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Neural control of lower urinary tract and targets for pharmacological therapy

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Abstract

Studies on the physiology and pharmacology of the lower urinary tract have brought new information and concepts about the complex neural control of micturition. There are many mechanisms, some proven and others not yet completely understood, in which pharmacological agents may act facilitating the filling, storage, and emptying of the bladder. This review describes the peripheral innervation and the main pathways involved in lower urinary tract control. It also presents potential targets for the treatment of voiding dysfunctions.

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Abbreviations

5-HT:

Serotonin

Ach:

Acetylcholine

AR:

Adrenoceptor

ATP:

Adenosine tri-phosphate

BTX-A:

Botulinum toxin A

cAMP:

Adenyl cyclase-cyclic adenosine monophosphate

CCK:

Cholecystokinin

CNS:

Central nervous system

DSM:

Detrusor smooth muscle

ENK:

Enkephalin

EUS:

External urethral sphincter

IC:

Interstitial cystitis

IPSS:

International Prostate Symptom Score

IUS:

Internal urethral sphincter

LUT:

Lower urinary tract

M:

Muscarinic receptors

N:

Nicotinic receptors

NANC:

Non-cholinergic non-adrenergic

NE:

Noradrenaline

NK:

Neurokinin

NO:

Nitric oxide

NPY:

Neuropeptide Y

OAB:

Overactive bladder

PBS:

Painful bladder syndrome

PGs:

Prostaglandins

PNS:

Peripheral nervous system

P2X:

Purinergic receptors

RTX:

Resiniferatoxin

SP:

Substance P

SUI:

Stress urinary incontinence

TRPV:

Vanilloid receptors

TX:

Thromboxane

VIP:

Vasoactive intestinal peptide

References

  1. Elbadawi A (1996) Functional anatomy of the organs of micturition. Urol Clin N Am 23(2):177–210

    Article  CAS  Google Scholar 

  2. Chai TC, Steers WD (1996) Neurophysiology of micturition and continence. Urol Clin N Am 23(2):221–236

    Article  CAS  Google Scholar 

  3. Sugaya K et al (2005) Central nervous control of micturition and urine storage. J Smooth Muscle Res 3:117–132

    Article  Google Scholar 

  4. Au JLS et al (1991) Evidence of significant absorption of sodium salicylate from urinary bladder of rats. J Pharmacol Exp Ther 258:357–364

    PubMed  CAS  Google Scholar 

  5. Fry CH, Chacko S, Wachter S, Kanai AJ, Takeda M, Young JS (2013) Cell biology. In: Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence, 5th edn. Health Publications, Plymouth

    Google Scholar 

  6. Steers WD (1998) Physiology and pharmacology of the bladder and urethra. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds), Campbell’s urology, 7th edn. Saunders, Philadelphia, pp 870–915

    Google Scholar 

  7. Sugaya K, de Groat WC (2000) Influence of temperature on activity of the isolated whole bladder preparation of neonatal and adult rats. Am J Physiol 278:R238–R246

    CAS  Google Scholar 

  8. Unger CA, Tunitsky-Bitton E, Muffly T, Barber MD (2014) Neuroanatomy, neurophysiology, and dysfunction of the female lower urinary tract: a review. Female Pelvic Med Reconstr Surg 20(2):65–75

    Article  PubMed  Google Scholar 

  9. Girão MJBC et al (2002) Neurofisiologia da micção. In: Girão MJBC (ed) Cirurgia vaginal e uroginecologia, 2nd edn. Ed Artes Médicas, Porto Alegre, pp 13–20

    Google Scholar 

  10. De Groat WC, Booth AM, Yoshimura N (1993) Neurophysiology of micturition and its modification in animals models of human disease. In: Maggi CA (ed): The autonomic nervous system. Nervous control of the urogenital system, vol 3, Harwood Academic, Chur, pp 227–289

    Google Scholar 

  11. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    PubMed  CAS  Google Scholar 

