Visceral Pain and Hypersensitivity Disorders

  • Rosario Privitera
  • Praveen AnandEmail author


Visceral pain and hypersensitivity disorders are common but poorly understood, and their specific treatment is even more limited than for somatic disorders. Visceral hypersensitivity is mediated by small sensory fibers, the Aδ and C afferents, and results from their lowered activation thresholds, change in phenotype, or altered regional density. Visceral and somatic hypersensitivities share some neuropathological mechanisms, as well as convergent signaling pathways, considered to be responsible in the spinal cord for referred pain and dysmotility. However, some mechanisms are distinct, both in the normal state and chronic pain conditions. The transient receptor potential vanilloid type 1 (TRPV1, heat and capsaicin) receptor plays a major role in visceral pain, and also purinergic receptor P2X3, which is selectively expressed by a subset of nociceptors. Neurotrophic factors, particularly nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF), are known to regulate nociceptor function in health and disease; overexposure of nociceptors to neurotrophic factors is a key underlying mechanism in a number of chronic visceral pain syndromes, including irritable bowel syndrome, bladder pain syndrome/interstitial cystitis, and fibromyalgia. Patients with visceral pain are more likely to have other pain conditions, and growing documentation suggests a link with genetic predisposition and environmental triggers.


Transient receptor potential (TRP) channel Transient receptor potential vanilloid type 1 (TRPV1) Purinergic receptor P2X3 Irritable bowel syndrome Bladder pain syndrome/interstitial cystitis Fibromyalgia Voltage-gated sodium channel (Nav


  1. 1.
    Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Sarkar S, Aziz Q, Woolf CJ, Hobson AR, Thompson DG. Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet. 2000;356:1154–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut. 1973;14:125–32.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Salet GA, Samsom M, Roelofs JM, van Berge Henegouwen GP, Smout AJ, Akkermans LM. Responses to gastric distension in functional dyspepsia. Gut. 1998;42:823–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Shembalkar P, Anand P, Junaid I, Fowler C, Williams NS. Neuropathic pain with vesical and rectal hyperreflexia and cocontraction after pelvic surgery. J Neurol Neurosurg Psychiatry. 2001;70:410–1.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Talley NJ, Gabriel SE, Harmsen WS, Zinsmeister AR, Evans RW. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology. 1995;109:1736–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Fullerton S. Functional digestive disorders (FDD) in the year 2000-economic impact. Eur J Surg Suppl. 1998;582:62–4.Google Scholar
  8. 8.
    Klinkman MS, Stevens D, Gorenflo DW. Episodes of care for chest pain: a preliminary report from MIRNET. Michigan Research Network. J Fam Pract. 1994;38:345–52.PubMedGoogle Scholar
  9. 9.
    Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997;112:2120–37.PubMedCrossRefGoogle Scholar
  10. 10.
    Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71–80.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ahangari A. Prevalence of chronic pelvic pain among women: an updated review. Pain Physician. 2014;17:E141–7.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, Nyberg L, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011;186:540–4.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Berry SH, Bogart LM, Pham C, Liu K, Nyberg L, Stoto M, et al. Development, validation and testing of an epidemiological case definition of interstitial cystitis/painful bladder syndrome. J Urol. 2010;183:1848–52.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hall SA, Link CL, Pulliam SJ, Hanno PM, Eggers PW, Kusek JW, et al. The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: results from the Boston area community health survey. J Urol. 2008;180:593–8.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Smith CP. Male chronic pelvic pain: an update. Indian J Urol. 2016;32:34–9.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Rottenstreich M, Glick Y, Gofrit ON. Chronic scrotal pain in young adults. BMC Res Notes. 2017;10:241.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Pukall CF, Goldstein AT, Bergeron S, Foster D, Stein A, Kellogg-Spadt S, et al. Vulvodynia: definition, prevalence, impact, and pathophysiological factors. J Sex Med. 2016;13:291–304.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Sengupta JN. Visceral pain: the neurophysiological mechanism. Handb Exp Pharmacol. 2009;194:31–74.CrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Al-Chaer ED, Kawasaki M, Pasricha PJ. A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology. 2000;119:1276–85.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Verne GN, Himes NC, Robinson ME, Gopinath KS, Briggs RW, Crosson B, et al. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Pain. 2003;103:99–110.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–33.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Cervero F. Visceral pain: mechanisms of peripheral and central sensitization. Ann Med. 1995;27:235–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Anand P, Aziz Q, Willert R, van Oudenhove L. Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil. 2007;19:29–46.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Watkins LR, Maier SF. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu Rev Psychol. 2000;51:29–57.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Jones MP, Dilley JB, Drossman D, Crowell MD. Brain-gut connections in functional GI disorders: anatomic and physiologic relationships. Neurogastroenterol Motil. 2006;18:91–103.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Van Oudenhove L, Demyttenaere K, Tack J, Aziz Q. Central nervous system involvement in functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2004;18:663–80.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Gibson SJ, Polak JM, Anand P, Blank MA, Yiangou Y, Su HC, et al. A VIP/PHI-containing pathway links urinary bladder and sacral spinal cord. Peptides. 1986;7:205–19.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Anand P, Gibson SJ, Yiangou Y, Christofides ND, Polak JM, Bloom SR. PHI-like immunoreactivity co-locates with the VIP-containing system in human lumbosacral spinal cord. Neurosci Lett. 1984;46:191–6.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Anand P, Ghatei MA, Christofides ND, Blank MA, McGregor GP, Morrison JF, et al. Differential neuropeptide expression after visceral and somatic nerve injury in the cat and rat. Neurosci Lett. 1991;128:57–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Anand P, Gibson SJ, McGregor GP, Blank MA, Ghatei MA, Bacarese-Hamilton AJ, et al. A VIP-containing system concentrated in the lumbosacral region of human spinal cord. Nature. 1983;305:143–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Gooneratne ML, Facer P, Knowles CH, Chan CL, Lunniss PJ, Scott SM, et al. Normalization of substance P levels in rectal mucosa of patients with faecal incontinence treated successfully by sacral nerve stimulation. Br J Surg. 2008;95:477–83.PubMedCrossRefGoogle Scholar
  33. 33.
    Costigan M, Woolf CJ. Pain: molecular mechanisms. J Pain. 2000;1:35–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Yiangou Y, Facer P, Baecker PA, Ford AP, Knowles CH, Chan CL, et al. ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease. Neurogastroenterol Motil. 2001;13:365–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, et al. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet. 2001;357:1338–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Yiangou Y, Facer P, Ford A, Brady C, Wiseman O, Fowler CJ, et al. Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int. 2001;87:774–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Yiangou Y, Facer P, Smith JA, Sangameswaran L, Eglen R, Birch R, et al. Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Eur J Gastroenterol Hepatol. 2001;13:891–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Woolf CJ. Phenotypic modification of primary sensory neurons: the role of nerve growth factor in the production of persistent pain. Philos Trans R Soc Lond Ser B Biol Sci. 1996;351:441–8.CrossRefGoogle Scholar
  40. 40.
    Sciberras DG, Goldenberg MM, Bolognese JA, James I, et al. Inflammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation. Br J Clin Pharmacol. 1987;24:753–61.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci U S A. 1994;91:12013–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Chan CLH, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet. 2003;361:385–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol. 2004;16:897–902.PubMedCrossRefGoogle Scholar
  44. 44.
    Yoshida N, Uchiyama K, Kuroda M, Sakuma K, KoKura S, Ichikawa H, Naito Y, et al. Interleukin-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease. Scand J Gastroenterol. 2004;39:816–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Tympanidis P, Casula MA, Yiangou Y, Terenghi G, Dowd P, Anand P. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur J Pain. 2004;8:129–33.PubMedCrossRefGoogle Scholar
  46. 46.
    LaMotte RH, Lundberg LE, Torebjörk HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol. 1992;448:749–64.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain. 1989;38:99–107.PubMedCrossRefGoogle Scholar
  48. 48.
    Koltzenburg M, Lundberg LE, Torebjörk HE. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain. 1992;51:207–19.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306:686–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Woolf CJ. Generation of acute pain: central mechanisms. Br Med Bull. 1991;47:523–33.PubMedCrossRefGoogle Scholar
  51. 51.
