Role of neurogenic inflammation in local communication in the visceral mucosa

Review

Abstract

Intense research has focused on the involvement of the nervous system in regard to cellular mechanisms underlying neurogenic inflammation in the pelvic viscera. Evidence supports the neural release of inflammatory factors, trophic factors, and neuropeptides in the initiation of inflammation. However, more recently, non-neuronal cells including epithelia, endothelial, mast cells, and paraneurons are likely important participants in nervous system functions. For example, the urinary bladder urothelial cells are emerging as key elements in the detection and transmission of both physiological and nociceptive stimuli in the lower urinary tract. There is mounting evidence that these cells are involved in sensory mechanisms and can release mediators. Further, localization of afferent nerves next to the urothelium suggests these cells may be targets for transmitters released from bladder nerves and that chemicals released by urothelial cells may alter afferent excitability. Modifications of this type of communication in a number of pathological conditions can result in altered release of epithelial-derived mediators, which can activate local sensory nerves. Taken together, these and other findings highlighted in this review suggest that neurogenic inflammation involves complex anatomical and physiological interactions among a number of cell types in the bladder wall. The specific factors and pathways that mediate inflammatory responses in both acute and chronic conditions are not well understood and need to be further examined. Elucidation of mechanisms impacting on these pathways may provide insights into the pathology of various types of disorders involving the pelvic viscera.

Keywords

Urothelium Urinary bladder Urethra Sensor function Interstitial cystitis Microbiota Mast cells 

Notes

Acknowledgments

This work was supported by the National Institute of Health through the following grants: R37 DK54824 to LAB and P30 DK079307 Pittsburgh Center for Kidney Research–O’Brien Pilot to FAK. The authors also thank Dr. Bronagh McDonnell for critical reading of the manuscript.

References

  1. 1.
    Grover S, Srivastava A, Lee R, Tewari AK, Te AE (2011) Role of inflammation in bladder function and interstitial cystitis. Ther Adv Urol 3(1):19–33PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Elbadawi AE, Light JK (1996) Distinctive ultrastructural pathology of nonulcerative interstitial cystitis: new observations and their potential significance in pathogenesis. Urol Int 56(3):137–162PubMedCrossRefGoogle Scholar
  3. 3.
    Brookoff D (2009) Genitourinary pain syndromes: interstitial cystitis, chronic prostatitis, pelvic floor dysfunction, and related disorders. In: Smith HS (ed) Current Therapy in Pain. Saunders-Elsevier, Philadelphia, p 209–215Google Scholar
  4. 4.
    Manikandan R, Kumar S, Dorairajan LN (2010) Hemorrhagic cystitis: a challenge to the urologist. Indian J Urol 26(2):159–166PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Taweel WA, Seyam R (2015) Neurogenic bladder in spinal cord injury patients. Res Rep Urol 7:85–99PubMedPubMedCentralGoogle Scholar
  6. 6.
    Cruz F (1998) Desensitization of bladder sensory fibers by intravesical capsaicin or capsaicin analogs. A new strategy for treatment of urge incontinence in patients with spinal detrusor hyperreflexia or bladder hypersensitivity disorders. Int Urogynecol J Pelvic Floor Dysfunct 9(4):214–220PubMedCrossRefGoogle Scholar
  7. 7.
    Ham BK, Kim JH, Oh MM, Lee JG, Bae JH (2012) Effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study. Int Neurourol J 16(1):41–46PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Birder L, Andersson KE (2013) Urothelial signaling. Physiol Rev 93(2):653–680PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Cheng F, Birder LA, Kullmann FA, Hornsby J, Watton PN, Watkins S, Thompson M, Robertson AM (2018) Layer-dependent role of collagen recruitment during loading of the rat bladder wall. Biomech Model Mechanobiol 17:403–417Google Scholar
  10. 10.
    de Groat WC, Griffiths D, Yoshimura N (2015) Neural control of the lower urinary tract. Compr Physiol 5(1):327–396PubMedPubMedCentralGoogle Scholar
  11. 11.
    de Groat WC, Yoshimura N (2015) Anatomy and physiology of the lower urinary tract. Handb Clin Neurol 130:61–108PubMedCrossRefGoogle Scholar
  12. 12.
    Cohen RJ, Garrett K, Golding JL, Thomas RB, McNeal JE (2002) Epithelial differentiation of the lower urinary tract with recognition of the minor prostatic glands. Hum Pathol 33(9):905–909Google Scholar
  13. 13.
    Andersson KE, McCloskey KD (2014) Lamina propria: the functional center of the bladder? Neurourol Urodyn 33(1):9–16PubMedCrossRefGoogle Scholar
  14. 14.
    McCloskey KD (2011) Interstitial cells of Cajal in the urinary tract. Handb Exp Pharmacol 202:233–254CrossRefGoogle Scholar
  15. 15.
    Wiseman OJ, Fowler CJ, Landon DN (2003) The role of the human bladder lamina propria myofibroblast. BJU Int 91(1):89–93PubMedCrossRefGoogle Scholar
  16. 16.
    Gabella G, Davis C (1998) Distribution of afferent axons in the bladder of rats. J Neurocytol 27(3):141–155PubMedCrossRefGoogle Scholar
  17. 17.
    Danziger ZC, Grill WM (2016) Sensory and circuit mechanisms mediating lower urinary tract reflexes. Auton Neurosci 200:21–28PubMedCrossRefGoogle Scholar
  18. 18.
    de Groat WC, Fraser MO, Yoshiyama M, Smerin S, Tai C, Chancellor MB, Yoshimura N, Roppolo JR (2001) Neural control of the urethra. Scand J Urol Nephrol Suppl 207:35–43Google Scholar
  19. 19.
    Kullmann FA, Chang HH, Gauthier C, McDonnell BM, Yeh JC, Clayton DR, Kanai AJ, de Groat WC, Apodaca GL, Birder LA (2017) Serotonergic paraneurons in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol 222(2).  https://doi.org/10.1111/apha.1291
  20. 20.