  12. Sugaya K et al (1988) Efferent and primary afferent neural pathways innervating the lower urinary tract of the cat. Nippon Hinyokika Gakkai Zasshi 79:68–887

    Google Scholar 

  13. Andersson KE (1993) Pharmacology of lower urinary tract smooth muscle and penile erection tissues. Pharmacol Rev 45:253–308

    Google Scholar 

  14. Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986

    Article  PubMed  CAS  Google Scholar 

  15. Morrison J, Birder L, Craggs M, De Groat WC, Downie J, Drake M, Fowler C, Thor K (2005) Neural control. Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence. Health Publications, Jersey, pp 363–422

    Google Scholar 

  16. Burnstock G (2001) Purinergic signaling in the lower urinary tract. Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology. Springer, Berlin, pp 423–515

    Google Scholar 

  17. Caulfield MP, Birdsall NJM (1998) International union of pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290

    PubMed  CAS  Google Scholar 

  18. Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, Takahashi S, Taketo MM (2000) Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 97:9579–9584

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Matsui M, Motomura D, Fujikawa T, Jiang J, Takahashi S, Manabe T, Taketo MM (2002) Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J Neurosci 22:10627–10632

    PubMed  CAS  Google Scholar 

  20. Bennett BC et al (1993) Role of nitric oxide in reflex urethral sphincter relaxation during micturition. Soc Neurosci Abstr 19:511

    Google Scholar 

  21. Mattiasson A et al (1987) Interaction between adrenergic and cholinergic nerve terminals in the rabbit, cat and man. J Urol 137:1017–1019

    PubMed  CAS  Google Scholar 

  22. Thornburry KD et al (1992) Medication by nitric oxide of neurogenic relaxation in the bladder neck muscle in sheep. J Physiol Lond 451:133–144

    Google Scholar 

  23. Andersson KE, Wein AJ (2004) Pharmacology of the lower urinary tract: basic for current and future treatments of urinary incontinence. Pharmacol Rev 56:581–631

    Article  PubMed  CAS  Google Scholar 

  24. Clemens JQ (2010) Basic bladder neurophysiology. Urol Clin N Am 37:487–494

    Article  Google Scholar 

  25. Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T et al (1999) Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 288(3):1367–1373

    PubMed  CAS  Google Scholar 

  26. Takeda H, Yamazaki Y, Akahane M, Igawa Y, Ajisawa Y, Nishizawa O (2000) Role of the beta (3)-adrenoceptor in urine storage in the rat: comparison between the selective beta (3)-adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants. J Pharmacol Exp Ther 293(3):939–945

    PubMed  CAS  Google Scholar 

  27. Igawa Y, Aizawa N, Homma Y (2010) Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder. Korean J Urol 51(12):811–818

    Article  PubMed  PubMed Central  Google Scholar 

  28. De Groat WC, Booth AM (1993) Synaptic transmission in pelvic ganglia. The autonomic nervous system, vol 3. In: Maggi CA (ed) Nervous control of the urogenital system. Harwood Academic, London, pp 291–347

    Google Scholar 

  29. Thor K, Morgan C, Nadelhaft I, Houston M, De Groat WC (1989) Organization of afferent and efferent pathways in the pudendal nerve of the female cat. J Comp Neurol 288:263–279

    Article  PubMed  CAS  Google Scholar 

  30. 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 35 [Suppl 201]:35–43

    Article  Google Scholar 

  31. Yoshimura N, De Groat WC (1997) Neural control of the lower urinary tract. Int J Urol 4:111–125

    Article  PubMed  CAS  Google Scholar 

  32. Gosling JA et al (1977) The autonomic innervation of the urethra of the human male and female bladder neck and proximal urethra. J Urol 118:302–305

    PubMed  CAS  Google Scholar 

  33. Elbadawi A, Atta MA (1985) Ultrastructural analysis of vesicourethral innervation: evidence for somatomotor plus autonomic innervation of the feline rhabdosphincter. Neurourol Urodyn 4:23–36

