The neurobiology of visceral nociceptors

Chronic Abdominal and Visceral Pain: Theory and Practice

Volumn , Issue , 2006, Pages 45-66

  Brierley, Stuart M ^a   Blackshaw, L Ashley ^a  

^a UNIVERSITY OF ADELAIDE   (Australia)

Author keywords

[No Author keywords available]

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EID: 85077527069     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (206)

1. Camilleri M. Management of the irritable bowel syndrome. Gastroenterology 2001; 120:652-668.
2. Drossman D, Corazziari E, Talley N, Thompson W, Whitehead W. Rome II: a multinational consensus document on functional gastrointestinal disorders. Gut 1999; 45:1-81.
3. Hungin A, Whorwell P, Tack J, Mearin F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment Pharmacol Ther 2003; 17:643-650.
4. Camilleri M, Choi MG. Review article: irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11:3-15.
5. Jones J, Boorman J, Cann P, et al. British Society of Gastroenterology guidelines for the management of the irritable bowel syndrome. Gut 2000; 47(suppl 2):ii1-ii19.
6. Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut 2000; 46:78-82.
7. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology 2000; 119:654-660.
8. Ragnarsson G, Bodemar G. Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatients samples. Scand J Gastroenterol 1999; 34:993-1000.
9. Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritable bowel syndrome: systematic review. Am J Gastroenterol 2005; 100:1174-1184.
10. Spiller R. Neuropathology of IBS? Gastroenterology 2002; 123:2144-2147.
11. Spiller RC. Irritable bowel syndrome. Br Med Bull 2005; 72:15-29.
12. Spiller R. Postinfectious irritable bowel syndrome (1). Gastroenterology 2003; 124:1662-1671.
13. Ritchie J. Pain from distention of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut 1973; 6:105-112.
14. Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two distinct perceptual alterations in irritable bowel syndrome. Gut 1997; 41:505-512.
15. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126: 693-702.
16. Lembo T, Munakata J, Mertz H, et al. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology 1994; 107:1686-1696.
17. Verne GN, Himes NC, Robinson ME, et al. Central representation of visceral and cutaneous hyper-sensitivity in the irritable bowel syndrome. Pain 2003; 103:99-110.
18. Munakata J, Naliboff B, Harraf F, et al. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology 1997; 112:55-63.
19. Chadwick V, Chen W, Shu D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002; 122:1778-1783.
20. Dunlop S, Jenkins D, Neal K, Spiller R. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003; 125:1651-1659.
21. Wilhelmsen I. The role of psychosocial factors in gastrointestinal disorders. Gut 2000; 47(suppl 4): iv73-iv75.
22. Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2001; 280:G519-G524.
23. Schmulson M, Lee OY, Chang L, Naliboff B, Mayer EA. Symptom differences in moderate to severe IBS patients based on predominant bowel habit. Am J Gastroenterol 1999; 94:2929-2935.
24. Mayer EA. Psychological stress and colitis. Gut 2000; 46:595-596.
25. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut 2000; 47:861-869.
26. Emmanuel AV, Mason HJ, Kamm MA. Relationship between psychological state and level of activity of extrinsic gut innervation in patients with a functional gut disorder. Gut 2001; 49:209-213.
27. Berthoud HR, Patterson LM, Willing AE, Mueller K, Neuhuber WL. Capsaicin-resistant vagal afferent fibers in the rat gastrointestinal tract: anatomical identification and functional integrity. Brain Res 1997; 746:195-206.
28. Blackshaw LA, Gebhart GF. The pharmacology of gastrointestinal nociceptive pathways. Curr Opin Pharmacol 2002; 2:642-649.
29. Berthoud HR, Jedrezejewska A, Powley TL. Simultaneous labeling of vagal innervation of the gut and afferent projections form the visceral forebrain with Dil injected into the dorsal vagal complex in the rat. J Comp Neurol 1990; 301:65-79.
30. Baron R, Janig W, McLachlan EM. The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. III. The colonic nerves, incorporating an analysis of all components of the lumbar prevertebral outflow. J Comp Neurol 1985; 238:158-168.
31. Baron R, Janig W, McLachlan EM. The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. II. The lumbar splanchnic nerves. J Comp Neurol 1985; 238:147-157.
32. Baron R, Janig W, McLachlan EM. The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. I. The hypogastric nerve. J Comp Neurol 1985; 238:135-146.
