Urogenit Tract Infect.  2018 Aug;13(2):26-34. 10.14777/uti.2018.13.2.26.

Potential Mechanisms Underlying the Increased Excitability of the Bladder Afferent Pathways in Interstitial Cystitis/Bladder Pain Syndrome

Affiliations
  • 1Department of Urology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea. urokds@schmc.ac.kr

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic debilitating disorder associated with lower urinary tract symptoms, including frequency, urgency, and suprapubic pain, which inconveniences the patients and seriously impairs their quality of life. Although the etiology of IC/BPS is unknown, intense research has been conducted focusing on the involvement of the bladder afferent nerve in regard to the cellular mechanisms underlying neurogenic inflammation of the urinary bladder. The involvement of neurogenic inflammation in patients with IC/BPS is supported by several animal models of bladder inflammation as well as clinical studies. Chronic bladder inflammation can result in functional and anatomical changes in the primary afferent neurons through the expression of inflammation-related proteins/receptors in the urinary bladder and bladder afferent pathways, leading to pain symptoms in patients with IC/BPS. In addition, neurogenic inflammation of the bladder mucosa can induce the central sensitization as well as the peripheral sensitization, and the neuroimmune overactivity and toll-like receptor (TLR) signaling of the immune cells involve complex mechanisms of central sensitization. This review presents the potential mechanisms underlying the afferent hyperexcitability of the bladder in IC/BPS and summarizes the neurogenic inflammation, neurotrophic factors, TLRs, and neuroimmune communication.

Keyword

Afferent pathways; Urinary bladder; Interstitial cystitis; Physiopathology; Neurogenic inflammation

MeSH Terms

Afferent Pathways*
Central Nervous System Sensitization
Cystitis, Interstitial
Humans
Inflammation
Lower Urinary Tract Symptoms
Models, Animal
Mucous Membrane
Nerve Growth Factors
Neurogenic Inflammation
Neurons, Afferent
Quality of Life
Toll-Like Receptors
Urinary Bladder*
Nerve Growth Factors
Toll-Like Receptors