    Article  Google Scholar 

  34. Kakizaki H et al (1986) Na electromyographic study of the urethral rhabdosphincter in normal and chronically rhizotomized cats. Analysis of electrical potentials evoked by sympathetic and parasympathetic ganglia of the cat. In: Hanin I (ed) Dynamics of cholinergic function. Plenum Press, New York, pp 1057–1066

    Google Scholar 

  35. Maggi CA (1993) The dual, sensory and efferent function of the capsaicin-sensitive primary sensory neurons in the urinary bladder and urethra. In: Maggi CA (ed) Nervous control of the urogenital system. Harwood Academic, London pp 383–422

    Google Scholar 

  36. Morrison JFB (1999) The activation of bladder wall afferent nerves. Exp Physiol 84:131–136

    PubMed  CAS  Google Scholar 

  37. Pinna C et al (1999) Prostaglandin-release impairment in the bladder epithelium of streptozotocin-induced diabetic rats. Eur J Pharmacol 388:267–273

    Article  Google Scholar 

  38. Downie JW, Karmazyn M (1984) Mechanical trauma to bladder epithelium liberates prostanoids which modulate neurotransmission in rabbit detrusor muscle. J Pharmacol Exp Ther 230:445–449

    PubMed  CAS  Google Scholar 

  39. Chuang Y, Fraser MO, Yu Y, Chancellor MB, De Groat WC, Yoshimura N (2001) The role of bladder afferent pathways in the bladder hyperactivity induced by intravesical administration of nerve growth factor. J Urol 165:975–979

    Article  PubMed  CAS  Google Scholar 

  40. Rong W, Spyer KM, Burnstock G (2002) Activation and sensitization of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder. J Physiol Lond 541:591–600

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Andersson KE, Appell R, Awad S, Chapple C, Drutz H, Fourcroy J, Finkbeiner AE, Haab F, Wein A (2002) Pharmacological treatment of urinary incontinence. In: Khoury S, Wein A (eds) Incontinence, 1st international consultation on incontinence. Plymbridge, Plymouth, pp 479–512

    Google Scholar 

  42. Keast JR, De Groat WC (1992) Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J Comp Neurol 319:615–623

    Article  PubMed  CAS  Google Scholar 

  43. Christianson JA, Liang R, Davis BM, Fraser MO, Pezzone MA (2004) Retrograde labeling of urinary bladder and distal colonic afferents: a potential role of dichotomizing afferents in the overlap of chronic pelvic pain disorders. Gastroenterology 126:A115

    Google Scholar 

  44. Pezzone MA, Liang R, Fraser MO (2005) A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology 128:1953–1964

    Article  PubMed  Google Scholar 

  45. Gupta SK, Sathyan G (1999) Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 39:289–296

    PubMed  CAS  Google Scholar 

  46. Chancellor MB, Yoshimura N (2002) V. Physiology and pharmacology of the bladder and urethra. In: Walsh, PC, Retik AB, Vaughan ED Jr, Wein AJ (eds) Campbell’s urology, vol 2, 8th edn. Saunders, Philadelphia, pp 831–886

    Google Scholar 

  47. Chapple CR, Yamanishi T, Chess-Williams R (2002) Muscarinic receptor subtypes and management of the overactive bladder. Urology 60:82–88

    Article  PubMed  Google Scholar 

  48. Yoshimura N, Chancellor MB (2002) Current and future pharmacological treatment for overactive bladder. J Urol 168:1897–1913

    Article  PubMed  CAS  Google Scholar 

  49. Levin RM et al (1986) Functional effects of the purinergic innervation of the rabbit urinary bladder. J Pharmacol Exp Ther 236:1327–1332

    Google Scholar 

  50. Gibson SJ et al (1986) A VIP/PHI pathways links urinary bladder and sacral spinal cord. Peptides 7 [Suppl 1]:205–219

    Article  PubMed  CAS  Google Scholar 

  51. De Groat WC et al (1983) Role of neuropeptides in the sacral autonomic reflex pathways of the cat. J Auton Nerv Syst 7:339–350