33. Baron R, Janig W, Kollmann W. Sympathetic and afferent somata projecting in hindlimb nerves and the anatomical organization of the lumbar sympathetic nervous system of the rat. J Comp Neurol 1988; 275:460-468.
34. Baron R, Janig W. Afferent and sympathetic neurons projecting into lumbar visceral nerves of the male rat. J Comp Neurol 1991; 314:429-436.
35. Sengupta J, Gebhart G. The sensory innervation of the colon and its modulation. Curr Opin Gastroenterol 1998; 14:15-20.
36. Janig W, Koltzenburg M. Receptive properties of sacral primary afferent neurons supplying the colon. J Neurophysiol 1991; 65:1067-1077.
37. Janig W, Koltzenburg M. On the function of spinal primary afferent fibres supplying colon and urinary bladder. J Auton Nerv Syst 1990; 30(suppl):S89-S96.
38. Nadelhaft I, Vera PL. Neurons labelled after the application of tracer to the distal stump of the transected hypogastric nerve in the rat. J Auton Nerv Syst 1991; 36:87-96.
39. Ness TJ, Gebhart GF. Characterization of neurons responsive to noxious colorectal distension in the T13-L2 spinal cord of the rat. J Neurophysiol 1988; 60:1419-1438.
40. Hulsebosch CE, Coggeshall RE. An analysis of the axon populations in the nerves to the pelvic viscera in the rat. J Comp Neurol 1982; 211:1-10.
41. Traub RJ, Hutchcroft K, Gebhart GF. The peptide content of colonic afferents decreases following colonic inflammation. Peptides 1999; 20:267-273.
42. Keast J, de Groat W. Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J Comp Neurol 1992; 319:615-623.
43. Robinson DR, McNaughton PA, Evans ML, Hicks GA. Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling. Neurogastroenterol Motil 2004; 16:113-124.
44. Berthoud HR, Patterson LM, Neumann F, Neuhuber WL. Distribution and structure of vagal afferent intraganglionic laminar endings (IGLEs) in the rat gastrointestinal tract. Anat Embryol (Berl) 1997; 195:183-191.
45. Phillips RJ, Powley TL. Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Res Brain Res Rev 2000; 34:1-26.
46. Fox EA, Phillips RJ, Martinson FA, Baronowsky EA, Powley TL. Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse: morphology and topography. J Comp Neurol 2000; 428:558-576.
47. Wang FB, Powley TL. Topographic inventories of vagal afferents in gastrointestinal muscle. J Comp Neurol 2000; 421:302-324.
48. Zagorodnyuk VP, Brookes SJ. Transduction sites of vagal mechanoreceptors in the guinea pig esophagus. J Neurosci 2000; 20:6249-6255.
49. Zagorodnyuk VP, Chen BN, Brookes SJ. Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach. J Physiol 2001; 534:255-268.
50. Zagorodnyuk VP, Chen BN, Costa M, Brookes SJ. Mechanotransduction by intraganglionic laminar endings of vagal tension receptors in the guinea-pig oesophagus. J Physiol 2003; 553:575-587.
51. Berthoud HR, Blackshaw LA, Brookes SJ, Grundy D. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol Motil 2004; 16(suppl 1):28-33.
52. Neuhuber WL, Kressel M, Stark A, Berthoud HR. 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 1998; 70:92-102.
53. Neuhuber W. Sensory vagal innervation of the rat esophagus and cardia. A light and electron microscopic anterograde tracing study. J Auton Nerv Syst 1987; 20:243-255.
54. Lynn PA, Olsson C, Zagorodnyuk V, Costa M, Brookes SJ. Rectal intraganglionic laminar endings are transduction sites of extrinsic mechanoreceptors in the guinea pig rectum. Gastroenterology 2003; 125:786-794.
55. Lynn PA, Zagorodnyuk VP, Hennig GW, Costa M, Brookes SJH. Mechanical activation of rectal intraganglionic laminar endings in the guinea pig distal gut. J Physiol (Lond) 2005; 564:589-601.
56. Zagorodnyuk VP, Lynn P, Costa M, Brookes SJH. Mechanisms of mechanotransduction by specialized low threshold mechanoreceptors in the guinea pig rectum. Am J Physiol Gastrointest Liver Physiol 2005; 289(3):G397-G406.
57. Olsson C, Costa M, Brookes SJ. Neurochemical characterization of extrinsic innervation of the guinea pig rectum. J Comp Neurol 2004; 470:357-371.