    Barry CM, Ji E, Sharma H, Yap P, Spencer NJ, Matusica D, Haberberger RV (2017) Peptidergic nerve fibers in the urethra: morphological and neurochemical characteristics in female mice of reproductive age. Neurourol Urodyn.  https://doi.org/10.1002/nau.23434
  21. 21.
    Maggi CA, Santicioli P, Geppetti P, Patacchini R, Frilli S, Astolfi M, Fusco B, Meli A (1988) Simultaneous release of substance P- and calcitonin gene-related peptide (CGRP)-like immunoreactivity from isolated muscle of the guinea pig urinary bladder. Neurosci Lett 87(1-2):163–167PubMedCrossRefGoogle Scholar
  22. 22.
    Koltzenburg M, McMahon SB (1986) Plasma extravasation in the rat urinary bladder following mechanical, electrical and chemical stimuli: evidence for a new population of chemosensitive primary sensory afferents. Neurosci Lett 72(3):352–356PubMedCrossRefGoogle Scholar
  23. 23.
    Yu Y, Fraser MO, de Groat WC (2004) Effects of ZD6169, a K ATP channel opener, on neurally-mediated plasma extravasation in the rat urinary bladder induced by chemical or electrical stimulation of nerves. Brain Res 996(1):41–46PubMedCrossRefGoogle Scholar
  24. 24.
    Bjorling DE, Jerde TJ, Zine MJ, Busser BW, Saban MR, Saban R (1999) Mast cells mediate the severity of experimental cystitis in mice. J Urol 162(1):231–236PubMedCrossRefGoogle Scholar
  25. 25.
    Bjorling DE, Saban MR, Saban R (1994) Neurogenic inflammation of guinea-pig bladder. Mediat Inflamm 3(3):189–197CrossRefGoogle Scholar
  26. 26.
    Ruggieri MR, Filer-Maerten S, Hieble JP, Hay DW (2000) Role of neurokinin receptors in the behavioral effect of intravesical antigen infusion in guinea pig bladder. J Urol 164(1):197–202PubMedCrossRefGoogle Scholar
  27. 27.
    Ahluwalia A, Giuliani S, Scotland R, Maggi CA (1998) Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats. Br J Pharmacol 124(1):190–196PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Pinter E, Szolcsanyi J (1995) Plasma extravasation in the skin and pelvic organs evoked by antidromic stimulation of the lumbosacral dorsal roots of the rat. Neuroscience 68(2):603–614PubMedCrossRefGoogle Scholar
  29. 29.
    Jasmin L, Janni G, Ohara PT, Rabkin SD (2000) CNS induced neurogenic cystitis is associated with bladder mast cell degranulation in the rat. J Urol 164(3 Pt 1):852–855PubMedCrossRefGoogle Scholar
  30. 30.
    Rudick CN, Pavlov VI, Chen MC, Klumpp DJ (2012) Gender specific pelvic pain severity in neurogenic cystitis. J Urol 187(2):715–724PubMedCrossRefGoogle Scholar
  31. 31.
    Jasmin L, Janni G (2003) Experimental neurogenic cystitis. Adv Exp Med Biol 539(Pt A):319–335PubMedGoogle Scholar
  32. 32.
    Spanos C, Pang X, Ligris K, Letourneau R, Alferes L, Alexacos N, Sant GR, Theoharides TC (1997) Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol 157(2):669–672PubMedCrossRefGoogle Scholar
  33. 33.
    Smith AL, Leung J, Kun S, Zhang R, Karagiannides I, Raz S, Lee U, Glovatscka V, Pothoulakis C, Bradesi S, Mayer EA, Rodriguez LV (2011) The effects of acute and chronic psychological stress on bladder function in a rodent model. Urology 78(4):967 e1–967 e7CrossRefGoogle Scholar
  34. 34.
    Mingin GC, Peterson A, Erickson CS, Nelson MT, Vizzard MA (2014) Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice. Am J Phys Regul Integr Comp Phys 307(7):R893–R900Google Scholar
  35. 35.
    Chang A, Butler S, Sliwoski J, Valentino R, Canning D, Zderic S (2009) Social stress in mice induces voiding dysfunction and bladder wall remodeling. Am J Physiol Ren Physiol 297(4):F1101–F1108CrossRefGoogle Scholar
  36. 36.
    Buffington CA (2011) Idiopathic cystitis in domestic cats—beyond the lower urinary tract. J Vet Intern Med 25(4):784–796PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, Jacques TS, Fowler CJ, Anand P (2004) P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 46(2):247–253PubMedCrossRefGoogle Scholar
  38. 38.
    De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert L, Fowler CJ (1997) Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study with long-term followup. J Urol 158(6):2087–2092PubMedCrossRefGoogle Scholar
  39. 39.
    Sculptoreanu A, de Groat WC, Buffington CA, Birder LA (2005) Abnormal excitability in capsaicin-responsive DRG neurons from cats with feline interstitial cystitis. Exp Neurol 193(2):437–443PubMedCrossRefGoogle Scholar
  40. 40.
    Roppolo JR, Tai C, Booth AM, Buffington CA, de Groat WC, Birder LA (2005) Bladder Adelta afferent nerve activity in normal cats and cats with feline interstitial cystitis. J Urol 173(3):1011–1015PubMedCrossRefGoogle Scholar
  41. 41.
    Gao Y, Zhang R, Chang HH, Rodriguez LV (2017) 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.  https://doi.org/10.1002/nau.23374
  42. 42.
    de Groat WC, Yoshimura N (2010) Changes in afferent activity after spinal cord injury. Neurourol Urodyn 29(1):63–76PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    de Groat WC, Yoshimura N (2012) Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp Neurol 235(1):123–132PubMedCrossRefGoogle Scholar
  44. 44.
    Yoshimura N, de Groat WC (1997) Plasticity of Na+ channels in afferent neurones innervating rat urinary bladder following spinal cord injury. J Physiol 503(Pt 2):269–276PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Cheng CL, Ma CP, de Groat WC (1995) Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Res 678(1-2):40–48PubMedCrossRefGoogle Scholar
  46. 46.
    Natura G, von Banchet GS, Schaible HG (2005) Calcitonin gene-related peptide enhances TTX-resistant sodium currents in cultured dorsal root ganglion neurons from adult rats. Pain 116(3):194–204PubMedCrossRefGoogle Scholar
  47. 47.