    Article  PubMed  Google Scholar 

  52. Smith CP, Chancellor MB (2004) Emerging role of botulinum toxin in the treatment of voiding dysfunction. J Urol 171:2128–2137

    Article  PubMed  CAS  Google Scholar 

  53. Schurch B, De Seze M, Denys P et al (2005) Botulinum toxin type A is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 174:196–200

    Article  PubMed  CAS  Google Scholar 

  54. Smith CP, Boone TB, De Groat WC, Chancellor MB, Somogyi GT (2003) Effect of stimulation intensity and botulinum toxin isoform on rat bladder strip contractions. Brain Res Bull 61:165–171

    Article  PubMed  CAS  Google Scholar 

  55. Smith CP, Franks ME, Mcneil BK, Ghosh R, De Groat WC, Chancellor MB, Somogyi GT (2003) Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract. J Urol 169:1896–1900

    Article  PubMed  CAS  Google Scholar 

  56. Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP (2004) Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 45:987–993

    Article  PubMed  CAS  Google Scholar 

  57. Barrick S, De Groat WC, Birder LA (2004) Regulation of chemical and mechanical-evoked ATP release from urinary bladder urothelium by botulinum toxin A. Soc Neurosci 541:5

    Google Scholar 

  58. 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 172:1529–1532

    Article  PubMed  CAS  Google Scholar 

  59. Vemulakonda VM, Somogyi GT, Kiss S, Salas NA, Boone TB, Smith CP (2005) Inhibitory effect of intravesically applied botulinum toxin a in chronic bladder inflammation. J Urol 173:621–624

    Article  PubMed  CAS  Google Scholar 

  60. Prieto D et al (1989) Distribution and density of neuropeptide Y immunoreactive nerve fibers and cells in the horse urinary bladder. J Auton Nerv Syst 27:173–180

    Article  PubMed  CAS  Google Scholar 

  61. Zoubek J et al (1993) A comparison of inhibitory effects of neuropeptide Y on rat urinary bladder, urethra and vas deferens. Am J Physiol 265:R537–R543

    PubMed  CAS  Google Scholar 

  62. Danuser H, Thor KB (1995) Inhibition of central sympathetic somatic outflow to the lower urinary tract of the cats by alpha-1 adrenergic receptor antagonist prazosin. J Urol 153:1308–1312

    Article  PubMed  CAS  Google Scholar 

  63. Jensen D (1981) Pharmacological studies of uninhibited neurogenic bladder: the influence of adrenergic excitatory and inhibitory drugs on the cystometrogram of neurological patients with normal and uninhibited bladder. Acta Neurol Scand 64:401–426

    Article  PubMed  Google Scholar 

  64. Nergardh A, Boreus LO (1972) Autonomic receptor function in the lower urinary tract of man and cat. Scand J Urol Nephrol 6:32–36

    Article  PubMed  CAS  Google Scholar 

  65. Nordling L (1983) Influence of the sympathetic nervous system on lower urinary tract in man. Neurourol Urodyn 2:3–45

    Article  Google Scholar 

  66. Williams JH, Brading A (1992) Urethral sphincter: normal function and changes in disease. In: Daniel EE, Tomira T, Tschuida S, Watanabe M (eds) Sphincters. CRC Press, Boca Raton, pp 315–338

    Google Scholar 

  67. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T et al (2007) Effect of (R)-2-(2-aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2phenylethyl) amino] ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321(2):642–647

    Article  PubMed  CAS  Google Scholar 

  68. Suguita MAA, Girão MJBC, Simões MJ, Sartori MGF, Baracat EC, Rodrigues de Lima GA (2000) morphologic and morphometric study of the vesical mucosa and urethra of castrated female rats following estrogen and/or progestogen replacement. Clin Exp Obstet Gynecol 27:176–178

    PubMed  CAS  Google Scholar 

  69. Girão MJBC, Jármy-DiBella ZIK, Sartori MGF, Baracat EC, Lima GR (2001) Doppler velocimetry parameters of periurethral vessels in postmenopausal incontinent women receiving estrogen replacement. Int Urogynecol J 2:241–246