58. Berthoud HR, Powley TL. Vagal afferent innervation of the rat fundic stomach: morphological characterization of the gastric tesion receptor. J Comp Neurol 1992; 319:261-276.
59. Ward S, Bayguinov J, Won K, Grundy D, Berthoud H. Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract. J Comp Neurol 2003; 465:121-135.
60. Clerc N, Mazzia C. 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 1994; 347:171-186.
61. Lewin GR, Moshourab R. Mechanosensation and Pain. J Neurobiol 2004; 61:30-44.
62. Koltzenburg M, Stucky CL, Lewin GR. Receptive properties of mouse sensory neurons innervating hairy skin. J Neurophysiol 1997; 78:1841-1850.
63. Cervero F. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol Rev 1994; 74:95-138.
64. Sengupta JN, Gebhart GF. Characterization of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat. J Neurophysiol 1994; 71:2046-2060.
65. Morrison JFB. Splanchnic slowly adapting mechanoreceptors with punctate receptove fields in the mesentery and the gastrointestinal tract of the cat. J Physiol 1973; 233:349-361.
66. Janig W, Koltzenburg M. The neural basis of consciously perceived sensations from the gut. In: Singer MV, Goebell H, eds. Nerves in the Gastrointestinal Tract. Lancester: MTP Press, 1989: 183-197.
67. Blumberg H, Haupt P, Janig W, Kohler W. Encoding of visceral noxious stimuli in the discharge patterns of visceral afferent fibres from the colon. Pflugers Arch 1983; 398:33-40.
68. Janig W, Haupt-Schade P, Kohler W. Afferent innervation of the colon: the neurophysiological basis for visceral sensation and pain. In: In: Basic and Clinical Aspects of Chronic Abdominal Pain. Amsterdam: Elsevier, 1993:71-86.
69. Sengupta JN, Gebhart GF. Mechanosensitive properties of pelvic nerve afferent fibers innervating the urinary bladder of the rat. J Neurophysiol 1994; 72:2420-2430.
70. Grundy D. What activates visceral afferents?. Gut 2004; 53:5ii-8ii.
71. Page AJ, Blackshaw LA. An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach. J Physiol 1998; 512(Pt 3):907-916.
72. Page AJ, Martin CM, Blackshaw LA. Vagal mechanoreceptors and chemoreceptors in mouse stomach and esophagus. J Neurophysiol 2002; 87:2095-2103.
73. Haupt P, Janig W, Kohler W. Response pattern of visceral afferent fibres, supplying the colon, upon chemical and mechanical stimuli. Pflugers Arch 1983; 398:41-47.
74. Berthoud HR, Lynn PA, Blackshaw LA. Vagal and spinal mechanosensors in the rat stomach and colon have multiple receptive fields. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1371-R1381.
75. Su X, Gebhart GF. Mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat are polymodal in character. J Neurophysiol 1998; 80:2632-2644.
76. Lynn PA, Blackshaw LA. In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon. J Physiol 1999; 518(Pt 1):271-282.
77. Hicks GA, Coldwell JR, Schindler M, et al. Excitation of rat colonic afferent fibres by 5-HT(3) receptors. J Physiol 2002; 544:861-869.
78. Bahns E, Halsband U, Janig W. Responses of sacral visceral afferents from the lower urinary tract, colon and anus to mechanical stimulation. Pflugers Arch 1987; 410:296-303.
79. Ruhl A, Thewissen M, Ross H, Cleveland S, Frieling T, Enck P. Discharge patterns of intramural mechanoreceptive afferents during selective distension of the cat's rectum. Neurogastroenterol Motil 1998; 10:219-225.
80. Brierley SM, Jones RCW III, Gebhart GF, Blackshaw LA. Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 2004; 127:166-178.
81. Bahr R, Bartel B, Blumberg H, Janig W. Secondary functional properties of lumbar visceral preganglionic neurons. J Auton Nerv Syst 1986; 15:141-152.
82. Bahr R, Bartel B, Blumberg H, Janig W. Functional characterization of preganglionic neurons projecting in the lumbar splanchnic nerves: neurons regulating motility. J Auton Nerv Syst 1986; 15:109-130.
83. Bessou P, Perl ER. Amovement receptor of the small intestine. J Physiol 1966; 182:404-426.
84. Brierley SM, Jones RCW III, Xu L, Gebhart GF, Blackshaw LA. Activation of splanchnic and pelvic colonic afferents by bradykinin in mice. Neurogastroenterol & Motility 2005; 17(6):854-862.