    Moraes ER, Kushmerick C, Naves LA (2014) Characteristics of dorsal root ganglia neurons sensitive to Substance P. Mol Pain 10:73PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    de Groat WC, Yoshimura N (2006) Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. Prog Brain Res 152:59–84PubMedCrossRefGoogle Scholar
  49. 49.
    Christmas TJ, Rode J, Chapple CR, Milroy EJ, Turner-Warwick RT (1990) Nerve fibre proliferation in interstitial cystitis. Virchows Arch A Pathol Anat Histopathol 416(5):447–451PubMedCrossRefGoogle Scholar
  50. 50.
    Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC (1995) Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol 75(6):744–750PubMedCrossRefGoogle Scholar
  51. 51.
    Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, Freeman A, Scaravilli F, Fowler CJ, Anand P (2004) 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 93(6):770–776Google Scholar
  52. 52.
    Schneider H, Wilbrandt K, Ludwig M, Beutel M, Weidner W (2005) Prostate-related pain in patients with chronic prostatitis/chronic pelvic pain syndrome. BJU Int 95(2):238–243PubMedCrossRefGoogle Scholar
  53. 53.
    Lee UJ, Ackerman AL, Wu A, Zhang R, Leung J, Bradesi S, Mayer EA, Rodriguez LV (2015) Chronic psychological stress in high-anxiety rats induces sustained bladder hyperalgesia. Physiol Behav 139:541–548PubMedCrossRefGoogle Scholar
  54. 54.
    Robbins M, DeBerry J, Ness T (2007) Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats. Physiol Behav 91(5):544–550PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10(9):895–926PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Birder LA, Wolf-Johnston AS, Chib MK, Buffington CA, Roppolo JR, Hanna-Mitchell AT (2010) Beyond neurons: Involvement of urothelial and glial cells in bladder function. Neurourol Urodyn 29(1):88–96PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Dodds KN, Beckett EA, Evans SF, Grace PM, Watkins LR, Hutchinson MR (2016) Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry 6(9):e888PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Farmer MA, Huang L, Martucci K, Yang CC, Maravilla KR, Harris RE, Clauw DJ, Mackey S, Ellingson BM, Mayer EA, Schaeffer AJ, Apkarian AV, Network MR (2015) Brain white matter abnormalities in female interstitial cystitis/bladder pain syndrome: a MAPP network neuroimaging study. J Urol 194(1):118–126PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Deutsch G, Deshpande H, Frolich MA, Lai HH, Ness TJ (2016) Bladder distension increases blood flow in pain related brain structures in subjects with interstitial cystitis. J Urol 196(3):902–910PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Pandita RK, Andersson KE (2002) Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol 168(3):1230–1234PubMedCrossRefGoogle Scholar
  61. 61.
    Aizawa N, Igawa Y, Andersson KE, Iijima K, Nishizawa O, Wyndaele JJ (2011) Effects of intravesical instillation of ATP on rat bladder primary afferent activity and its relationship with capsaicin-sensitivitiy. Neurourol Urodyn 30:163–168PubMedCrossRefGoogle Scholar
  62. 62.
    Ferguson DR, Kennedy I, Burton TJ (1997) ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—a possible sensory mechanism? J Physiol 505(Pt 2):503–511PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Vlaskovska M, Kasakov L, Rong W, Bodin P, Bardini M, Cockayne DA, Ford AP, Burnstock G (2001) P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 21(15):5670–5677PubMedGoogle Scholar
  64. 64.
    Smith CP, Vemulakonda VM, Kiss S, Boone TB, Somogyi GT (2005) Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int 47(4):291–297PubMedCrossRefGoogle Scholar
  65. 65.
    Kumar V, Chapple CR, Surprenant AM, Chess-Williams R (2007) Enhanced adenosine triphosphate release from the urothelium of patients with painful bladder syndrome: a possible pathophysiological explanation. J Urol 178(4 Pt 1):1533–1536PubMedCrossRefGoogle Scholar
  66. 66.
    Sun Y, Chai TC (2006) Augmented extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis. Am J Phys Cell Phys 290(1):C27–C34CrossRefGoogle Scholar
  67. 67.
    Birder LA, Barrick SR, Roppolo JR, Kanai AJ, de Groat WC, Kiss S, Buffington CA (2003) Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium. Am J Physiol Renal Physiol 285(3):F423–F429PubMedCrossRefGoogle Scholar
  68. 68.
    Birder LA, Ruan HZ, Chopra B, Xiang Z, Barrick S, Buffington CA, Roppolo JR, Ford AP, de Groat WC, Burnstock G (2004) Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis. Am J Physiol Ren Physiol 287(5):F1084–F1091CrossRefGoogle Scholar
  69. 69.
    Tempest HV, Dixon AK, Turner WH, Elneil S, Sellers LA, Ferguson DR (2004) P2X and P2X receptor expression in human bladder urothelium and changes in interstitial cystitis. BJU Int 93(9):1344–1348PubMedCrossRefGoogle Scholar
  70. 70.
    Sun Y, Chai TC (2004) Up-regulation of P2X3 receptor during stretch of bladder urothelial cells from patients with interstitial cystitis. J Urol 171(1):448–452PubMedCrossRefGoogle Scholar
  71. 71.
    Dang K, Lamb K, Cohen M, Bielefeldt K, Gebhart GF (2008) Cyclophosphamide-induced bladder inflammation sensitizes and enhances P2X receptor function in rat bladder sensory neurons. J Neurophysiol 99(1):49–59PubMedCrossRefGoogle Scholar
  72. 72.
    Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407(6807):1011–1015PubMedCrossRefGoogle Scholar
  73. 73.
    Kullmann FA, Wells GI, Langdale CL, Zheng J, Thor KB (2013) Stability of the acetic acid-induced bladder irritation model in alpha chloralose-anesthetized female cats. PLoS One 8(9):e73771PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Gevaert T, De Vos R, Everaerts W, Libbrecht L, Van Der Aa F, van den Oord J, Roskams T, De Ridder D (2011) Characterization of upper lamina propria interstitial cells in bladders from patients with neurogenic detrusor overactivity and bladder pain syndrome. J Cell Mol Med 15(12):2586–2593PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Chun SY, Lim GJ, Kwon TG, Kwak EK, Kim BW, Atala A, Yoo JJ (2007) Identification and characterization of bioactive factors in bladder submucosa matrix. Biomaterials 28(29):4251–4256PubMedCrossRefGoogle Scholar
  76. 76.