Reference

1. Konkle KS, Berry SH, Elliott MN, Hilton L, Suttorp MJ, Clauw DJ, et al. Comparison of an interstitial cystitis/bladder pain syndrome clinical cohort with symptomatic community women from the RAND interstitial cystitis epidemiology study. J Urol. 2012; 187:508–512.
Article
2. Choe JH, Son H, Song YS, Kim JC, Lee JZ, Lee KS. Prevalence of painful bladder syndrome/interstitial cystitis-like symptoms in women: a population-based study in Korea. World J Urol. 2011; 29:103–108.
Article
3. Hanno PM, Burks DA, Clemens JQ, Dmochowski RR, Erickson D, Fitzgerald MP, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol. 2011; 185:2162–2170.
Article
4. Yoshimura N, Oguchi T, Yokoyama H, Funahashi Y, Yoshikawa S, Sugino Y, et al. Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. Int J Urol. 2014; 21:18–25.
Article
5. Chancellor MB, Yoshimura N. Treatment of interstitial cystitis. Urology. 2004; 63:85–92.
Article
6. Grover S, Srivastava A, Lee R, Tewari AK, Te AE. Role of inflammation in bladder function and interstitial cystitis. Ther Adv Urol. 2011; 3:19–33.
Article
7. Birder LA, Kullmann FA. Role of neurogenic inflammation in local communication in the visceral mucosa. Semin Immunopathol. 2018; 40:261–279.
Article
8. Schrepf A, O'Donnell M, Luo Y, Bradley CS, Kreder K, Lutgendorf S. Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: associations with painful symptoms. Pain. 2014; 155:1755–1761.
Article
9. Birder L, Andersson KE. Urothelial signaling. Physiol Rev. 2013; 93:653–680.
Article
10. Yoshimura N, Kaiho Y, Miyazato M, Yunoki T, Tai C, Chancellor MB, et al. Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol. 2008; 377:437–448.
Article
11. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008; 9:453–466.
Article
12. de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015; 5:327–396.
Article
13. de Groat WC, Yoshimura N. Anatomy and physiology of the lower urinary tract. Handb Clin Neurol. 2015; 130:61–108.
Article
14. Habler HJ, Janig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol. 1990; 425:545–562.
Article
15. Fall M, Lindstrom S, Mazieres L. A bladder-to-bladder cooling reflex in the cat. J Physiol. 1990; 427:281–300.
Article
16. Yoshimura N, Seki S, Chancellor MB, de Groat WC, Ueda T. Targeting afferent hyperexcitability for therapy of the painful bladder syndrome. Urology. 2002; 59:61–67.
Article
17. Geppetti P, Nassini R, Materazzi S, Benemei S. The concept of neurogenic inflammation. BJU Int. 2008; 101:Suppl 3. 2–6.
Article
18. Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation. Br J Pharmacol. 2013; 170:38–45.
Article
19. Sculptoreanu A, de Groat WC, Tony Buffington CA, Birder LA. Abnormal excitability in capsaicin-responsive DRG neurons from cats with feline interstitial cystitis. Exp Neurol. 2005; 193:437–443.
Article
20. Roppolo JR, Tai C, Booth AM, Buffington CA, de Groat WC, Birder LA. Bladder Adelta afferent nerve activity in normal cats and cats with feline interstitial cystitis. J Urol. 2005; 173:1011–1015.
Article
21. Gao Y, Zhang R, Chang HH, Rodriguez LV. The role of C-fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: a multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study. Neurourol Urodyn. 2018; 37:673–680.
Article
22. Vizzard MA, Erdman SL, de Groat WC. Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic bladder irritation. J Comp Neurol. 1996; 370:191–202.
Article
23. Vizzard MA, Boyle MM. Increased expression of growth-associated protein (GAP-43) in lower urinary tract pathways following cyclophosphamide (CYP)-induced cystitis. Brain Res. 1999; 844:174–187.
Article
24. Vizzard MA. Up-regulation of pituitary adenylate cyclase-activating polypeptide in urinary bladder pathways after chronic cystitis. J Comp Neurol. 2000; 420:335–348.
Article
25. Vizzard MA. Alterations in neuropeptide expression in lumbosacral bladder pathways following chronic cystitis. J Chem Neuroanat. 2001; 21:125–138.
Article
26. Dattilio A, Vizzard MA. Up-regulation of protease activated receptors in bladder after cyclophosphamide induced cystitis and colocalization with capsaicin receptor (VR1) in bladder nerve fibers. J Urol. 2005; 173:635–639.
Article
27. Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC. Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol. 1995; 75:744–750.
Article
28. Marchand JE, Sant GR, Kream RM. Increased expression of substance P receptor-encoding mRNA in bladder biopsies from patients with interstitial cystitis. Br J Urol. 1998; 81:224–228.
Article
29. Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001; 57:47–55.
Article
30. Theoharides TC, Pang X, Letourneau R, Sant GR. Interstitial cystitis: a neuroimmunoendocrine disorder. Ann N Y Acad Sci. 1998; 840:619–634.
31. Christmas TJ, Rode J, Chapple CR, Milroy EJ, Turner-Warwick RT. Nerve fibre proliferation in interstitial cystitis. Virchows Arch A Pathol Anat Histopathol. 1990; 416:447–451.
Article
32. 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; 93:770–776.
Article
33. Ochodnicky P, Cruz CD, Yoshimura N, Cruz F. Neurotrophins as regulators of urinary bladder function. Nat Rev Urol. 2012; 9:628–637.
Article
34. Okragly AJ, Niles AL, Saban R, Schmidt D, Hoffman RL, Warner TF, et al. Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients. J Urol. 1999; 161:438–441. discussion 441-2.
Article
35. 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; 79:572–577.