    Woolf CJ. An overview of the mechanisms of hyperalgesia. Pulm Pharmacol. 1995;8:161–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44:293–9.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8:1–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999;96:7723–30.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Neumann S, Doubell TP, Leslie T, Woolf CJ. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature. 1996;384:360–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Oddiah D, Anand P, McMahon SB, Rattray M. Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport. 1998;9:1455–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79:572–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Woolf CJ, King AE. Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord. J Neurosci. 1990;10:2717–26.PubMedCrossRefGoogle Scholar
  59. 59.
    Simone DA, Baumann TK, Collins JG, LaMotte RH. Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin. Brain Res. 1989;486:185–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Woolf CJ, Wall PD. Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci. 1986;6:1433–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Qin C, Foreman RD. Viscerovisceral convergence of urinary bladder and colorectal inputs to lumbosacral spinal neurons in rats. Neuroreport. 2004;15:467–71.PubMedCrossRefGoogle Scholar
  62. 62.
    Christianson JA, Liang R, Ustinova EE, Davis BM, Fraser MO, Pezzone MA. Convergence of bladder and colon sensory innervation occurs at the primary afferent level. Pain. 2007;128:235–43.PubMedCrossRefGoogle Scholar
  63. 63.
    Abrams P, Cardozo L, Fall M, Griddiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61:37–49.PubMedCrossRefGoogle Scholar
  64. 64.
    Novi JM, Jeronis S, Srinivas S, Srinivasan R, Morgan MA, Arya LA. Risk of irritable bowel syndrome and depression in women with interstitial cystitis: a case-control study. J Urol. 2005;174:937–40.PubMedCrossRefGoogle Scholar
  65. 65.
    Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, et al. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol. 2010;184:1358–63.PubMedCrossRefGoogle Scholar
  66. 66.
    Costantini R, Affaitati G, Wesselmann U, Cazkanski P, Giamberardino MA. Visceral pain as a triggering factor for fibromyalgia symptoms in comorbid patients. Pain. 2017;158:1925–37.PubMedCrossRefGoogle Scholar
  67. 67.
    Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–43.PubMedCrossRefGoogle Scholar
  68. 68.
    Üçeyler N, Kewenig S, Kafke W, Kittel-Schneider S, Sommer C. Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls. BMC Neurol. 2014;14:185.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Doppler K, Rittner HL, Deckart M, Sommer C. Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia. Pain. 2015;156:2319–25.PubMedCrossRefGoogle Scholar
  70. 70.
    Leinders M, Doppler K, Klein T, Deckart M, Rittner H, Sommer C, et al. Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain. 2016;157:2493–503.PubMedCrossRefGoogle Scholar
  71. 71.
    Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136:1857–67.PubMedCrossRefGoogle Scholar
  72. 72.
    Hobson AR, Aziz Q. Central nervous system processing of human visceral pain in health and disease. News Physiol Sci. 2003;18:109–14.PubMedGoogle Scholar
  73. 73.
    Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377–90.PubMedCrossRefGoogle Scholar
  74. 74.
    Farmer AD, Aziz Q. Visceral pain hypersensitivity in functional gastrointestinal disorders. Br Med Bull. 2009;91:123–36.PubMedCrossRefGoogle Scholar
  75. 75.
    Whitehead WE, Holtkotter B, Enck P, Hoelzl R, Holmes KD, Anthony J, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98:1187–92.PubMedCrossRefGoogle Scholar
  76. 76.
    Lémann M, Dederding JP, Flourié B, Franchisseur C, Rambaud JC, Jian R. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. The irritable stomach syndrome. Dig Dis Sci. 1991;36:1249–54.PubMedCrossRefGoogle Scholar
  77. 77.