    Browne C, Davis NF, Mac Craith E, Lennon GM, Mulvin DW, Quinlan DM, Mc Vey GP, Galvin DJ (2015) A narrative review on the pathophysiology and management for radiation cystitis. Ther Adv Urol 2015:346812Google Scholar
  77. 77.
    Zwaans BM, Krueger S, Bartolone SN, Chancellor MB, Marples B, Lamb LE (2016) Modeling of chronic radiation-induced cystitis in mice. Adv Radiat Oncol 1(4):333–343PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Foditsch EE, Roider K, Patras I, Hutu I, Bauer S, Janetschek G, Zimmermann R (2017) Structural changes of the urinary bladder after chronic complete spinal cord injury in minipigs. Int Neurourol J 21(1):12–19PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Deveaud CM, Macarak EJ, Kucich U, Ewalt DH, Abrams WR, Howard PS (1998) Molecular analysis of collagens in bladder fibrosis. J Urol 160(4):1518–1527PubMedCrossRefGoogle Scholar
  80. 80.
    Ochodnicky P, Cruz CD, Yoshimura N, Cruz F (2012) Neurotrophins as regulators of urinary bladder function. Nat Rev Urol 9(11):628–637PubMedCrossRefGoogle Scholar
  81. 81.
    Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139(2):267–284PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Bjorling DE, Jacobsen HE, Blum JR, Shih A, Beckman M, Wang ZY, Uehling DT (2001) Intravesical Escherichia coli lipopolysaccharide stimulates an increase in bladder nerve growth factor. BJU Int 87(7):697–702PubMedCrossRefGoogle Scholar
  83. 83.
    Cruz CD (2014) Neurotrophins in bladder function: what do we know and where do we go from here? Neurourol Urodyn 33(1):39–45PubMedCrossRefGoogle Scholar
  84. 84.
    Chen W, Ye DY, Han DJ, Fu GQ, Zeng X, Lin W, Liang Y (2016) Elevated level of nerve growth factor in the bladder pain syndrome/interstitial cystitis: a meta-analysis. Springerplus 5(1):1072PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Liu HT, Kuo HC (2012) Increased urine and serum nerve growth factor levels in interstitial cystitis suggest chronic inflammation is involved in the pathogenesis of disease. PLoS One 7(9):e44687PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Dmitrieva N, Shelton D, Rice AS, McMahon SB (1997) The role of nerve growth factor in a model of visceral inflammation. Neuroscience 78(2):449–459PubMedCrossRefGoogle Scholar
  87. 87.
    Zvara P, Vizzard MA (2007) Exogenous overexpression of nerve growth factor in the urinary bladder produces bladder overactivity and altered micturition circuitry in the lumbosacral spinal cord. BMC Physiol 7:9PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Schnegelsberg B, Sun TT, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA (2010) Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Phys Regul Integr Comp Phys 298(3):R534–R547Google Scholar
  89. 89.
    Yoshimura N, Bennett NE, Hayashi Y, Ogawa T, Nishizawa O, Chancellor MB, de Groat WC, Seki S (2006) Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats. J Neurosci 26(42):10847–10855PubMedCrossRefGoogle Scholar
  90. 90.
    Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F, Cruz CD (2010) Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience 166(3):907–916PubMedCrossRefGoogle Scholar
  91. 91.
    DeBerry JJ, Saloman JL, Dragoo BK, Albers KM, Davis BM (2015) Artemin immunotherapy is effective in preventing and reversing cystitis-induced bladder hyperalgesia via TRPA1 regulation. J Pain 16(7):628–636PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Bespalov MM, Saarma M (2007) GDNF family receptor complexes are emerging drug targets. Trends Pharmacol Sci 28(2):68–74PubMedCrossRefGoogle Scholar
  93. 93.
    Merighi A (2016) Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain. Expert Opin Ther Targets 20(2):193–208PubMedCrossRefGoogle Scholar
  94. 94.
    Ikeda-Miyagawa Y, Kobayashi K, Yamanaka H, Okubo M, Wang S, Dai Y, Yagi H, Hirose M, Noguchi K (2015) Peripherally increased artemin is a key regulator of TRPA1/V1 expression in primary afferent neurons. Mol Pain 11:8PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Lippoldt EK, Ongun S, Kusaka GK, McKemy DD (2016) Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRalpha3. Proc Natl Acad Sci U S A 113(16):4506–4511PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Okragly AJ, Niles AL, Saban R, Schmidt D, Hoffman RL, Warner TF, Moon TD, Uehling DT, Haak-Frendscho M (1999) 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 161(2):438–441 discussion 441-2PubMedCrossRefGoogle Scholar
  97. 97.
    Guan NN, Nilsson KF, Wiklund PN, Gustafsson LE (2014) Release and inhibitory effects of prostaglandin D2 in guinea pig urinary bladder and the role of urothelium. Biochim Biophys Acta 1840(12):3443–3451PubMedCrossRefGoogle Scholar
  98. 98.
    Saban R, Undem BJ, Keith IM, Saban MR, Tengowski MW, Graziano FM, Bjorling DE (1994) Differential release of prostaglandins and leukotrienes by sensitized guinea pig urinary bladder layers upon antigen challenge. J Urol 152(2 Pt 1):544–549PubMedCrossRefGoogle Scholar
  99. 99.
    Sun Y, Keay S, De Deyne PG, Chai TC (2001) Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J Urol 166(5):1951–1956PubMedCrossRefGoogle Scholar
  100. 100.
    Gonzalez EJ, Arms L, Vizzard MA (2014) The role(s) of cytokines/chemokines in urinary bladder inflammation and dysfunction. Biomed Res Int 2014:120525PubMedPubMedCentralGoogle Scholar
  101. 101.