Article
36. Bjorling DE, Jacobsen HE, Blum JR, Shih A, Beckman M, Wang ZY, et al. Intravesical Escherichia coli lipopolysaccharide stimulates an increase in bladder nerve growth factor. BJU Int. 2001; 87:697–702.
Article
37. Dmitrieva N, Shelton D, Rice AS, McMahon SB. The role of nerve growth factor in a model of visceral inflammation. Neuroscience. 1997; 78:449–459.
Article
38. Zvara P, Vizzard MA. Exogenous overexpression of nerve growth factor in the urinary bladder produces bladder overactivity and altered micturition circuitry in the lumbosacral spinal cord. BMC Physiol. 2007; 7:9.
Article
39. Qiao LY, Vizzard MA. Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression and phosphorylation in rat micturition pathways. J Comp Neurol. 2002; 454:200–211.
Article
40. Qiao L, Vizzard MA. Up-regulation of tyrosine kinase (Trka, Trkb) receptor expression and phosphorylation in lumbosacral dorsal root ganglia after chronic spinal cord (T8-T10) injury. J Comp Neurol. 2002; 449:217–230.
Article
41. Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010; 58:360–365.
Article
42. Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F, et al. Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience. 2010; 166:907–916.
Article
43. Abdiche YN, Malashock DS, Pons J. Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. Protein Sci. 2008; 17:1326–1335.
Article
44. Nickel JC, Mills IW, Crook TJ, Jorga A, Smith MD, Atkinson G, et al. Tanezumab reduces pain in women with interstitial cystitis/bladder pain syndrome and patients with nonurological associated somatic syndromes. J Urol. 2016; 195:942–948.
Article
45. Evans RJ, Moldwin RM, Cossons N, Darekar A, Mills IW, Scholfield D. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol. 2011; 185:1716–1721.
Article
46. Dodds KN, Beckett EA, Evans SF, Grace PM, Watkins LR, Hutchinson MR. Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry. 2016; 6:e888.
Article
47. Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013; 74:630–636.
Article
48. Reynolds WS, Dmochowski R, Wein A, Bruehl S. Does central sensitization help explain idiopathic overactive bladder? Nat Rev Urol. 2016; 13:481–491.
Article
49. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014; 14:217–231.
Article
50. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009; 10:23–36.
Article
51. Tabasi M, Asadi Karam MR, Habibi M, Yekaninejad MS, Bouzari S. Phenotypic assays to determine virulence factors of uropathogenic Escherichia coli (UPEC) isolates and their correlation with antibiotic resistance pattern. Osong Public Health Res Perspect. 2015; 6:261–268.
Article
52. Reygaert WC. Innate immune response to urinary tract infections involving Escherichia coli. J Clin Cell Immunol. 2014; 5:280.
Article
53. Abraham SN, Sun D, Dale JB, Beachey EH. Conservation of the D-mannose-adhesion protein among type 1 fimbriated members of the family Enterobacteriaceae. Nature. 1988; 336:682–684.
Article
54. Zhou G, Mo WJ, Sebbel P, Min G, Neubert TA, Glockshuber R, et al. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. J Cell Sci. 2001; 114:4095–4103.
Article
55. Agier J, Pastwinska J, Brzezinska-Blaszczyk E. An overview of mast cell pattern recognition receptors. Inflamm Res. 2018; 06. 16. [Epub]. DOI: 10.1007/s00011-018-1164-5.
Article
56. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124:783–801.
Article
57. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the drosophila toll protein signals activation of adaptive immunity. Nature. 1997; 388:394–397.
Article
58. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140:805–820.
Article
59. Behzadi E, Behzadi P. The role of toll-like receptors (TLRs) in urinary tract infections (UTIs). Cent European J Urol. 2016; 69:404–410.
Article
60. Song J, Duncan MJ, Li G, Chan C, Grady R, Stapleton A, et al. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog. 2007; 3:e60.
Article
61. Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008; 28:20–29.
Article
62. Schrepf A, Bradley CS, O'Donnell M, Luo Y, Harte SE, Kreder K, et al. Toll-like receptor 4 and comorbid pain in interstitial cystitis/bladder pain syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study. Brain Behav Immun. 2015; 49:66–74.
Article
63. Kwok YH, Tuke J, Nicotra LL, Grace PM, Rolan PE, Hutchinson MR. TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers. PLoS ONE. 2013; 8:e77799.
Article
64. Ellis A, Wieseler J, Favret J, Johnson KW, Rice KC, Maier SF, et al. Systemic administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain. J Pain. 2014; 15:407–421.
Article
65. Ichihara K, Aizawa N, Akiyama Y, Kamei J, Masumori N, Andersson KE, et al. Toll-like receptor 7 is overexpressed in the bladder of Hunner-type interstitial cystitis, and its activation in the mouse bladder can induce cystitis and bladder pain. Pain. 2017; 158:1538–1545.
Article
66. Andersson KE, Birder L. Current pharmacologic approaches in painful bladder research: an update. Int Neurourol J. 2017; 21:235–242.
Article
67. Rosen JM, Klumpp DJ. Mechanisms of pain from urinary tract infection. Int J Urol. 2014; 21:Suppl 1. 26–32.
Article
68. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009; 458:1191–1195.
Article
69. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002; 71:635–700.
Article
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