    Google Scholar 

  70. Sartori MGF, Girão MJBC, de Jesus SM, Sartori JP, Baracat EC, Rodrigues de Lima G (2001) Quantitative evaluation of collagen and muscle fibers in the lower urinary tract of castrated and under-hormone replacement female rats. Clin Exp Obstet Gynecol 28:92–96

    PubMed  CAS  Google Scholar 

  71. De Deus JM, Girão MJ, Sartori MG et al (2003) Glycosaminoglycan profile in bladder and urethra of castrated rats treated with estrogen, progestogen, and raloxifene. Am J Obstet Gynecol 189(6):1654–1659

    Article  PubMed  Google Scholar 

  72. Robinson D, Cardozo LD (2003) The role of estrogens in female lower urinary tract dysfunction. Urology 62 [Suppl 4A]:45–51

    Article  PubMed  Google Scholar 

  73. Hendrix SL, Cochrane BB et al (2005) Effects of estrogen with and without progestin on urinary incontinence. JAMA 293(8):935–1001

    Article  PubMed  CAS  Google Scholar 

  74. Sairam K, Kulinskaya E, McNicholas TA et al (2002) Sildenafil influences lower urinary tract symptoms. BJU Int 90:836–839

    Article  PubMed  CAS  Google Scholar 

  75. McVary KT, Monnig W, Camps JL Jr et al (2007) Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 177:1071–1077

    Article  PubMed  CAS  Google Scholar 

  76. McVary KT, Roehrborn CG, Kaminetsky JC et al (2007) Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 177:1401–1407

    Article  PubMed  CAS  Google Scholar 

  77. Stief CG, Porst H, Neuser D et al (2008) A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 53:1236–1244

    Article  PubMed  CAS  Google Scholar 

  78. Janig W, Morrison JFB (1986) Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. In: Cervero F, Morrison JFB (eds) Visceral sensation. Progress in brain research, vol 67. Elsevier, Amsterdam, pp 87–114

    Chapter  Google Scholar 

  79. Hisamitsu T, de Groat WC (1984) Inhibitory effect of opioid peptides and morphine applied intrathecally and intracerebroventricularly on the micturition reflex in the cat. Brain Res 298:51–65

    Article  PubMed  CAS  Google Scholar 

  80. Booth AM et al (1985) Regulation of urinary bladder capacity by edogenous opioid peptides. J Urol 133:339–342

    PubMed  CAS  Google Scholar 

  81. Herman RM et al (1988) The effect of low dose intrathecal morphine on impaired micturition reflexes in human subjects with spinal cord lesions. Anesthesiology 69:313–318

    Article  PubMed  CAS  Google Scholar 

  82. Lecci A et al (1993) Evidence against a peripheral role of tachykinins in the initiation of micturition reflexes in the anesthetized rat. J Pharmacol Exp Ther 264:1327–1332

    PubMed  CAS  Google Scholar 

  83. Giuliani R et al (1993) Characterization of tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors. J Pharmacol Exp Ther 267:590–595

    PubMed  CAS  Google Scholar 

  84. Chancellor MB, Yoshimura MD (2004) Neurophysiology of stress urinary incontinence. Rev Urol 6 [Suppl 3]:S19–S28

    PubMed  PubMed Central  Google Scholar 

  85. Rajaofetra N et al (1992) Serotoninergic, noradrenergic and peptidergic innervation of Onuf’s nucleus of normal and transected spinal cords of baboons. J Comp Neurol 318:1–17

    Article  PubMed  CAS  Google Scholar 

  86. Norton PA et al (2002) Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 187:40–48

    Article  PubMed  CAS  Google Scholar 

  87. Thor KB, Donatucci C (2004) Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women. J Urol 172(1):27–33

    Article  PubMed  CAS  Google Scholar 

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Bortolini, M.A.T., Bilhar, A.P.M. & Castro, R.A. Neural control of lower urinary tract and targets for pharmacological therapy. Int Urogynecol J 25, 1453–1462 (2014). https://doi.org/10.1007/s00192-014-2452-4

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