    Hang L, Wullt B, Shen Z, Karpman D, Svanborg C (1998) Cytokine repertoire of epithelial cells lining the human urinary tract. J Urol 159(6):2185–2192PubMedCrossRefGoogle Scholar
  102. 102.
    Smet PJ, Moore KH, Jonavicius J (1997) Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Investig 77(1):37–49PubMedGoogle Scholar
  103. 103.
    Nimmo AJ, Morrison JF, Whitaker EM (1988) A comparison of the distribution of substance P and calcitonin gene-related peptide receptors in the rat bladder. Q J Exp Physiol 73(5):789–792PubMedCrossRefGoogle Scholar
  104. 104.
    Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313(5997):54–56PubMedCrossRefGoogle Scholar
  105. 105.
    Miyoshi H, Nakaya Y (1995) Calcitonin gene-related peptide activates the K+ channels of vascular smooth muscle cells via adenylate cyclase. Basic Res Cardiol 90(4):332–336PubMedCrossRefGoogle Scholar
  106. 106.
    Persson K, Garcia-Pascual A, Andersson KE (1991) Difference in the actions of calcitonin gene-related peptide on pig detrusor and vesical arterial smooth muscle. Acta Physiol Scand 143(1):45–53PubMedCrossRefGoogle Scholar
  107. 107.
    Lu B, Figini M, Emanueli C, Geppetti P, Grady EF, Gerard NP, Ansell J, Payan DG, Gerard C, Bunnett N (1997) The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat Med 3(8):904–907PubMedCrossRefGoogle Scholar
  108. 108.
    Lembeck F, Donnerer J, Tsuchiya M, Nagahisa A (1992) The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation. Br J Pharmacol 105(3):527–530PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Saban R (2015) Angiogenic factors, bladder neuroplasticity and interstitial cystitis-new pathobiological insights. Transl Androl Urol 4(5):555–562PubMedPubMedCentralGoogle Scholar
  110. 110.
    Jaromi P, Garab D, Hartmann P, Bodnar D, Nyiri S, Santha P, Boros M, Jancso G, Szabo A (2017) Capsaicin-induced rapid neutrophil leukocyte activation in the rat urinary bladder microcirculatory bed. Neurourol Urodyn.  https://doi.org/10.1002/nau.23376
  111. 111.
    Kullmann F, Wolf-Johnston A, Bastacky S (2016) L. Birder, (377) Is pain a consequence of tissue remodeling in interstitial cystitis/bladder pain syndrome? J Pain 17(4S):S69CrossRefGoogle Scholar
  112. 112.
    Kiuchi H, Tsujimura A, Takao T, Yamamoto K, Nakayama J, Miyagawa Y, Nonomura N, Takeyama M, Okuyama A (2009) Increased vascular endothelial growth factor expression in patients with bladder pain syndrome/interstitial cystitis: its association with pain severity and glomerulations. BJU Int 104(6):826–831 discussion 831PubMedCrossRefGoogle Scholar
  113. 113.
    Saban R, Saban MR, Maier J, Fowler B, Tengowski M, Davis CA, Wu XR, Culkin DJ, Hauser P, Backer J, Hurst RE (2008) Urothelial expression of neuropilins and VEGF receptors in control and interstitial cystitis patients. Am J Physiol Ren Physiol 295(6):F1613–F1623CrossRefGoogle Scholar
  114. 114.
    Tamaki M, Saito R, Ogawa O, Yoshimura N, Ueda T (2004) Possible mechanisms inducing glomerulations in interstitial cystitis: relationship between endoscopic findings and expression of angiogenic growth factors. J Urol 172(3):945–948PubMedCrossRefGoogle Scholar
  115. 115.
    Saban MR, Backer JM, Backer MV, Maier J, Fowler B, Davis CA, Simpson C, Wu XR, Birder L, Freeman MR, Soker S, Hurst RE, Saban R (2008) VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. Am J Physiol Ren Physiol 295(1):F60–F72CrossRefGoogle Scholar
  116. 116.
    Ghassemifar R, Lai CM, Rakoczy PE (2006) VEGF differentially regulates transcription and translation of ZO-1alpha+ and ZO-1alpha- and mediates trans-epithelial resistance in cultured endothelial and epithelial cells. Cell Tissue Res 323(1):117–125PubMedCrossRefGoogle Scholar
  117. 117.
    Saban MR, Davis CA, Avelino A, Cruz F, Maier J, Bjorling DE, Sferra TJ, Hurst RE, Saban R (2011) VEGF signaling mediates bladder neuroplasticity and inflammation in response to BCG. BMC Physiol 11:16PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Pang X, Boucher W, Triadafilopoulos G, Sant GR, Theoharides TC (1996) Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis. Urology 47(3):436–438PubMedCrossRefGoogle Scholar
  119. 119.
    Letourneau R, Pang X, Sant GR, Theoharides TC (1996) Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis. Br J Urol 77(1):41–54PubMedCrossRefGoogle Scholar
  120. 120.
    Theoharides TC, Sant GR, el-Mansoury M, Letourneau R, Ucci AA Jr, Meares EM Jr (1995) Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol 153(3 Pt 1):629–636PubMedGoogle Scholar
  121. 121.
    Letourneau R, Sant GR, el-Mansoury M, Theoharides TC (1992) Activation of bladder mast cells in interstitial cystitis. Int J Tissue React 14(6):307–312PubMedGoogle Scholar
  122. 122.
    Theoharides TC, Kempuraj D, Sant GR (2001) Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57(6 Suppl 1):47–55PubMedCrossRefGoogle Scholar
  123. 123.
    Sant GR, Kempuraj D, Marchand JE, Theoharides TC (2007) The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology 69(4 Suppl):34–40PubMedCrossRefGoogle Scholar
  124. 124.
    Keith IM, Jin J, Saban R (1995) Nerve-mast cell interaction in normal guinea pig urinary bladder. J Comp Neurol 363(1):28–36PubMedCrossRefGoogle Scholar
  125. 125.
    el-Mansoury M, Boucher W, Sant GR, Theoharides TC (1994) Increased urine histamine and methylhistamine in interstitial cystitis. J Urol 152(2 Pt 1):350–353PubMedCrossRefGoogle Scholar
  126. 126.