85. Brierley SM, Jones RCW III, Xu L, et al. Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice. J Physiol 2005; 567:267-281.
86. Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol 2001; 280:G787-G794.
87. Blackshaw LA. Receptors and transmission in the brain-gut axis: potential for novel therapies. IV. GABA(B) receptors in the brain-gastroesophageal axis. Am J Physiol Gastrointest Liver Physiol 2001; 281:G311-G315.
88. Bueno L, Fioramonti J, Delvaux M, Frexinos J. Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology 1997; 112:1714-1743.
89. Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut 2002; 51:19i-23i.
90. Bueno L, Fioramonti J, Garcia-Villar R. Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. III. Visceral afferent pathways: a source of new therapeutic targets for abdominal pain. Am J Physiol Gastrointest Liver Physiol 2000; 278:G670-G676.
91. Grundy D, Winchester W. Molecular mechanisms in the control of gastrointestinal function. Curr Opin Pharmacol 2003; 3:S1-S4.
92. Cervero F, Laird JM. Role of ion channels in mechanisms controlling gastrointestinal pain pathways. Curr Opin Pharmacol 2003; 3:608-612.
93. Cervero F, Laird JM. Understanding the signaling and transmission ofvisceral nociceptive events. J Neurobiol 2004; 61:45-54.
94. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389:816-824.
95. Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288:306-313.
96. Caterina MJ, Julius D. The vanilloid receptor: a Molecular Gateway to the Pain Pathway. Annu Rev Neurosci 2001; 24:487-517.
97. Davis JB, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405:183-187.
98. North RA. P2X3 receptors and peripheral pain mechanisms. J Physiol 2004; 554:301-308.
99. North RA. Molecular Physiology of P2X Receptors. Physiol Rev 2002; 82:1013-1067.
100. Berkley KJ, Robbins A, Sato Y. Functional differences between afferent fibers in the hypogastric and pelvic nerves innervating female reproductive organs in the rat. J Neurophysiol 1993; 69: 533-544.
101. Franz M, Mense S. Muscle receptors with group IV afferent fibres responding to application of bradykinin. Brain Res 1975; 92:369-383.
102. Messlinger K, Pawlak M, Schepelmann K, Schmidt RF. Responsiveness of slowly conducting articular afferents to bradykinin: effects of an experimental arthritis. Pain 1994; 59:335-343.
103. Mizumura K, Minagawa M, Tsujii Y, Kumazawa T. The effects of bradykinin agonists and antagonists on visceral polymodal receptor activities. Pain 1990; 40:221-227.
104. Shin J et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci U S A 2002; 99:10150-10155.
105. Tjen ALSC, Pan HL, Longhurst JC. Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats. J Physiol 1998; 510(Pt 2):633-641.
106. Brunsden AM, Grundy D. Sensitization of visceral afferents to bradykinin in rat jejunum in vitro. J Physiol 1999; 521(Pt 2):517-527.
107. Koltzenburg M, Kress M, Reeh PW. The nociceptor sensitization by bradykinin does not depend on sympathetic neurons. Neuroscience 1992; 46:465-473.
108. Neugebauer V, Schaible HG, Schmidt RF. Sensitization of articular afferents to mechanical stimuli by bradykinin. Pflugers Arch 1989; 415:330-335.
109. Rong W, Hillsley K, Davis JB, Hicks GA, Winchester WJ, Grundy D. Jejunal afferent nerve sensitivity in wild type and TRPV1 knockout mice. J Physiol (Lond) 2004; 560:867-881.
110. Souslova V, Cesare P, Ding Y, et al. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 2000; 407:1015-1017.
111. Cockayne DA et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 2000; 407:1011-1015.
112. Dai Y, Fukuoka T, Wang H, et al. Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. Pain 2004; 108: 258-266.
113. Yiangou Y, Facer P, Baecker PA, et al. ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease. Neurogastroenterol Motil 2001; 13:365-369.
114. Yiangou Y, Facer P, Dyer NHC, et al. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 2001; 357:1338-1339.
115. Yiangou Y, Facer P, Smith JAM, et al. Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Eu J Gastroenterol Hepatol 2001; 13:891-896.
116. Stadnicki A, Pastucha E, Nowaczyk G, et al. Immunolocalization and expression of kinin B1R and B2R receptors in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2005; 289:G361-G366.
