-1 receptor antagonism in a human model of visceral hypersensitivity. Aliment Pharmacol Ther 25:309–316PubMedGoogle Scholar
  158. Wyman JB, Dent J, Heddle R, Dodds WJ, Toouli J, Downton J (1990) Control of belching by the lower oesophageal sphincter. Gut 31:639–646PubMedGoogle Scholar
  159. Young RL, Page AJ, O'Donnell TA, Cooper NJ, Blackshaw LA (2007) Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5. Am J Physiol Gastrointest Liver Physiol 292:G501–G511PubMedGoogle Scholar
  160. Young RL, Cooper NJ, Blackshaw LA (2008) Chemical coding and central projections of gastric vagal afferent neurons. Neurogastroenterol Motil 20(6):708–718PubMedGoogle Scholar
  161. Yu S, Kollarik M, Ouyang A, Myers AC, Undem BJ (2007) Mast cell-mediated long-lasting increases in excitability of vagal C fibers in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 293:G850–G856PubMedGoogle Scholar
  162. Yu S, Undem BJ, Kollarik M (2005) Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J Physiol 563:831–842PubMedGoogle Scholar
  163. Zagorodnyuk VP, Brookes SJ (2000) Transduction sites of vagal mechanoreceptors in the guinea pig esophagus. J Neurosci 20:6249–6255PubMedGoogle Scholar
  164. Zagorodnyuk VP, Chen BN, Brookes SJ (2001) Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach. J Physiol 534:255–268PubMedGoogle Scholar
  165. Zagorodnyuk VP, D'Antona G, Brookes SJ, Costa M (2002) Functional GABAB receptors are present in guinea pig nodose ganglion cell bodies but not in peripheral mechanosensitive endings. Auton Neurosci 102:20–29PubMedGoogle Scholar
  166. Zagorodnyuk VP, Chen BN, Costa M, Brookes SJ (2003) Mechanotransduction by intraganglionic laminar endings of vagal tension receptors in the guinea-pig oesophagus. J Physiol 553:575–587PubMedGoogle Scholar
  167. Zhang X, Dagerlind A, Elde RP, Castel MN, Broberger C, Wiesenfeld-Hallin Z, Hokfelt T (1993) Marked increase in cholecystokinin B receptor messenger RNA levels in rat dorsal root ganglia after peripheral axotomy. Neuroscience 57:227–233PubMedGoogle Scholar
  168. Zhang Q, Lehmann A, Rigda R, Dent J, Holloway RH (2002) Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 50:19–24PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Nerve Gut Research Laboratory, Level 1 Hanson Institute, Frome Road, Royal Adelaide Hospital, Discipline of Medicine and Discipline of Physiology, School of Molecular and Biomedical SciencesUniversity of AdelaideAdelaideAustralia

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