    Saban R, D'Andrea MR, Andrade-Gordon P, Derian CK, Dozmorov I, Ihnat MA, Hurst RE, Davis CA, Simpson C, Saban MR (2007) Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation. BMC Physiol 7:4PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    D'Andrea MR, Saban MR, Nguyen NB, Andrade-Gordon P, Saban R (2003) Expression of protease-activated receptor-1, -2, -3, and -4 in control and experimentally inflamed mouse bladder. Am J Pathol 162(3):907–923PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger PC (2014) Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 52:871–876PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Brubaker L, Wolfe AJ (2017) Microbiota in 2016: associating infection and incontinence with the female urinary microbiota. Nat Rev Urol 14(2):72–74PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, Malone-Lee J (2013) Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol 51(7):2054–2062PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, Kliethermes S, Schreckenberger PC, Brubaker L, Gai X, Wolfe AJ (2014) The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. MBio 5(4):e01283–e01214PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Pearce MM, Zilliox MJ, Rosenfeld AB, Thomas-White KJ, Richter HE, Nager CW, Visco AG, Nygaard IE, Barber MD, Schaffer J, Moalli P, Sung VW, Smith AL, Rogers R, Nolen TL, Wallace D, Meikle SF, Gai X, Wolfe AJ, Brubaker L, Pelvic Floor Disorders N (2015) The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol 213(3):347 e1–347 11CrossRefGoogle Scholar
  133. 133.
    Thomas-White KJ, Hilt EE, Fok C, Pearce MM, Mueller ER, Kliethermes S, Jacobs K, Zilliox MJ, Brincat C, Price TK, Kuffel G, Schreckenberger P, Gai X, Brubaker L, Wolfe AJ (2016) Incontinence medication response relates to the female urinary microbiota. Int Urogynecol J 27(5):723–733PubMedCrossRefGoogle Scholar
  134. 134.
    Schilling JD, Mulvey MA, Vincent CD, Lorenz RG, Hultgren SJ (2001) Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol 166:1148–1155PubMedCrossRefGoogle Scholar
  135. 135.
    Thumbikat P, Berry RE, Zhou G, Billips BK, Yaggie RE, Zaichuk T, Sun TT, Schaeffer AJ, Klumpp DJ (2009) Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog 5:1–17CrossRefGoogle Scholar
  136. 136.
    Wood MW, Breitschwerdt EB, Nordone SK, Linder KE, Gookin JL (2011) Uropathogenic E. coli promote a paracellular urothelial barrier defect characterized by altered tight junction integrity, epithelial cell sloughing and cytokine release. J Comp Pathol 5:1–9Google Scholar
  137. 137.
    Birder LA, Klumpp DJ (2016) Host responses to urinary tract infections and emerging therapeutics: sensation and pain within the urinary tract. In: Mulvey MA, Stapleton AE, Klumpp DJ (eds) Microbiol spectrum. Northwestern University, ChicagoGoogle Scholar
  138. 138.
    Abraham SN, Miao Y (2015) The nature of immune responses to urinary tract infections. Nat Rev Immunol 15:655–663PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Mo L (2004) Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1 fimbriated Eschericia coli. Am J Physiol Ren Physiol 286:F795–F802CrossRefGoogle Scholar
  140. 140.
    Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB, Ganz T (1998) Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 101:1633–1642PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Rosen JM, Klumpp DJ (2014) Mechanisms of pain from urinary tract infection. Int J Urol 21:26–32PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, Manenschijn JA, Fernandez-Pena C, Talavera A, Kichko T, Navia B, Sanchez A, Senaris R, Reeh P, Perez-Garcia MT, Lopez-Lopez JR, Voets T, Belmonte C, Talavera K, Viana F (2014) TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat Commun 5:3125PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Palea S, Corsi M, Artibani W, Ostardo E, Pietra C (1996) Pharmacological characterization of tachykinin NK2 receptors on isolated human urinary bladder, prostatic urethra and prostate. J Pharmacol Exp Ther 277(2):700–705PubMedGoogle Scholar
  144. 144.
    Warner FJ, Miller RC, Burcher E (2003) Human tachykinin NK2 receptor: a comparative study of the colon and urinary bladder. Clin Exp Pharmacol Physiol 30(9):632–639Google Scholar
  145. 145.
    Tramontana M, Patacchini R, Lecci A, Giuliani S, Maggi CA (1998) Tachykinin NK2 receptors in the hamster urinary bladder: in vitro and in vivo characterization. Naunyn Schmiedeberg's Arch Pharmacol 358(3):293–300CrossRefGoogle Scholar
  146. 146.
    Quinn T, Collins C, Baird AW (2004) Mechanisms of neurokinin A- and substance P-induced contractions in rat detrusor smooth muscle in vitro. BJU Int 94(4):651–657PubMedCrossRefGoogle Scholar
  147. 147.
    Giuliani S, Patacchini R, Barbanti G, Turini D, Rovero P, Quartara L, Giachetti A, Maggi CA (1993) Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors. J Pharmacol Exp Ther 267(2):590–595PubMedGoogle Scholar
  148. 148.
    Templeman L, Sellers DJ, Chapple CR, Rosario DJ, Hay DP, Chess-Williams R (2003) Investigation of neurokinin-2 and -3 receptors in the human and pig bladder. BJU Int 92(7):787–792PubMedCrossRefGoogle Scholar
  149. 149.
    Maggi CA, Santicioli P, Giuliani S, Regoli D, Meli A (1986) Activation of micturition reflex by substance P and substance K: indirect evidence for the existence of multiple tachykinin receptors in the rat urinary bladder. J Pharmacol Exp Ther 238(1):259–266PubMedGoogle Scholar
  150. 150.
    Maggi CA, Santicioli P, Geppetti P, Furio M, Frilli S, Conte B, Fanciullacci M, Giuliani S, Meli A (1987) The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons. Brain Res 415(1):1–13PubMedCrossRefGoogle Scholar
  151. 151.
    Kullmann FA, Kurihara R, Ye L, Wells GI, McKenna DG, Burgard EC, Thor KB (2013) Effects of the 5-HT4 receptor agonist, cisapride, on neuronally evoked responses in human bladder, urethra, and ileum. Auton Neurosci 176(1-2):70–77PubMedCrossRefGoogle Scholar
  152. 152.