117. Vulchanova L, Riedl MS, Shuster SJ, et al. Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology 1997; 36:1229-1242.
118. Vulchanova L, Riedl MS, Shuster SJ, et al. P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eu J Neurosci 1998; 10:3470-3478.
119. Barden JA, Bennett MR. Distribution of P2X purinoceptor clusters on individual rat dorsal root ganglion cells. Neurosci Lett 2000; 287:183-186.
120. Bradbury EJ, Burnstock G, McMahon SB. The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 1998; 12:256-268.
121. Guo A, Vulchanova L, Wang J, Li X, Elde R. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eu J Neurosci 1999; 11:946-958.
122. Petruska JC, Cooper BY, Gu JG, Rau KK, Johnson RD. Distribution of P2X1, P2X2, and P2X3 receptor subunits in rat primary afferents: relation to population markers and specific cell types. J Chem Neuroanat 2000; 20:141-162.
123. Wynn G, Rong W, Xiang Z, Burnstock G. Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum. Gastroenterology 2003; 125:1398-1409.
124. Chen CC, Akopian AN, Sivilottit L, Colquhoun D, Burnstock G, Wood JN. A P2X purinceptor expressed by a subset of sensory neurons. Nature 1995; 377:428-431.
125. Aoki Y, Takahashi Y, Ohtori S, Moriya H, Takahashi K. Distribution and immunocytochemical characterization of dorsal root ganglion neurons innervating the lumbar intervertebral disc in rats: a review. Life Sci 2004; 74:2627-2642.
126. Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB. ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 1997; 17:5297-5304.
127. Burgard EC, Niforatos W, van Biesen T, et al. P2X receptor-mediated ionic currents in dorsal root ganglion neurons. J Neurophysiol 1999; 82:1590-1598.
128. Chen M, Gu J. A P2X receptor-mediated nociceptive afferent pathway to lamina I of the spinal cord. Mol Pain 2005; 1:4.
129. Grubb BD, Evans RJ. Characterization of cultured dorsal root ganglion neuron P2X receptors. Eu J Neurosci 1999; 11:149-154.
130. Petruska JC, Cooper BY, Johnson RD, Gu JG. Distribution patterns of different P2x receptor pheno-types in acutely dissociated dorsal root ganglion neurons of adult rats. Exper Brain Res 2000; 134:126-132.
131. Burnstock G. P2X receptors in sensory neurones. Br J Anaesth 2000; 84:476-488.
132. Kirkup AJ, Booth CE, Chessell IP, Humphrey PP, Grundy D. Excitatory effect of P2X receptor activation on mesenteric afferent nerves in the anaesthetised rat. J Physiol 1999; 520(Pt 2):551-563.
133. Page AJ, O'Donnell TA, Blackshaw LA. P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation. J physiol (lond) 2000; 523(Pt 2):403-411.
134. Brierley SM, Carter R, Jones CRW, et al. Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice. J Physiol 2005; 567:267-281.
135. Marceau F, Hess JF, Bachvarov DR. The B1 Receptors for Kinins. Pharmacol Rev 1998; 50:357-386.
136. Leeb-Lundberg LMF, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL. International Union of Pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005; 57:27-77.
137. Hall JM. Bradykinin receptors. Gen Pharmac 1997; 28:1-6.
138. Pan HL, Chen SR. Myocardial ischemia recruits mechanically insensitive cardiac sympathetic afferents in cats. J Neurophysiol 2002; 87:660-668.
139. Kajekar R, Proud D, Myers AC, Meeker SN, Undem BJ. Characterization of vagal afferent subtypes stimulated by bradykinin in guinea pig trachea. J Pharmacol Exp Ther 1999; 289:682-687.
140. Maubach KA, Grundy D. The role of prostaglandins in the bradykinin-induced activation of serosal afferents of the rat jejunum in vitro. J Physiol 1999; 515(Pt 1):277-285.
141. Bandell M, Story GM, Hwang SW, et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 2004; 41:849-857.
142. Clapham DE, Montell C, Schultz G, Julius D. International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels. Pharmacol Rev 2003; 55:591-596.
143. Caterina MJ, Julius D. Sense and specificity: a molecular identity for nociceptors. Curr Opin Neurobiol 1999; 9:525-530.