    Arnold SJ, Facer P, Yiangou Y, Chen MX, Plumpton C, Tate SN, et al. Decreased potassium channel IK1 and its regulator neurotrophin-3 (NT-3) in inflamed human bowel. Neuroreport. 2003;14:191–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Yiangou Y, Facer P, Birch R, Sangameswaran L, Eglen R, Anand P. P2X3 receptor in injured human sensory neurons. Neuroreport. 2000;11:993–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Akbar A, Yiangou Y, Facer P, Walters JR, Anand P, Ghosh S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 2008;57:923–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Akbar A, Yiangou Y, Facer P, Brydon WG, Walters JR, Anand P, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut. 2010;59:767–74.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Yiangou Y, Facer P, Chessell IP, Bountra C, Chan C, Fertleman C, et al. Voltage-gated ion channel Nav1.7 innervation in patients with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (familial rectal pain). Neurosci Lett. 2007;427:77–82.PubMedCrossRefGoogle Scholar
  82. 82.
    Siah KTH, Wong RK, Whitehead WE. Chronic constipation and constipation-predominant IBS: separate and distinct disorders or a spectrum of disease? Gastroenterol Hepatol (N Y). 2016;12:171–8.Google Scholar
  83. 83.
    Knowles CH, Scott SM, Wellmer A, Misra VP, Pilot MA, Williams NS, et al. Sensory and autonomic neuropathy in patients with idiopathic slow-transit constipation. Br J Surg. 1999;86:54–60.PubMedCrossRefGoogle Scholar
  84. 84.
    Cheng W, Au DK, Knowles CH, Anand P, Tam PK. Hirschsprung’s disease: a more generalised neuropathy? J Pediatr Surg. 2001;36:296–300.PubMedCrossRefGoogle Scholar
  85. 85.
    Facer P, Knowles CH, Tam PK, Ford AP, Dyer N, Baecker PA, et al. Novel capsaicin (VR1) and purinergic (P2X3) receptors in Hirschsprung’s intestine. J Pediatr Surg. 2001;36:1679–84.PubMedCrossRefGoogle Scholar
  86. 86.
    Facer P, Knowles CH, Thomas PK, Tam PK, Williams NS, Anand P. Decreased tyrosine kinase C expression may reflect developmental abnormalities in Hirschsprung’s disease and idiopathic slow-transit constipation. Br J Surg. 2001;88:545–52.PubMedCrossRefGoogle Scholar
  87. 87.
    Gaitonde P, Rostron J, Longman L, Field EA. Burning mouth syndrome and vulvodynia coexisting in the same patient: a case report. Dent Update. 2002;29:75–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Yilmaz Z, Renton T, Yiangou Y, Zakrzewska J, Chessell IP, Bountra C, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007;14:864–71.PubMedCrossRefGoogle Scholar
  89. 89.
    Mukerji G, Yiangou Y, Grogono J, Underwood J, Agarwal SK, Khullar V, et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol. 2006;176:367–73.PubMedCrossRefGoogle Scholar
  90. 90.
    Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev. 2009;60:255–66.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Mukerji G, Yiangou Y, Agarwal SK, Anand P. Increased cannabinoid receptor 1-immunoreactive nerve fibers in overactive and painful bladder disorders and their correlation with symptoms. Urology. 2010;75:1514.e15–20.CrossRefGoogle Scholar
  92. 92.
    Mukerji G, Yiangou Y, Corcoran SL, Selmer IS, Smith GD, Benham CD, et al. Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations. BMC Urol. 2006;6:6.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Mukerji G, Waters J, Chessell IP, Bountra C, Agarwal SK, Anand P. Pain during ice water test distinguishes clinical bladder hypersensitivity from overactivity disorders. BMC Urol. 2006;6:31.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Mukerji G, Yiangou Y, Agarwal SK, Anand P. Transient receptor potential vanilloid receptor subtype 1 in painful bladder syndrome and its correlation with pain. J Urol. 2006;176:797–801.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, et al. Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int. 2004;93:770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Apostolidis A, Brady CM, Yiangou Y, Davis J, Fowler CJ, Anand P. Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin. Urology. 2005;65:400–5.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, et al. P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol. 2004;46:247–53.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol. 2005;174:977–82; discussion 982.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Peripheral Neuropathy Unit, Centre for Clinical Translation, Division of Brain SciencesImperial College London, Hammersmith HospitalLondonUK

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