    Kullmann FA, Katofiasc M, Thor KB, Marson L (2017) Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4-10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats. Naunyn Schmiedeberg's Arch Pharmacol 390(2):163–173CrossRefGoogle Scholar
  153. 153.
    Henderson L, Farrelly P, Dickson AP, Goyal A (2016) Management strategies for idiopathic urethritis. J Pediatr Urol 12(1):35 e1–35 e5CrossRefGoogle Scholar
  154. 154.
    Bachmann LH, Manhart LE, Martin DH, Sena AC, Dimitrakoff J, Jensen JS, Gaydos CA (2015) Advances in the understanding and treatment of male urethritis. Clin Infect Dis 61(Suppl 8):S763–S769PubMedCrossRefGoogle Scholar
  155. 155.
    Tritschler S, Roosen A, Fullhase C, Stief CG, Rubben H (2013) Urethral stricture: etiology, investigation and treatments. Dtsch Arztebl Int 110(13):220–226PubMedPubMedCentralGoogle Scholar
  156. 156.
    Ben-Meir D, Yin M, Chow CW, Hutson JM (2005) Urethral polyps in prepubertal girls. J Urol 174(4 Pt 1):1443–1444PubMedCrossRefGoogle Scholar
  157. 157.
    Liedberg H (1989) Catheter induced urethral inflammatory reaction and urinary tract infection. An experimental and clinical study. Scand J Urol Nephrol Suppl 124:1–43PubMedGoogle Scholar
  158. 158.
    Abelli L, Conte B, Somma V, Parlani M, Geppetti P, Maggi CA (1991) Mechanical irritation induces neurogenic inflammation in the rat urethra. J Urol 146(6):1624–1626Google Scholar
  159. 159.
    Nordling L, Lundeberg T, Brolin J, Liedberg H, Ekman P, Theodorsson E (1992) The role of sensory nerves in catheter-induced urethral inflammation. Eur Urol 21(1):75–78PubMedCrossRefGoogle Scholar
  160. 160.
    Nordling L, Liedberg H, Ekman P, Lundeberg T (1990) Influence of the nervous system on experimentally induced urethral inflammation. Neurosci Lett 115(2-3):183–188PubMedCrossRefGoogle Scholar
  161. 161.
    Deckmann K, Filipski K, Krasteva-Christ G, Fronius M, Althaus M, Rafiq A, Papadakis T, Renno L, Jurastow I, Wessels L, Wolff M, Schutz B, Weihe E, Chubanov V, Gudermann T, Klein J, Bschleipfer T, Kummer W (2014) Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. Proc Natl Acad Sci U S A 111(22):8287–8292PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Di Sant’Agnese PA, Davis NS, Chen M, de Mesy Jensen KL (1987) Age-related changes in the neuroendocrine (endocrine-paracrine) cell population and the serotonin content of the guinea pig prostate. Lab Investig 57(6):729–736PubMedGoogle Scholar
  163. 163.
    di Sant’Agnese PA, de Mesy Jensen KL (1987) Endocrine-paracrine (APUD) cells of the human female urethra and paraurethral ducts. J Urol 137(6):1250–1254PubMedCrossRefGoogle Scholar
  164. 164.
    Hakanson R, Larsson LI, Sjoberg NO, Sundler F (1974) Amine-producing endocrine-like cells in the epithelium of urethra and prostate of the guinea-pig. A chemical, fluorescence histochemical, and electron microscopic study. Histochemie 38(3):259–270PubMedCrossRefGoogle Scholar
  165. 165.
    Hanyu S, Iwanaga T, Kano K, Fujita T (1987) Distribution of serotonin-immunoreactive paraneurons in the lower urinary tract of dogs. Am J Anat 180(4):349–356PubMedCrossRefGoogle Scholar
  166. 166.
    Iwanaga T, Han H, Hoshi O, Kanazawa H, Adachi I, Fujita T (1994) Topographical relation between serotonin-containing paraneurons and peptidergic neurons in the intestine and urethra. Biol Signals 3(5):259–270PubMedCrossRefGoogle Scholar
  167. 167.
    Iwanaga T, Hanyu S, Fujita T (1987) Serotonin-immunoreactive cells of peculiar shape in the urethral epithelium of the human penis. Cell Tissue Res 249(1):51–56PubMedCrossRefGoogle Scholar
  168. 168.
    Vittoria A, La Mura E, Cocca T, Cecio A (1990) Serotonin-, somatostatin- and chromogranin A-containing cells of the urethro-prostatic complex in the sheep. An immunocytochemical and immunofluorescent study. J Anat 171:169–178PubMedPubMedCentralGoogle Scholar
  169. 169.
    Yokoyama T, Saino T, Nakamuta N, Yamamoto Y (2017) Topographic distribution of serotonin-immunoreactive urethral endocrine cells and their relationship with calcitonin gene-related peptide-immunoreactive nerves in male rats. Acta Histochem 119(1):78–83PubMedCrossRefGoogle Scholar
  170. 170.
    Kummer W, Deckmann K (2017) Brush cells, the newly identified gatekeepers of the urinary tract. Curr Opin Urol 27(2):85–92PubMedCrossRefGoogle Scholar
  171. 171.
    Deckmann K, Kummer W (2016) Chemosensory epithelial cells in the urethra: sentinels of the urinary tract. Histochem Cell Biol 146(6):673–683PubMedCrossRefGoogle Scholar
  172. 172.
    Everaerts W, Gevaert T, Nilius B, De Ridder D (2008) On the origin of bladder sensing: Tr(i)ps in urology. Neurourol Urodyn 27(4):264–273PubMedCrossRefGoogle Scholar
  173. 173.
    Andersson KE, Gratzke C, Hedlund P (2010) The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int 106(8):1114–1127PubMedCrossRefGoogle Scholar
  174. 174.
    Chai TC, Gray ML, Steers WD (1998) The incidence of a positive ice water test in bladder outlet obstructed patients: evidence for bladder neural plasticity. J Urol 160(1):34–38PubMedCrossRefGoogle Scholar
  175. 175.