144. Tominaga M, Julius D. Capsaicin receptor in the pain pathway. Jap J Pharmacol 2000; 83:20-24.
145. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413:203-210.
146. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002; 416:52-58.
147. Jordt S-E, Julius D. Molecular basis for species-specific sensitivity to "hot" chili peppers. Cell 2002; 108:421-430.
148. Jordt SE, Tominaga M, Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 2000; 97:8134-8139.
149. Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998; 21:531-543.
150. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J. VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 2001; 13:2105-2114.
151. Hwang SJ, Min Oh J, Valtschanoff JG. Expression of the vanilloid receptor TRPV1 in rat dorsal root ganglion neurons supports different roles of the receptor in visceral and cutaneous afferents. Brain Res 2005; 1047:261-266.
152. Jordt S-E, McKemy DD, Julius D. Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 2003; 13:487-492.
153. Holzer P. Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve. Am J Physiol 1998; 275:G8-G13.
154. Bielefeldt K. Differential effects of capsaicin on rat visceral sensory neurons. Neuroscience 2000; 101:727-736.
155. Su X, Wachtel RE, Gebhart GF. Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia. Am J Physiol 1999; 277:G1180-G1188.
156. Blackshaw LA, Page AJ, Partosoedarso ER. Acute effects of capsaicin on gastrointestinal vagal afferents. Neuroscience 2000; 96:407-416.
157. Longhurst JC, Kaufman MP, Ordway GA, Musch TI. Effects of bradykinin and capsaicin on endings of afferent fibers from abdominal visceral organs. Am J Physiol 1984; 247:R552-R559.
158. Sugiura T, Bielefeldt K, Gebhart GF. TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. J Neurosci 2004; 24:9521-9530.
159. Chan C, Facer P, Davis J, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 2003; 361:385-391.
160. Kimball ES, Wallace NH, Schneider CR, D'Andrea MR, Hornby PJ. Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice. Neurogastroenterol Motil 2004; 16:1-8.
161. Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L. The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 1990; 68:325-345.
162. Bearcroft CP, Perrett D, Farthing MJ. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998; 42:42-46.
163. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000; 47:804-811.
164. O'Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000; 12:449-457.
165. Houghton LA, Atkinson W, Whitaker RP, Whorwell PJ, Rimmer MJ. Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome. Gut 2003; 52:663-670.
166. Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000; 355:1035-1040.
167. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 2004; 126:1657-1664.
168. Blackshaw LA, Grundy D. Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Auton Nerv Syst 1993; 45:41-50.
169. Hillsley K, Kirkup AJ, Grundy D. Direct and indirect actions of 5-hydroxytryptamine on the discharge of mesenteric afferent fibres innervating the rat jejunum. J Physiol 1998; 506(Pt 2):551-561.
170. Zhu JX, Zhu XY, Owyang C, Li Y. Intestinal serotonin acts as a paracrine substance to mediate vagal signal transmission evoked by luminal factors in the rat. J Physiol 2001; 530:431-442.
171. Zeitz KP, Guy N, Malmberg AB, et al. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci 2002; 22:1010-1019.
172. Danzebrink RM, Gebhart GF. Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. Brain Res 1991; 538:64-75.
173. McRoberts JA, Coutinho SV, Marvizon JC, et al. Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 2001; 120:1737-1748.
174. Sengupta JN, Petersen J, Peles S, Shaker R. Response properties of antral mechanosensitive afferent fibers and effects of ionotropic glutamate receptor antagonists. Neuroscience 2004; 125:711-723.
175. Page AJ, Young RL, Martin CM, et al. Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons. Gastroenterology 2005; 128:402-410.
176. Blackshaw LA, Staunton E, Lehmann A, Dent J. Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am J Physiol 1999; 277:G867-G874.
177. Page AJ, Blackshaw LA. GABA(B) receptors inhibit mechanosensitivity of primary afferent endings. J Neurosci 1999; 19:8597-8602.
178. Smid SD, Young RL, Cooper NJ, Blackshaw LA. GABA(B)R expressed on vagal afferent neurones inhibit gastric mechanosensitivity in ferret proximal stomach. Am J Physiol Gastrointest Liver Physiol 2001; 281:G1494-G1501.
179. Staunton E, Smid SD, Dent J, Blackshaw LA. Triggering of transient LES relaxations in ferrets: role of sympathetic pathways and effects of baclofen. Am J Physiol Gastrointest Liver Physiol 2000; 279:G157-G162.
180. Sengupta JN, Medda BK, Shaker R. Effect of GABA(B) receptor agonist on distension-sensitive pelvic nerve afferent fibers innervating rat colon. Am J Physiol Gastrointest Liver Physiol 2002; 283:G1343-G1351.
181. Page AJ, Slattery JA, O'Donnell TA, Cooper NJ, Young RL, Blackshaw L. Modulation of gastrooesophageal vagal afferents by galanin in mouse and ferret. J Physiol 2005; 563:809-819.
182. Hollenberg MD, Compton SJ. International Union of Pharmacology. XXVIII. Proteinase activated receptors. Pharmacol Rev 2002; 54:203-217.
183. Vergnolle N. Modulation of visceral pain and inflammation by protease-activated receptors. Br J Pharmacol 2004; 141:1264-1274.
184. Vergnolle N, Cellars L, Mencarelli A, et al. A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J Clin Invest 2004; 114:1444-1456.
185. Kirkup A, Bunnett N, Grundy D. A proteinase-activated receptor subtype 2 (PAR-2) agonist stimulates mesenteric afferent nerve discharge. Gastroenterology 2000; 118:A173.
186. Amadesi S, Nie J, Vergnolle N, et al. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 2004; 24: 4300-4312.
187. Beyak MJ, Ramji N, Krol KM, Kawaja MD, Vanner SJ. Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability. Am J Physiol Gastrointest Liver Physiol 2004; 287:G845-G855.
188. Krempels K, Hunyady B, O'Carroll A, Mezey E. Distribution of somatostatin receptor messenger RNAs in the rat gastrointestinal tract. Gastroenterology 1997; 112:1948-1960.
189. Hasler W, Soudah H, Owyang C. Somatostatin analog inhibits afferent response to rectal distention in diarrhea-predominant irritable bowel patients. J Pharmacol Exp Ther 1994; 268:1206-1211.
190. Booth CE, Kirkup AJ, Hicks GA, Humphrey PP, Grundy D. Somatostatin sst(2) receptor-mediated inhibition of mesenteric afferent nerves of the jejunum in the anesthetized rat. Gastroenterology 2001; 121:358-369.
191. Gillespie PG, Walker RG. Molecular basis of mechanosensory transduction. Nature 2001; 413: 194-202.
192. Welsh MJ, Price MP, Xie J. Biochemical basis of touch perception: mechanosensory function of degenerin/epithelial Na+ channels. J Biol Chem 2002; 277:2369-2372.
193. Suzuki M, Mizuno A, Kodaira K, Imai M. Impaired pressure sensation in mice lacking TRPV4. J Biol Chem 2003; 278:22664-22668.
194. Corey DP et al. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 2004; 432:723-730.
195. Liedtke WB. TRPV4 plays an evolutionary conserved role in the transduction of osmotic and mechanical stimuli in live animals. J Physiol (Lond) 2005; 567:53-58.
196. Driscoll M, Chalfie M. The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 1991; 349:588-593.
197. Benson CJ, Xie J, Wemmie JA, et al. Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc Natl Acad Sci U S A 2002; 99:2338-2343.
198. Price MP et al. The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 2000; 407:1007-1011.
199. Price MP, McIlwrath SL, Xie J, et al. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 2001; 32:1071-1083.
200. Page AJ, Brierley SM, Martin CM, et al. The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology 2004; 127:1739-1747.
201. Page A, Brierley SM, Martin CM, et al. Different contributions of ASIC channels 1a, 2 and 3 in gastrointestinal mechanosensory function. Gut 2005; 54(10):1408-1415.
202. Price MP, Thompson RJ, Eshcol JO, Wemmie JA, Benson CJ. Stomatin modulates gating of acid-sensing ion channels. J Biol Chem 2004; 279:53886-53891.
203. Tavernarakis N, Driscoll M. Molecular modeling of mechanotransduction in the nematode Caenor-habditis elegans. Annu Rev Physiol 1997; 59:659-689.
204. Chalfie M, Au M. Genetic control of differentiation of the caenorhabditis elegans touch receptor neurons. Science 1989; 243:1027-1033.
205. Cook SP, McCleskey EW. ATP, pain and a full bladder. Nature 2000; 407:951-952.
206. Wynn G, Ma B, Ruan HZ, Burnstock G. Purinergic component of mechanosensory transduction is increased in a rat model of colitis. Am J Physiol Gastrointest Liver Physiol 2004; 287:G647-G657.