    Silva C, Ribeiro MJ, Cruz F (2002) The effect of intravesical resiniferatoxin in patients with idiopathic detrusor instability suggests that involuntary detrusor contractions are triggered by C-fiber input. J Urol 168(2):575–579PubMedCrossRefGoogle Scholar
  176. 176.
    Silva C, Silva J, Ribeiro MJ, Avelino A, Cruz F (2005) Urodynamic effect of intravesical resiniferatoxin in patients with neurogenic detrusor overactivity of spinal origin: results of a double-blind randomized placebo-controlled trial. Eur Urol 48(4):650–655PubMedCrossRefGoogle Scholar
  177. 177.
    Lazzeri M, Beneforti P, Benaim G, Maggi CA, Lecci A, Turini D (1996) Intravesical capsaicin for treatment of severe bladder pain: a randomized placebo controlled study. J Urol 156(3):947–952PubMedCrossRefGoogle Scholar
  178. 178.
    Foster HE Jr, Lake AG (2014) Use of vanilloids in urologic disorders. Prog Drug Res 68:307–317PubMedGoogle Scholar
  179. 179.
    Palea S, Guilloteau V, Rekik M, Lovati E, Guerard M, Guardia MA, Lluel P, Pietra C, Yoshiyama M (2016) Netupitant, a potent and highly selective NK1 receptor antagonist, alleviates acetic acid-induced bladder overactivity in anesthetized guinea-pigs. Front Pharmacol 7:234PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Frenkl TL, Zhu H, Reiss T, Seltzer O, Rosenberg E, Green S (2010) A multicenter, double-blind, randomized, placebo controlled trial of a neurokinin-1 receptor antagonist for overactive bladder. J Urol 184(2):616–622PubMedCrossRefGoogle Scholar
  181. 181.
    Green SA, Alon A, Ianus J, McNaughton KS, Tozzi CA, Reiss TF (2006) Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol 176(6 Pt 1):2535–2540 discussion 2540PubMedCrossRefGoogle Scholar
  182. 182.
    Haab F, Braticevici B, Krivoborodov G, Palmas M, Zufferli Russo M, Pietra C (2014) Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder. Neurourol Urodyn 33(3):335–340PubMedCrossRefGoogle Scholar
  183. 183.
    Ford AP, Undem BJ (2013) The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci 7:267PubMedPubMedCentralGoogle Scholar
  184. 184.
    Moldwin R, Kitt M, Mangel J, Beyer R, Hanno P, Butera P, Ford A (2015) A phase 2 study in women with interstitial cystitis/bladder pain syndrome (IC/BPS) of the novel P2X3 antagonist AF-219, International Contionence. SocietyGoogle Scholar
  185. 185.
    Ikeda Y, Zabbarova I, Lemon K, Lamarre N, Epperly M, Kanai A (2015) Treatment of radiation cystitis via P75 receptor blockade. J Urol 193(4):e237Google Scholar
  186. 186.
    Nickel JC, Atkinson G, Krieger JN, Mills IW, Pontari M, Shoskes DA, Crook TJ (2012) Preliminary assessment of safety and efficacy in proof-of-concept, randomized clinical trial of tanezumab for chronic prostatitis/chronic pelvic pain syndrome. Urology 80(5):1105–1110PubMedCrossRefGoogle Scholar
  187. 187.
    Nickel JC, Mills IW, Crook TJ, Jorga A, Smith MD, Atkinson G, Krieger JN (2016) Tanezumab reduces pain in women with interstitial cystitis/bladder pain syndrome and patients with nonurological associated somatic syndromes. J Urol 195(4 Pt 1):942–948PubMedCrossRefGoogle Scholar
  188. 188.
    Evans RJ, Moldwin RM, Cossons N, Darekar A, Mills IW, Scholfield D (2011) Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol 185(5):1716–1721PubMedCrossRefGoogle Scholar
  189. 189.
    Peng CH, Jhang JF, Shie JH, Kuo HC (2013) Down regulation of vascular endothelial growth factor is associated with decreased inflammation after intravesical OnabotulinumtoxinA injections combined with hydrodistention for patients with interstitial cystitis—clinical results and immunohistochemistry analysis. Urology 82(6):1452 e1–1452 e6CrossRefGoogle Scholar
  190. 190.
    Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE (2008) Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int 101(3):366–370PubMedCrossRefGoogle Scholar
  191. 191.
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB (2004) Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 172(4 Pt 1):1529–1532PubMedCrossRefGoogle Scholar
  192. 192.
    Chuang YC, Tyagi P, Huang CC, Yoshimura N, Wu M, Kaufman J, Chancellor MB (2009) Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes. J Urol 182(2):786–792PubMedCrossRefGoogle Scholar
  193. 193.
    Rapp DE, Turk KW, Bales GT, Cook SP (2006) Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175(3 Pt 1):1138–1142PubMedCrossRefGoogle Scholar
  194. 194.
    Hanna-Mitchell AT, Wolf-Johnston AS, Barrick SR, Kanai AJ, Chancellor MB, de Groat WC, Birder LA (2015) Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn 34(1):79–84PubMedCrossRefGoogle Scholar
  195. 195.
    Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB (2004) Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology 64(5):871–875 discussion 875PubMedCrossRefGoogle Scholar
  196. 196.
    Kuo HC, Jiang YH, Tsai YC, Kuo YC (2016) Intravesical botulinum toxin-A injections reduce bladder pain of interstitial cystitis/bladder pain syndrome refractory to conventional treatment—a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. Neurourol Urodyn 35(5):609–614PubMedCrossRefGoogle Scholar
  197. 197.
    Shie JH, Liu HT, Wang YS, Kuo HC (2013) Immunohistochemical evidence suggests repeated intravesical application of botulinum toxin A injections may improve treatment efficacy of interstitial cystitis/bladder pain syndrome. BJU Int 111(4):638–646PubMedCrossRefGoogle Scholar
  198. 198.
    Jhang JF, Kuo HC (2016) Botulinum toxin A and lower urinary tract dysfunction: Pathophysiology and mechanisms of action. Toxins (Basel) 8(4):120CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of Chemical Biology and PharmacologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations