Neurourology pp 79-111 | Cite as

Pharmacology of the Lower Urinary Tract

  • Naoki YoshimuraEmail author
  • Eiichiro Takaoka
  • Takahisa Suzuki
  • Joonbeom Kwon


The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, and external urethral sphincter. This activity is in turn controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. Various neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide, and neuropeptides, both in the periphery and the central nervous system have been implicated in the neural regulation of the lower urinary tract. Injuries or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunctions such as urinary frequency, urgency, pain and incontinence or inefficient voiding and urinary retention. This chapter will review recent advances in our understanding of the pharmacology in the control of lower urinary tract function and the targets for drug therapy.


  1. 1.
    Somogyi GT, Tanowitz M, de Groat WC. M-1 muscarinic receptor mediated facilitation of acetylcholine release in the rat urinary bladder but not in the heart. J Physiol. 1994;480:81–9.Google Scholar
  2. 2.
    Wang P, Luthin GR, Ruggieri MR. Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther. 1995;273:959–66.Google Scholar
  3. 3.
    Eglen RS, Hedge SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev. 1996;48:531.Google Scholar
  4. 4.
    Yamaguchi O, Shishido K, Tamura K, Ogawa T, Fujimura T, Ohtsuka M. Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol. 1996;156:1208–13.Google Scholar
  5. 5.
    Hegde SS, Choppin A, Bonhaus D, Briaud S, Loeb M, Moy TM, Loury D, et al. Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol. 1997;120:1409–18.Google Scholar
  6. 6.
    Kondo S, Morita T, Tashima Y. Muscarinic cholinergic receptor subtypes in human detrusor muscle studied by labeled and nonlabeled pirenzepine, AFDX-116 and 4DAMP. Urol Int. 1995;54:150–3.Google Scholar
  7. 7.
    Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev. 2004;56:581–631.Google Scholar
  8. 8.
    Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br J Pharmacol. 2005;144:1089–99.Google Scholar
  9. 9.
    Eglen RM, Reddy H, Watson N, Challiss RA. Muscarinic acetylcholine receptor subtypes in smooth muscle. Trends Pharmacol Sci. 1994;15:114–9.Google Scholar
  10. 10.
    Harriss DR, Marsh KA, Birmingham AT, Hill SJ. Expression of muscarinic M3-receptors coupled to inositol phospholipid hydrolysis in human detrusor cultured smooth muscle cells. J Urol. 1995;154:1241–5.Google Scholar
  11. 11.
    Lai FM, Cobuzzi A, Spinelli W. Characterization of muscarinic receptors mediating the contraction of the urinary detrusor muscle in cynomolgus monkeys and guinea pigs. Life Sci. 1998;62:1179–86.Google Scholar
  12. 12.
    Sellers DJ, Chess-Williams R. Muscarinic agonists and antagonists: effects on the urinary bladder. Handb Exp Pharmacol. 2012;208:375–400.Google Scholar
  13. 13.
    Fry CH, Skennerton D, Wood D, Wu C. The cellular basis of contraction in human detrusor smooth muscle from patients with stable and unstable bladders. Urology. 2002;59:3–12.Google Scholar
  14. 14.
    Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84:935–86.Google Scholar
  15. 15.
    Schneider T, Fetscher C, Krege S, Michel MC. Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004;309:1148–53.Google Scholar
  16. 16.
    Schneider T, Hein P, Michel MC. Signal transduction underlying carbachol-induced contraction of rat urinary bladder. I. Phospholipases and Ca2+ sources. J Pharmacol Exp Ther. 2004;308:47–53.Google Scholar
  17. 17.
    Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC. Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedeberg's Arch Pharmacol. 2008;377:449–62.Google Scholar
  18. 18.
    Ehlert FJ, Griffin MT, Abe DM, Vo TH, Taketo MM, Manabe T, Matsui M. The M2 muscarinic receptor mediates contraction through indirect mechanisms in mouse urinary bladder. J Pharmacol Exp Ther. 2005;313:368–78.Google Scholar
  19. 19.
    Braverman AS, Ruggieri MR Sr. Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol. 2003;285:R701–8.Google Scholar
  20. 20.
    Braverman AS, Doumanian LR, Ruggieri MR Sr. M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. II. Denervated rat bladder. J Pharmacol Exp Ther. 2006;316:875–80.Google Scholar
  21. 21.
    Braverman AS, Tibb AS, Ruggieri MR Sr. M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. I. Normal rat bladder. J Pharmacol Exp Ther. 2006;316:869–74.Google Scholar
  22. 22.
    Pontari MA, Braverman AS, Ruggieri MR Sr. The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Am J Physiol Regul Integr Comp Physiol. 2004;286:R874–80.Google Scholar
  23. 23.
    Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, et al. 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. 2000;97:9579–84.Google Scholar
  24. 24.
    Matsui M, Motomura D, Fujikawa T, Jiang J, Takahashi S, Manabe T. Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J Neurosci. 2002;22:10627–32.Google Scholar
  25. 25.
    Igawa Y, Zhang X, Nishizawa O, Umeda M, Iwata A, Taketo MM, et al. Cystometric findings in mice lacking muscarinic M2 or M3 receptors. J Urol. 2004;172:2460–4.Google Scholar
  26. 26.
    D'Agostino G, Kilbinger H, Chiari MC, Grana E. Presynaptic inhibitory muscarinic receptors modulating [3H] acetylcholine release in the rat urinary bladder. J Pharmacol Exp Ther. 1986;239:522–8.Google Scholar
  27. 27.
    Somogyi GT, de Groat WC. Evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder. J Auton Nerv Syst. 1992;37:89–S97.Google Scholar
  28. 28.
    Somogyi GT, M Tanowitz. M1 muscarinic receptor facilitation of ACh and noradrenaline release in the rat urinary bladder is mediated by protein kinase C. J Physiol. 1996; 496:245–254.Google Scholar
  29. 29.
    D'Agostino G, Tanowitz M, Zernova G, de Groat WC. M4 muscarinic autoreceptor-mediated inhibition of -3H-acetylcholine release in the rat isolated urinary bladder. J Pharmacol Exp Ther. 1997;283:750–6.Google Scholar
  30. 30.
    Braverman AS, Kohn IJ, Luthin GR, Ruggieri MR. Prejunctional M1 facilitory and M2 inhibitory muscarinic receptors mediate rat bladder contractility. Am J Phys. 1998;274:R517–23.Google Scholar
  31. 31.
    D'Agostino G, Bolognesi ML, Lucchelli A, Vicini D, Balestra B, Spelta V. Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 receptor subtype. Br J Pharmacol. 2000;129:493–500.Google Scholar
  32. 32.
    Somogyi GT, Zernova GV, Tanowitz M, de Groat WC. Role of L- and N-type Ca2+ channels in muscarinic receptor-mediated facilitation of ACh and noradrenaline release in the rat urinary bladder. J Physiol. 1997;499:645–54.Google Scholar
  33. 33.
    de Groat WC, Booth AM. Synaptic transmission in pelvic ganglia. C. A. Maggi. London. Harwood Academic Publishers. 1993;1:291–347.Google Scholar
  34. 34.
    Michel MC. Therapeutic modulation of urinary bladder function: multiple targets at multiple levels. Annu Rev Pharmacol Toxicol. 2015;55:269–87.Google Scholar
  35. 35.
    Hanna-Mitchell AT, Beckel JM, Barbadora S, Kanai AJ, de Groat WC, Birder LA. Non-neuronal acetylcholine and urinary bladder urothelium. Life Sci. 2007;80:2298–302.Google Scholar
  36. 36.
    McLatchie LM, Young JS, Fry CH. Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations. Br J Pharmacol. 2014;171:3394–403.Google Scholar
  37. 37.
    Nandigama R, Bonitz M, Papadakis T, Schwantes U, Bschleipfer T, Kummer W. Muscarinic acetylcholine receptor subtypes expressed by mouse bladder afferent neurons. Neuroscience. 2010;168:842–50.Google Scholar
  38. 38.
    De Wachter S, Wyndaele JJ. Intravesical oxybutynin: a local anesthetic effect on bladder C afferents. J Urol. 2003;169:1892–5.Google Scholar
  39. 39.
    Iijima K, De Wachter S, Wyndaele JJ. Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve. Eur Urol. 2007;52:842–7.Google Scholar
  40. 40.
    Matsumoto Y, Miyazato M, Furuta A, Torimoto K, Hirao Y, Chancellor MB. Differential roles of M2 and M3 muscarinic receptor subtypes in modulation of bladder afferent activity in rats. Urology. 2010;75:862–7.Google Scholar
  41. 41.
    Matsumoto Y, Miyazato M, Yokoyama H, Kita M, Hirao Y, Chancellor MB. Role of M2 and M3 muscarinic acetylcholine receptor subtypes in activation of bladder afferent pathways in spinal cord injured rats. Urology. 2012; 79:1184. e15–20.Google Scholar
  42. 42.
    Chess-Williams R, Hashitani H. Cell biology (Committee 2). In: Incontinence, 6th Edition, 6th International Consultation on Incontinence, Tokyo, Japan; 2017.p. 143–258.Google Scholar
  43. 43.
    Johnston L, Carson C, Lyons AD, Davidson RA, McCloskey KD. Cholinergic-induced Ca2+ signaling in interstitial cells of Cajal from the guinea pig bladder. Am J Physiol Renal Physiol. 2008;294:F645–55.Google Scholar
  44. 44.
    Kim SO, Jeong HS. Spontaneous electrical activity of cultured interstitial cells of cajal from mouse urinary bladder. Korean J Physiol Pharmacol. 2013;17:531–6.Google Scholar
  45. 45.
    Burnstock G, Dumsday B, Smythe A. Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide. Br J Pharmacol. 1972;44:451–61.Google Scholar
  46. 46.
    Chancellor MB, Kaplan SA, Blaivas JG. The cholinergic and purinergic components of detrusor contractility in a whole rabbit bladder model. J Urol. 1992;148:906–9.Google Scholar
  47. 47.
    Burnstock G. P2 purinoceptors: historical perspective and classification. Ciba Found Symp. 1996;198:1–28; discussion 29–34.Google Scholar
  48. 48.
    Palea S, Artibani W, Ostardo E, Trist DG, Pietra C. Evidence for purinergic neurotransmission in human urinary bladder affected by interstitial cystitis. J Urol. 1993;150:2007–12.Google Scholar
  49. 49.
    Burnstock G. In: Abbracchio M, Williams W, editors. Handbook of experimental pharmacology on “Purinergic and Pyrimidinergic Signalling”. Berlin: Springer; 2000.Google Scholar
  50. 50.
    O'Reilly BA, Kosaka AH, Chang TK, Ford AP, Popert R, McMahon SB. A quantitative analysis of purinoceptor expression in the bladders of patients with symptomatic outlet obstruction. BJU Int. 2001;87:617–22.Google Scholar
  51. 51.
    Inoue R, Brading AF. The properties of the ATP-induced depolarization and current in single cells isolated from the guinea-pig urinary bladder. Br J Pharmacol. 1990;100:619–25.Google Scholar
  52. 52.
    Inoue T, Gabella G. A vascular network closely linked to the epithelium of the urinary bladder of the rat. Cell Tissue Res. 1991;263:137–43.Google Scholar
  53. 53.
    McMurray G, Dass N. Purinergic mechanisms in primate urinary bladder. Br J Urol. 1997;80:182.Google Scholar
  54. 54.
    Lee HY, Bardini M, Burnstock G. Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J Urol. 2000;163:2002–7.Google Scholar
  55. 55.
    Valera S, Talabot F, Evans RJ, Gos A, Antonarakis SE, Morris MA. Characterization and chromosomal localization of a human P2X receptor from the urinary bladder. Receptors Channels. 1995;3:283–9.Google Scholar
  56. 56.
    O'Reilly BA, Kosaka AH, Chang TK, Ford AP, Popert R, Rymer JM, et al. A quantitative analysis of purinoceptor expression in human fetal and adult bladders. J Urol. 2001;165:1730–4.Google Scholar
  57. 57.
    Burnstock G. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci. 2001;22:182–8.Google Scholar
  58. 58.
    Theobald RJ Jr, de Groat WD. The effects of purine nucleotides on transmission in vesical parasympathetic ganglia of the cat. J Auton Pharmacol. 1989;9:167–81.Google Scholar
  59. 59.
    Nishimura T, Tokimasa T. Purinergic cation channels in neurons of rabbit vesical parasympathetic ganglia. Neurosci Lett. 1996;212:215–7.Google Scholar
  60. 60.
    Zhong Y, Dunn PM, Xiang Z, Bo X, Burnstock G. Pharmacological and molecular characterization of P2X receptors in rat pelvic ganglion neurons. Br J Pharmacol. 1998;125:771–81.Google Scholar
  61. 61.
    Zhong Y, Dunn PM. Burnstock. Multiple P2X receptors on guinea-pig pelvic ganglion neurons exhibit novel pharmacological properties. Br J Pharmacol. 2001;132:221–33.Google Scholar
  62. 62.
    Ferguson DR, Kennedy I, Burton TJ. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes--a possible sensory mechanism? J Physiol. 1997;505:503–11.Google Scholar
  63. 63.
    Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, et al. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol. 2005;567:621–39.Google Scholar
  64. 64.
    Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407:1011–5.Google Scholar
  65. 65.
    Takezawa K, Kondo M, Kiuchi H, Ueda N, Soda T, Fukuhara S, et al. Authentic role of ATP signaling in micturition reflex. Sci Rep. 2016;6:19585.Google Scholar
  66. 66.
    Takezawa K, Kondo M, Nonomura N, Shimada S. Urothelial ATP signaling: what is its role in bladder sensation? Neurourol Urodyn. 2017;36:966–72.Google Scholar
  67. 67.
    Wang EC, Lee JM, Ruiz WG, Balestreire EM, von Bodungen M, Barrick S, et al. ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells. J Clin Invest. 2005;115:2412–22.Google Scholar
  68. 68.
    Zhong Y, Banning AS, Cockayne DA, Ford AP, Burnstock G, Mcmahon SB, et al. Bladder and cutaneous sensory neurons of the rat express different functional P2X receptors. Neuroscience. 2003;120:667–75.Google Scholar
  69. 69.
    Dang K, Bielefeldt K, Gebhart GF. Differential responses of bladder lumbosacral and thoracolumbar dorsal root ganglion neurons to purinergic agonists, protons, and capsaicin. J Neurosci. 2005;25:3973–84.Google Scholar
  70. 70.
    Dmitrieva N, Burnstock G. ATP and 2-methylthio ATP activate bladder reflexes and induce discharge of bladder sensory neurones. Soc Neurosci Abstr. 1998;24:2088.Google Scholar
  71. 71.
    Namasivayam S, Eardley I, Morrison JF. Purinergic sensory neurotransmission in the urinary bladder: an in vitro study in the rat. BJU Int. 1999;84:854–60.Google Scholar
  72. 72.
    Pandita RK, Andersson KE. Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol. 2002;168:1230–4.Google Scholar
  73. 73.
    Zhang X, Igawa Y, Ishizuka O, Nishizawa O, Andersson KE. Effects of resiniferatoxin desensitization of capsaicin-sensitive afferents on detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP in conscious rats. Naunyn Schmiedeberg's Arch Pharmacol. 2003;367:473–9.Google Scholar
  74. 74.
    Nishiguchi J, Hayashi Y, Chancellor MB, de Miguel F, de Groat WC, Kumon H, et al. Detrusor overactivity induced by intravesical application of adenosine 5′-triphosphate under different delivery conditions in rats. Urology. 2005;66:1332–7.Google Scholar
  75. 75.
    Morrison J, Namasivayam S, Eardley I. ATP may be a natural modulator of the sensitivity of bladder mechanoreceptors during slow distensions. 1st International Consultation on Incontinence;1998. Monaco, p 84.Google Scholar
  76. 76.
    Akasu TP, Shinnick-Gallagher P. Gallagher JP Adenosine mediates a slow hyperpolarizing synaptic potential in autonomic neurones. Nature. 1984;311:62–5.Google Scholar
  77. 77.
    Olah ME, Ren H, Stiles GL. Adenosine receptors: protein and gene structure. Arch Int Pharmacodyn Ther. 1995;329:135–50.Google Scholar
  78. 78.
    Fry CH, Ikeda Y, Harvey R, Wu C, Sui GP. Control of bladder function by peripheral nerves: avenues for novel drug targets. Urology. 2004;63:24–31.Google Scholar
  79. 79.
    Yu W, Zacharia LC, Jackson EK, Apodaca G. Adenosine receptor expression and function in bladder uroepithelium. Am J Physiol Cell Physiol. 2006;291:C254–65.Google Scholar
  80. 80.
    Durnin L. Hayoz, Corrigan RD, Yanez A, Koh SD, Mutafova-Yambolieva VN. Urothelial purine release during filling of murine and primate bladders. Am J Physiol Renal Physiol. 2016;311:F708–16.Google Scholar
  81. 81.
    Andersson KE. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. [Review]. Pharmacol Rev. 1993;45:253–308.Google Scholar
  82. 82.
    Morita T, Ando M, Kihara K, Oshima H. Species differences in cAMP production and contractile response induced by beta-adrenoceptor subtypes in urinary bladder smooth muscle. Neurourol Urodyn. 1993;12:185–90.Google Scholar
  83. 83.
    Levin RM, Wein AJ. Neurophysiology and neuropharmacology. Bladder. J. Fitzpatrick and R. Krane. New York, Churchill Livingstone; 1995; p. 47–70.Google Scholar
  84. 84.
    Nishimoto T, Latifpour J, Wheeler MA, Yoshida M, Weiss RM. Age-dependent alterations in beta-adrenergic responsiveness of rat detrusor smooth muscle. J Urol. 1995;153:1701–5.Google Scholar
  85. 85.
    Igawa Y, Yamazaki Y, Takeda H, Hayakawa K, Akahane M, Ajisawa Y. Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol. 1999;126:819–25.Google Scholar
  86. 86.
    Yamaguchi O. Beta3-adrenoceptors in human detrusor muscle. Urology. 2002;59:25–9.Google Scholar
  87. 87.
    Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol. 2003;170:649–53.Google Scholar
  88. 88.
    Coelho A, Antunes-Lopes T, Gillespie J, Cruz F. Beta-3 adrenergic receptor is expressed in acetylcholine-containing nerve fibers of the human urinary bladder: An immunohistochemical study. Neurourol Urodyn. 2017;197:785.Google Scholar
  89. 89.
    Silva I, Costa AF, Moreira S, Ferreirinha F, Magalhães-Cardoso MT, et al. Inhibition of cholinergic neurotransmission by beta3-adrenoceptors depends on adenosine release and A1-receptor activation in human and rat urinary bladders. Am J Physiol Renal Physiol. 2017;313:388–403.Google Scholar
  90. 90.
    Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R. The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int. 2007;99:669–73.Google Scholar
  91. 91.
    Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedeberg's Arch Pharmacol. 2008;377:473–81.Google Scholar
  92. 92.
    Bridgeman MB, Friia NJ, Taft C, Shah M. Mirabegron: beta3-adrenergic receptor agonist for the treatment of overactive bladder. Ann Pharmacother. 2013;4:1029–38.Google Scholar
  93. 93.
    Abrams P, Kelleher C, Staskin D, Rechberger T, Kay R. Martina. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015;67:577–88.Google Scholar
  94. 94.
    Aizawa N, Homma Y, Igawa Y. Effects of L-arginine, mirabegron, and oxybutynin on the primary bladder afferent nerve activities synchronized with reflexic, rhythmic bladder contractions in the rat. Neurourol Urodyn. 2015;34:368–74.Google Scholar
  95. 95.
    Sadananda P, Drake MJ, Paton JF, Pickering AE. A functional analysis of the influence of beta3-adrenoceptors on the rat micturition cycle. J Pharmacol Exp Ther. 2013;347:506–15.Google Scholar
  96. 96.
    Aizawa N, Gandaglia G, Hedlund P, Fujimura T, Fukuhara H, Montorsi F, et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int. 2015;117:821–8.Google Scholar
  97. 97.
    Hampel C, Dolber PC, Smith MP, Savic SL. Th roff JW, Thor KB, et al. Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction. J Urol. 2002;167:1513–21.Google Scholar
  98. 98.
    Chen Q, Takahashi S, Zhong S, Hosoda C, Zheng HY, Ogushi T, et al. Function of the lower urinary tract in mice lacking alpha1d-adrenoceptor. J Urol. 2005;174:370–4.Google Scholar
  99. 99.
    Malloy BJ, Price DT, Price RR, Bienstock AM, Dole MK, Funk BL, et al. Alpha1-adrenergic receptor subtypes in human detrusor. J Urol. 1998;160:937–43.Google Scholar
  100. 100.
    Yono M, Foster HE Jr, Shin D, Takahashi W, Pouresmail M, Latifpour J. Doxazosin-induced up-regulation of alpha 1A-adrenoceptor mRNA in the rat lower urinary tract. Can J Physiol Pharmacol. 2004;82:872–8.Google Scholar
  101. 101.
    Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147:S88–119.Google Scholar
  102. 102.
    Yalla SV, Rossier AB, Gabilondo FB, Di Benedetto M, Gittes RF. Functional contribution of autonomic innervation to urethral striated sphincter: Studies with parasympathomimetic, parasympatholytic and alpha adrenergic blocking agents in spinal cord injury and control male subjects. J Urol. 1997;117:494.Google Scholar
  103. 103.
    Awad SA, Downie JW, Kiruluta HG. Alpha-adrenergic agents in urinary disorders of the proximal urethra. Part I. Sphincteric incontinence. Br J Urol. 1978;50:332–5.Google Scholar
  104. 104.
    Nordling J. Influence of the sympathetic nervous system on lower urinary tract in man. Neurourol Urodynam. 1983;2:3.Google Scholar
  105. 105.
    Mattiasson A, Andersson KE, Sjögren C. Adrenoceptors and cholinoceptors controlling noradrenaline release from adrenergic nerves in the urethra of rabbit and man. J Urol. 1984;131:1190–5.Google Scholar
  106. 106.
    Testa R, Guarneri L, Ibba M, Strada G, Poggesi E, Taddei C. Characterization of alpha 1-adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit, dog and man. Eur J Pharmacol. 1993;249:307–15.Google Scholar
  107. 107.
    Awad SA, Downie JW, Lywood DW, Young RA, Jarzylo SV. Sympathetic activity in the proximal urethra in patients with urinary obstruction. J Urol. 1976;115:545–7.Google Scholar
  108. 108.
    Keating GM. Silodosin: a review of its use in the treatment of the signs and symptoms of benign prostatic hyperplasia. Drugs. 2015;75:207–17.Google Scholar
  109. 109.
    Nishino Y, Masue T, Miwa K, Takahashi Y, Ishihara S, Deguchi T. Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study. BJU Int. 2006;97:747–51.Google Scholar
  110. 110.
    Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193–9.Google Scholar
  111. 111.
    Willette RN, Sauermelch C, Hieble JP. Role of alpha-1 and alpha-2 adrenoceptors in the sympathetic control of the proximal urethra. J Pharmacol Exp Ther. 1990;252:706–10.Google Scholar
  112. 112.
    de Groat WC, Booth AM, Yoshimural Y. Neurophysiology of micturition and its modification in animal models of human disease. C. A. Maggi. London. Harwood Academic Publishers. 1993;1:227–90.Google Scholar
  113. 113.
    Andersson KE, Garcia Pascual A, Persson K, Forman A, Tøttrup A. Electrically-induced, nerve-mediated relaxation of rabbit urethra involves nitric oxide. J Urol. 1992;147:253–9.Google Scholar
  114. 114.
    Andersson KE, Persson K. Nitric oxide synthase and the lower urinary tract: possible implications for physiology and pathophysiology. Scand J Urol Nephrol Suppl. 1995;175:43–53.Google Scholar
  115. 115.
    Bennett BC, Kruse MN, Roppolo JR, Flood HD, Fraser M, et al. Neural control of urethral outlet activity in vivo: role of nitric oxide. J Urol. 1995;153:2004–9.Google Scholar
  116. 116.
    Fraser MO, Flood HD. Urethral smooth muscle relaxation is mediated by nitric oxide (NO) released from parasympathetic postganglionic neurons. J Urol. 1995;153:461A.Google Scholar
  117. 117.
    Vizzard MA, Erdman SL, Förstermann U, de Groat WC. Differential distribution of nitric oxide synthase in neural pathways to urogenital organs (urethra, penis, urinary bladder) of the rat. Brain Res. 1994;646:279–91.Google Scholar
  118. 118.
    Lies B, Groneberg D, Friebe A. Correlation of cellular expression with function of NO-sensitive guanylyl cyclase in the murine lower urinary tract. J Physiol. 2013;591:5365–75.Google Scholar
  119. 119.
    Truss MC, Becker AJ, Ückert S, Schultheiss D, Machtens S, et al. Selective pharmacological manipulation of the smooth muscle tissue of the genitourinary tract: a glimpse into the future. BJU Int. 1999;83(Suppl 2):36–41.Google Scholar
  120. 120.
    Truss MC, Stief CG, Uckert S, Becker AJ, Wefer J, Schultheiss D, et al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol. 2001;19:344–50.Google Scholar
  121. 121.
    Rice A. Topical spinal administration of a nitric oxide synthase inhibitor prevents the hyperreflexia associated with a rat model of persistent visceral pain. Neurosci Lett. 1995;187:111.Google Scholar
  122. 122.
    Kakizaki H, de Groat WC. Role of spinal nitric oxide in the facilitation of the micturition reflex by bladder irritation. J Urol. 1996;155:355–60.Google Scholar
  123. 123.
    Lagos P, Ballejo G. Role of spinal nitric oxide synthase-dependent processes in the initiation of the micturition hyperreflexia associated with cyclophosphamide-induced cystitis. Neuroscience. 2004;125:663–70.Google Scholar
  124. 124.
    Pandita RK, Persson K, Andersson KE. Capsaicin-induced bladder overactivity and nociceptive behaviour in conscious rats: involvement of spinal nitric oxide. J Auton Nerv Syst. 1997;67:184–91.Google Scholar
  125. 125.
    Birder LA, Apodaca G, de Groat WC, Kanai AJ. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Phys. 1998;275:F226–9.Google Scholar
  126. 126.
    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.Google Scholar
  127. 127.
    Zvara P, Folsom JB, Kliment J Jr, Dattilio AL, Moravcíková A, Plante MK, et al. Increased expression of neuronal nitric oxide synthase in bladder afferent cells in the lumbosacral dorsal root ganglia after chronic bladder outflow obstruction. Brain Res. 2004;1002:35–42.Google Scholar
  128. 128.
    Ozawa H, Chancellor MB, Jung SY, Yokoyama T, Fraser MO, Yu Y, et al. Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol. 1999;162:2211–6.Google Scholar
  129. 129.
    Pandita RK, Mizusawa HK. Intravesical oxyhemoglobin initiates bladder overactivity in conscious, normal rats. J Urol. 2004;164:545–50.Google Scholar
  130. 130.
    Masuda H, Kim JH, Kihara K, Chancellor MB, de Groat WC, Yoshimura N. Inhibitory roles of peripheral nitrergic mechanisms in capsaicin-induced detrusor overactivity in the rat. BJU Int. 2007;100:912–8.Google Scholar
  131. 131.
    Yoshimura N, Seki S, de Groat WC. Nitric oxide modulates Ca(2+) channels in dorsal root ganglion neurons innervating rat urinary bladder. J Neurophysiol. 2001;86:304–11.Google Scholar
  132. 132.
    Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61:994–1003.Google Scholar
  133. 133.
    Cantrell MA, Baye J, Vouri SM. Tadalafil: a phosphodiesterase-5 inhibitor for benign prostatic hyperplasia. Pharmacotherapy. 2013;33:639–49.Google Scholar
  134. 134.
    Flood HD, Liu JL, Fraser MO, de Groat WC. Sex differences in the nitric oxide (NO)--mediated smooth muscle component and striated muscle component of urethral relaxation in rats. Neurourol Urodyn. 1995;14:517.Google Scholar
  135. 135.
    Kakizaki H, Fraser MO, de Groat WC. Reflex pathways controlling urethral striated and smooth muscle function in the male rat. Am J Phys. 1997;272:R1647.Google Scholar
  136. 136.
    Alexandre EC, de Oliveira MG, Campos R, Kiguti LR, Calmasini FB, Silva FH, et al. How important is the alpha1-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of alpha1-adrenoceptor to urethral contractility. Am J Physiol Renal Physiol. 2017;312:F1026–34.Google Scholar
  137. 137.
    de Groat WC. Spinal cord projections and neuropeptides in visceral afferent neurons. Prog Brain Res. 1986;67:165–87.Google Scholar
  138. 138.
    de Groat WC. Neuropeptides in pelvic afferent pathways. Experientia. 1989;56:334–61.Google Scholar
  139. 139.
    Keast JR, de Groat WC. Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J Comp Neurol. 1992;319:615–23.Google Scholar
  140. 140.
    Maggi CA. The dual, sensory and efferent function of the capsaicin-sensitive primary sensory nerves in the bladder and urethra. C. A. Maggi. London. Harwood Academic Publishers. 1993;1:383–422.Google Scholar
  141. 141.
    Vizzard MA. Alterations in neuropeptide expression in lumbosacral bladder pathways following chronic cystitis. J Chem Neuroanat. 2001;21:125–38.Google Scholar
  142. 142.
    Vizzard MA. Neurochemical plasticity and the role of neurotrophic factors in bladder reflex pathways after spinal cord injury. Prog Brain Res. 2006;152:97–115.Google Scholar
  143. 143.
    Keast JR, Stephensen TM. Glutamate and aspartate immunoreactivity in dorsal root ganglion cells supplying visceral and somatic targets and evidence for peripheral axonal transport. J Comp Neurol. 2000;424:577–87.Google Scholar
  144. 144.
    Kawatani M, Rutigliano M, de Groat WC. Vasoactive intestinal polypeptide produces ganglionic depolarization and facilitates muscarinic excitatory mechanisms in a sympathetic ganglion. Science. 1985;229:879–81.Google Scholar
  145. 145.
    Kawatani M, Nagel J, de Groat WC. Identification of neuropeptides in pelvic and pudendal nerve afferent pathways to the sacral spinal cord of the cat. J Comp Neurol. 1986;249:117–32.Google Scholar
  146. 146.
    Kawatani M, Suzuki T, de Groat WC. Corticotropin releasign factor-like Immunoreactivity in Afferent projections to the sacral spinal cord of the cat. J Auton Nerv Syst. 1996;61:218–26.Google Scholar
  147. 147.
    Morrison J, L Birder. Neural control. Incontinence. P. Abrams, C. L., K. S. and A. Wein. Plymouth, Health Publications: 2005;363–422.Google Scholar
  148. 148.
    Merrill L, Girard B, Arms L, Guertin P, Vizzard MA. Neuropeptide/Receptor expression and plasticity in micturition pathways. Curr Pharm Des. 2013;19:4411–22.Google Scholar
  149. 149.
    Ishizuka O, Igawa Y, Lecci A, Maggi CA, Mattiasson A, Andersson KE. Role of intrathecal tachykinins for micturition in unanaesthetized rats with and without bladder outlet obstruction. Br J Pharmacol. 1994;113:111–6.Google Scholar
  150. 150.
    Ishizuka O, Alm P, Larsson B, Mattiasson A, Andersson KE. Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rats. Neuroscience. 1995;66:1009–14.Google Scholar
  151. 151.
    Khawaja AM, Rogers DF. Tachykinins: receptor to effector. Int J Biochem Cell Biol. 1996;28:721–38.Google Scholar
  152. 152.
    Lecci A, Maggi CA. Tachykinins as modulators of the micturition reflex in the central and peripheral nervous system. Regul Pept. 2001;101:1–18.Google Scholar
  153. 153.
    Morrison JF, Sato A, Sato Y, Yamanishi T. The influence of afferent inputs from skin and viscera on the activity of the bladder and the skeletal muscle surrounding the urethra in the rat. Neurosci Res. 1995;23:195–205.Google Scholar
  154. 154.
    Kamo I, Chancellor MB, de Groat WC, Yoshimura N. Differential effects of activation of peripheral and spinal tachykinin neurokinin(3) receptors on the micturition reflex in rats. J Urol. 2005;174:776–81.Google Scholar
  155. 155.
    Lecci A, Giuliani S, Garret C, Maggi CA. Evidence for a role of tachykinins as sensory transmitters in the activation of micturition reflex. Neuroscience. 1993;54:827–37.Google Scholar
  156. 156.
    Yamamoto T, Hanioka N, Maeda Y, Imazumi K, Hamada K, et al. Contribution of tachykinin receptor subtypes to micturition reflex in guinea pigs. Eur J Pharmacol. 2003;477:253–9.Google Scholar
  157. 157.
    Lecci A, Giuliani S, Santicioli P, Maggi CA. Involvement of spinal tachykinin NK1 and NK2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats. Eur J Pharmacol. 1994;259:129–35.Google Scholar
  158. 158.
    Ishizuka O, Mattiasson A, Andersson KE. Effects of neurokinin receptor antagonists on L-dopa induced bladder hyperactivity in normal conscious rats. J Urol. 1995;154:1548–51.Google Scholar
  159. 159.
    Lecci A, Giuliani S, Tramontana M, Criscuoli M, Maggi CA. MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo. Naunyn Schmiedeberg's Arch Pharmacol. 1997;356:182–8.Google Scholar
  160. 160.
    Doi T, Kamo I, Imai S, Okanishi S, Ishimaru T, Ikeura Y, et al. Effects of TAK-637, a tachykinin receptor antagonist, on lower urinary tract function in the guinea pig. Eur J Pharmacol. 1999;383:297–303.Google Scholar
  161. 161.
    Green SA, Alon A, Ianus J, McNaughton KS, Tozzi CA, Reiss TF. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol. 2006;176:2535–40; discussion 2540.Google Scholar
  162. 162.
    Frenkl TL, Zhu H, Reiss T, Seltzer O, Rosenberg E, Green S. A multicenter, double-blind, randomized, placebo controlled trial of a neurokinin-1 receptor antagonist for overactive bladder. J Urol. 2010;184:616–22.Google Scholar
  163. 163.
    Sculptoreanu A, de Groat WC. Protein kinase C is involved in neurokinin receptor modulation of N- and L-type Ca2+ channels in DRG neurons of the adult rat. J Neurophysiol. 2003;90:21–31.Google Scholar
  164. 164.
    Sculptoreanu A, Kullmann FA, de Groat WC. Neurokinin 2 receptor-mediated activation of protein kinase C modulates capsaicin responses in DRG neurons from adult rats. Eur J Neurosci. 2008;27:3171–81.Google Scholar
  165. 165.
    Yoshimura N, de Groat WC. Neural control of the lower urinary tract. Int J Urol. 1997;4:111–25.Google Scholar
  166. 166.
    Yoshiyama M, de Groat WC. The role of vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide in the neural pathways controlling the lower urinary tract. J Mol Neurosci. 2008;36:227–40.Google Scholar
  167. 167.
    May V, Vizzard MA. Bladder dysfunction and altered somatic sensitivity in PACAP−/− mice. J Urol. 2010;183:772–9.Google Scholar
  168. 168.
    Yoshiyama M, de Groat WC. Effects of intrathecal administration of pituitary adenylate cyclase activating polypeptide on lower urinary tract functions in rats with intact or transected spinal cords. Exp Neurol. 2008;211:449–55.Google Scholar
  169. 169.
    Zvarova K, Dunleavy JD, Vizzard MA. Changes in pituitary adenylate cyclase activating polypeptide expression in urinary bladder pathways after spinal cord injury. Exp Neurol. 2005;192:46–59.Google Scholar
  170. 170.
    Zvara P, Braas KM, May V, Vizzard MA. A role for pituitary adenylate cyclase activating polypeptide (PACAP) in detrusor hyperreflexia after spinal cord injury (SCI). Ann N Y Acad Sci. 2006;1070:622–8.Google Scholar
  171. 171.
    Braas KM, May V, Zvara P, Nausch B, Kliment J, Dunleavy JD. Role for pituitary adenylate cyclase activating polypeptide in cystitis-induced plasticity of micturition reflexes. Am J Physiol Regul Integr Comp Physiol. 2006;290:R951–62.Google Scholar
  172. 172.
    Miura A, Kawatani M, de Groat WC. Effects of pituitary adenylate cyclase activating polypeptide on lumbosacral preganglionic neurons in the neonatal rat spinal cord. Brain Res. 2001;895:223–32.Google Scholar
  173. 173.
    Breyer RM, Bagdassarian CK, Myers SA, Breyer MD. Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol. 2011;41:661–90.Google Scholar
  174. 174.
    Breyer MD, Hébert RL, Breyer RM. Prostanoid receptors and the urogenital tract. Curr Opin Investig Drugs. 2003;4:1343–53.Google Scholar
  175. 175.
    Rahnama'i MS, van Koeveringe GA, Essers PB, de Wachter SG, de Vente J, van Kerrebroeck PE, et al. Prostaglandin receptor EP1 and EP2 site in guinea pig bladder urothelium and lamina propria. J Urol. 2010;183:1241–7.Google Scholar
  176. 176.
    Beppu MI, Araki I, Yoshiyama M, Du S, Kobayashi H, Zakoji H, et al. Bladder outlet obstruction induced expression of prostaglandin E2 receptor subtype EP4 in the rat bladder: a possible counteractive mechanism against detrusor overactivity. J Urol. 2011;186:2463–9.Google Scholar
  177. 177.
    Saban R, Undem BJ, Keith IM, Saban MR, Tengowski MW, Graziano FM. Differential release of prostaglandins and leukotrienes by sensitized guinea pig urinary bladder layers upon antigen challenge. J Urol. 1994;152:544–9.Google Scholar
  178. 178.
    Schroder A, Newgreen D, Andersson KE. Detrusor responses to prostaglandin E2 and bladder outlet obstruction in wild-type and Ep1 receptor knockout mice. J Urol. 2004;172:1166–70.Google Scholar
  179. 179.
    Wang X, Momota Y, Yanase H, Narumiya S, Maruyama T, Kawatani M. Urothelium EP1 receptor facilitates the micturition reflex in mice. Biomed Res. 2008;29:105–11.Google Scholar
  180. 180.
    Chapple CR, Abrams P, Andersson KE, Radziszewski P, Masuda T, Small M, et al. Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome. J Urol. 2014;191:253–60.Google Scholar
  181. 181.
    Jones RL, Giembycz MA, Woodward DF. Prostanoid receptor antagonists: development strategies and therapeutic applications. Br J Pharmacol. 2009;158:104–45.Google Scholar
  182. 182.
    Chuang YC, Yoshimura N, Huang CC, Wu M, Tyagi P, Chancellor MB. Expression of E-series prostaglandin (EP) receptors and urodynamic effects of an EP4 receptor antagonist on cyclophosphamide-induced overactive bladder in rats. BJU Int. 2010;106:1782–7.Google Scholar
  183. 183.
    Bultitude MI, Hills NH, Shuttleworth KE. Clinical and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vitro and in vivo. Br J Urol. 1976;48:631–7.Google Scholar
  184. 184.
    Vadyanaathan S, Rao MS, Chary KS, Sharma PL, Das N. Enhancement of detrusor reflex activity by naloxone in patients with chronic neurogenic bladder dysfunction. J Urol. 1981;126:500.Google Scholar
  185. 185.
    Tammela T, Kontturi M, Käär K, Lukkarinen O. Intravesical prostaglandin F2 for promoting bladder emptying after surgery for female stress incontinence. Br J Urol. 1987;60:43–6.Google Scholar
  186. 186.
    Delaere KP, Thomas CM, Moonen WA, Debruyne FM. The value of intravesical prostaglandin E2 and F2a in women with abnormalities of bladder emptying. Br J Urol. 1981;53:3069.Google Scholar
  187. 187.
    Wagner G, Husslein P, Enzelsberger H. Is prostaglandin E2 really of therapeutic value for postoperative urinary retention? Results of a prospectively randomized double-blind study. Am J Obstet Gynecol. 1985;151:375–9.Google Scholar
  188. 188.
    Schussler B. Comparison of mode of action of prostaglandin E2 and sulprostone, a PGE2 derivative on the lower urinary tract in healthy women. Urol Res. 1990;18:349.Google Scholar
  189. 189.
    Sekido N, Kida J, Mashimo H, Wakamatsu D, Okada H, Matsuya H. Promising Effects of a Novel EP2 and EP3 Receptor Dual Agonist, ONO-8055, on Neurogenic Underactive Bladder in a Rat Lumbar Canal Stenosis Model. J Urol. 2006;196:609–16.Google Scholar
  190. 190.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–5.Google Scholar
  191. 191.
    Masaki T. Historical review: Endothelin. Trends Pharmacol Sci. 2004;25:219–24.Google Scholar
  192. 192.
    Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994;46:325–415.Google Scholar
  193. 193.
    Khan MA, Dashwood MR. Up-regulation of endothelin (ET(A) and ET(B)) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction. Urol Res. 1999;27(6):445–53.Google Scholar
  194. 194.
    Arteaga JL, Dashwood MR, Thompson CS, Mumtaz FH, Mikhailidis DP, Morgan RJ. Endothelin ET(B) receptors are involved in the relaxation to the pig urinary bladder neck. Neurourol Urodyn. 2012;31:688–94.Google Scholar
  195. 195.
    Saenz de Tejada I, Mueller JD, de Las Morenas A, Machado M, Moreland RB, Krane RJ. Endothelin in the urinary bladder. I. Synthesis of endothelin-1 by epithelia, muscle and fibroblasts suggests autocrine and paracrine cellular regulation. J Urol. 1992; 148:1290–8.Google Scholar
  196. 196.
    Maggi CA, Abelli L, Giuliani S, Somma V, Furio M, Patacchini R. Motor and inflammatory effect of hyperosmolar solutions on the rat urinary bladder in relation to capsaicin-sensitive sensory nerves. Gen Pharmacol. 1990;21:97–103.Google Scholar
  197. 197.
    Schroder A, Tajimi M, Matsumoto H, Schröder C, Brands M, Andersson KE. Protective effect of an oral endothelin converting enzyme inhibitor on rat detrusor function after outlet obstruction. J Urol. 2004;172:1171–4.Google Scholar
  198. 198.
    Ukai M, Yuyama H, Noguchi Y, Someya A, Okutsu H, Watanabe M, et al. Participation of endogenous endothelin and ETA receptor in premicturition contractions in rats with bladder outlet obstruction. Naunyn Schmiedeberg's Arch Pharmacol. 2006;373:197–203.Google Scholar
  199. 199.
    Ogawa T, Kamo I, Pflug BR, Nelson JB, Seki S, Igawa Y. Differential roles of peripheral and spinal endothelin receptors in the micturition reflex in rats. J Urol. 2004;172:1533–7.Google Scholar
  200. 200.
    Ogawa T, Sasatomi K, Hiragata S, Seki S, Nishizawa O, Chermansky CJ. Therapeutic effects of endothelin-A receptor antagonist on bladder overactivity in rats with chronic spinal cord injury. Urology. 2008;71:341–5.Google Scholar
  201. 201.
    Hanyu S, Iwanaga T, Kano K, Fujita T. Distribution of serotonin-immunoreactive paraneurons in the lower urinary tract of dogs. Am J Anat. 1987;180:349–56.Google Scholar
  202. 202.
    Kullmann FA Chang HH, Gauthier C, McDonnell BM, Yeh JC, Clayton DR, et al. Serotonergic paraneurons in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol. 2018;222(2).Google Scholar
  203. 203.
    Yokoyama T, Saino T, Nakamuta N, Yamamoto Y. Topographic distribution of serotonin-immunoreactive urethral endocrine cells and their relationship with calcitonin gene-related peptide-immunoreactive nerves in male rats. Acta Histochem. 2017;119:78–83.Google Scholar
  204. 204.
    Klarskov P, Hørby-Petersen J. Influence of serotonin on lower urinary tract smooth muscle in vitro. Br J Urol. 1986;58:507–13.Google Scholar
  205. 205.
    Candura SM, Messori E, Franceschetti GP, D'Agostino G, Vicini D, Tagliani M. Neural 5-HT4 receptors in the human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists. Br J Pharmacol. 1996;118:1965–70.Google Scholar
  206. 206.
    Darblade B, Behr-Roussel D, Gorny D, Lebret T, Benoit G, Hieble JP. Piboserod (SB 207266), a selective 5-HT4 receptor antagonist, reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle. World J Urol. 2005;23:147–51.Google Scholar
  207. 207.
    Palea S, Lluel P, Barras M, Duquenne C, Galzin AM, Arbilla S. Involvement of 5-hydroxytryptamine (HT)7 receptors in the 5-HT excitatory effects on the rat urinary bladder. BJU Int. 2004;94:1125–31.Google Scholar
  208. 208.
    Sakai T, Kasahara K, Tomita K, Ikegaki I, Kuriyama H. 5-Hydroxytryptamine-induced bladder hyperactivity via the 5-HT2A receptor in partial bladder outlet obstruction in rats. Am J Physiol Renal Physiol. 2013;304:F1020–7.Google Scholar
  209. 209.
    Michishita M, Yano K, Kasahara K, Tomita K, Matsuzaki O. Increased expression of 5-HT(2A) and 5-HT(2B) receptors in detrusor muscle after partial bladder outlet obstruction in rats. Biomed Res. 2015;36:187–94.Google Scholar
  210. 210.
    Krause JE, Chenard BL, Cortright DN. Transient receptor potential ion channels as targets for the discovery of pain therapeutics. Curr Opin Investig Drugs. 2005;6:48–57.Google Scholar
  211. 211.
    Clapham DE. Some like it hot: spicing up ion channels. Nature. 1997;389:783–4.Google Scholar
  212. 212.
    Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci. 2002;5:856–60.Google Scholar
  213. 213.
    Charrua A, Cruz CD, Cruz F, Avelino A. Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis. J Urol. 2007;177:1537–41.Google Scholar
  214. 214.
    Wang ZY, Wang P, Merriam FV, Bjorling DE. Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice. Pain. 2008;139:158–67.Google Scholar
  215. 215.
    Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS. 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.Google Scholar
  216. 216.
    Silva C, Ribeiro MJ, Cruz F. The effect of intravesical resiniferatoxin in patients with idiopathic detrusor instability suggests that involuntary detrusor contractions are triggered by C-fiber input. J Urol. 2002;168:575–9.Google Scholar
  217. 217.
    Lazzeri M, Beneforti P, Benaim G, Maggi CA, Lecci A, Turini D. Intravesical capsaicin for treatment of severe bladder pain: a randomized placebo controlled study. J Urol. 1996;156:947–52.Google Scholar
  218. 218.
    Lazzeri M, Beneforti P, Spinelli M, Zanollo A, Barbagli G, Turini D. Intravesical resiniferatoxin for the treatment of hypersensitive disorder: a randomized placebo controlled study. J Urol. 2000;164:676–9.Google Scholar
  219. 219.
    Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol. 2005;173:1590–4.Google Scholar
  220. 220.
    Charrua A, Cruz CD, Narayanan S, Gharat L, Gullapalli S, Cruz F, et al. GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models. J Urol. 2009;181:379–86.Google Scholar
  221. 221.
    Santos-Silva A, Charrua A, Cruz CD, Gharat L, Avelino A, Cruz F. Rat detrusor overactivity induced by chronic spinalization can be abolished by a transient receptor potential vanilloid 1 (TRPV1) antagonist. Auton Neurosci. 2012;166:35–8.Google Scholar
  222. 222.
    Kitagawa Y, Wada M, Kanehisa T, Miyai A, Usui K, Maekawa M, et al. JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function. J Urol. 2013;189:1137–46.Google Scholar
  223. 223.
    Majima T, Funahashi Y, Takai S, Goins WF, Gotoh M, Tyagi P, et al. Herpes Simplex Virus Vector-Mediated Gene Delivery of Poreless TRPV1 Channels Reduces Bladder Overactivity and Nociception in Rats. Hum Gene Ther. 2015;26:734–42.Google Scholar
  224. 224.
    Stein RJ, Santos S, Nagatomi J, Hayashi Y, Minnery BS, et al. Xavier M. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J Urol. 2004;172:1175–8.Google Scholar
  225. 225.
    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.Google Scholar
  226. 226.
    Tsukimi Y, Mizuyachi K, Yamasaki T, Niki T, Hayashi F. Cold response of the bladder in guinea pig: involvement of transient receptor potential channel, TRPM8. Urology. 2005;65(2):406–10.Google Scholar
  227. 227.
    Lashinger ES, Steiginga MS, Hieble JP, Leon LA, Gardner SD, Nagilla R, et al. AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am J Physiol Renal Physiol. 2008;295(3):F803–10.Google Scholar
  228. 228.
    Ito H, Aizawa N, Sugiyama R, Watanabe S, Takahashi N, Tajimi M, et al. Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int. 2016;117:484–94.Google Scholar
  229. 229.
    Mistretta FA, Russo A, Castiglione F, Bettiga A, Colciago G, Montorsi F, et al. DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats. J Pharmacol Exp Ther. 2016;356:200–11.Google Scholar
  230. 230.
    Hayashi T, Kondo T, Ishimatsu M, Takeya M, Igata S, Nakamura K, et al. Function and expression pattern of TRPM8 in bladder afferent neurons associated with bladder outlet obstruction in rats. Auton Neurosci. 2011;164:27–33.Google Scholar
  231. 231.
    Lei Z, Ishizuka O, Imamura T, Noguchi W, Yamagishi T, Yokoyama H, et al. Functional roles of transient receptor potential melastatin 8 (TRPM8) channels in the cold stress-induced detrusor overactivity pathways in conscious rats. Neurourol Urodyn. 2013;32:500–4.Google Scholar
  232. 232.
    Fajardo O, Meseguer V. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci. 2008;28:7863–75.Google Scholar
  233. 233.
    Caspani O, Heppenstall PA. TRPA1 and cold transduction: an unresolved issue? J Gen Physiol. 2009;133:245–9.Google Scholar
  234. 234.
    Nagata K, Duggan A, Kumar G, García-Añoveros J, et al. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci. 2005;25:4052–61.Google Scholar
  235. 235.
    Du S, Araki I, Mikami Y, Zakoji H, Beppu M, Yoshiyama M, et al. Amiloride-sensitive ion channels in urinary bladder epithelium involved in mechanosensory transduction by modulating stretch-evoked adenosine triphosphate release. Urology. 2007;69:590–5.Google Scholar
  236. 236.
    Streng T, Axelsson HE, Hedlund P, Andersson DA, Jordt SE, Bevan S, et al. Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol. 2008;53:391–9.Google Scholar
  237. 237.
    Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ. The role of transient receptor potential ankyrin 1 (TRPA1) channel in activation of single unit mechanosensitive bladder afferent activities in the rat. Neurourol Urodyn. 2014;33:544–9.Google Scholar
  238. 238.
    Andrade EL, Forner S, Bento AF, Leite DF, Dias MA, Leal PC, et al. TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury. Am J Physiol Renal Physiol. 2011;300:F1223–34.Google Scholar
  239. 239.
    Birder LA. TRPs in bladder diseases. Biochim Biophys Acta. 1772;2007:879–84.Google Scholar
  240. 240.
    Gevaert T, Vriens J, Segal A, Everaerts W, Roskams T, Talavera K, et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest. 2007;117:3453–62.Google Scholar
  241. 241.
    Thorneloe KS, AC Sulpizio. N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1 -piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther 2008; 326:432–42.Google Scholar
  242. 242.
    Xu X, Gordon E, Lin Z, Lozinskaya IM, Chen Y, Thorneloe KS, et al. Functional TRPV4 channels and an absence of capsaicin-evoked currents in freshly-isolated, guinea-pig urothelial cells. Channels (Austin). 2009; 3.Google Scholar
  243. 243.
    Yamada T, Ugawa S, Ueda T, Ishida Y, Kajita K, Shimada S, et al. Ugawa. Differential localizations of the transient receptor potential channels TRPV4 and TRPV1 in the mouse urinary bladder. J Histochem Cytochem. 2009;57:277–87.Google Scholar
  244. 244.
    Mochizuki T, Sokabe T, Araki I, Fujishita K, Shibasaki K, Uchida K, et al. The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J Biol Chem. 2009;Google Scholar
  245. 245.
    Aizawa N, Wyndaele JJ, Homma Y, Igawa Y, et al. Effects of TRPV4 cation channel activation on the primary bladder afferent activities of the rat. Neurourol Urodyn. 2012;31:148–55.Google Scholar
  246. 246.
    Merrill L, Vizzard MA. Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats. Am J Physiol Regul Integr Comp Physiol. 2014;307:471–80.Google Scholar
  247. 247.
    Yoshiyama M, Mochizuki T, Nakagomi H, Miyamoto T, Kira S, Mizumachi R, et al. Functional roles of TRPV1 and TRPV4 in control of lower urinary tract activity: dual analysis of behavior and reflex during the micturition cycle. Am J Physiol Renal Physiol. 2015;308:F1128–34.Google Scholar
  248. 248.
    Isogai A, Lee K, Mitsui R, Hashitani H, et al. Functional coupling of TRPV4 channels and BK channels in regulating spontaneous contractions of the guinea pig urinary bladder. Pflugers Arch. 2016;468:1573–85.Google Scholar
  249. 249.
    Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction. 1996;91:1585–614.Google Scholar
  250. 250.
    Ross SA, ElSohly MA, Sultana GN, Mehmedic Z, Hossain CF, Chandra S, et al. Flavonoid glycosides and cannabinoids from the pollen of Cannabis sativa L. Phytochem Anal. 2005;16:45–8.Google Scholar
  251. 251.
    Hedlund P. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn. 2014;33:46–53.Google Scholar
  252. 252.
    Fu W, Taylor BK. Activation of cannabinoid CB2 receptors reduces hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Neurosci Lett. 2015;595:1–6.Google Scholar
  253. 253.
    Jones MR, Wang ZY, Bjorling DE. Intrathecal cannabinoid-1 receptor agonist prevents referred hyperalgesia in acute acrolein-induced cystitis in rats. Am J Clin Exp Urol. 2015;3:28–35.Google Scholar
  254. 254.
    Wang ZY, Wang P, Bjorling DE, et al. Treatment with a cannabinoid receptor 2 agonist decreases severity of established cystitis. J Urol. 2014;191:1153–8.Google Scholar
  255. 255.
    Hedlund P, Gratzke C. The endocannabinoid system - a target for the treatment of LUTS? Nat Rev Urol. 2016;13:463–70.Google Scholar
  256. 256.
    Gandaglia G, Strittmatter F. The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn. 2013;33:1251–8.Google Scholar
  257. 257.
    Merriam FV, Wang ZY, Hillard CJ, Stuhr KL, Bjorling DE, et al. Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int. 2010;108:1145–9.Google Scholar
  258. 258.
    Smith CP, Chancellor MB. Emerging role of botulinum toxin in the management of voiding dysfunction. J Urol. 2004;171:2128–37.Google Scholar
  259. 259.
    Apostolidis A, Fowler CJ. The use of botulinum neurotoxin type A (BoNTA) in urology. J Neural Transm. 2008;115:593–605.Google Scholar
  260. 260.
    Apostolidis A, Rahnama'i MS, Fry C, Dmochowski R, Sahai A, et al. Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder? ICI-RS 2014. Neurourol Urodyn. 2016;35:293–8.Google Scholar
  261. 261.
    Tyagi P, Kashyap M, Yoshimura N, Chancellor M, Chermansky CJ. Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder. J Urol. 2016;197:982–90.Google Scholar
  262. 262.
    DasGupta BR. Structures of botulinum neurotoxin, its functional domains, and perspectives on the crystalline type A toxin. Therapy with Botulinum Toxin. J. Jankovic and M. Hallet. New York, Marcel Dekker: 1994; 15–39.Google Scholar
  263. 263.
    Schiavo G. O Rossetto. Botulinum neurotoxins are zinc proteins. J Biol Chem. 1992;267:23479–83.Google Scholar
  264. 264.
    Schiavo G, Santucci A, Dasgupta BR, Mehta PP, Jontes J, Benfenati F, et al. Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett. 1993;335:99–103.Google Scholar
  265. 265.
    Dykstra DD, Sidi AA. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol. 1988;139:919–22.Google Scholar
  266. 266.
    Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil. 1990;71:24–6.Google Scholar
  267. 267.
    Schurch B, Hauri D, Rodic B, Curt A, Meyer M, Rossier AB, et al. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. J Urol. 1996;155:1023–9.Google Scholar
  268. 268.
    Petit H, Wiart L. Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease. Spinal Cord. 1998;36:91–4.Google Scholar
  269. 269.
    Schurch B, Stöhrer M, Kramer G, Schmid DM, Gaul G. Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results J Urol 2000; 164:692–697.Google Scholar
  270. 270.
    Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A, Karsenty G, Schulte-Baukloh H, Schurch B, Wyndaele JJ; European Consensus Panel. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European Consensus report. Eur Urol. 2008.Google Scholar
  271. 271.
    Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, et al. Popat. 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 982–3.Google Scholar
  272. 272.
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol. 2004;172:1529–32.Google Scholar
  273. 273.
    Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arq Neuropsiquiatr. 2005;63:180–5.Google Scholar
  274. 274.
    Takahashi R. T Yunoki. Differential effects of botulinum neurotoxin A on bladder contractile responses to activation of efferent nerves, smooth muscles and afferent nerves in rats. J Urol. 2012;188:1993–9.Google Scholar
  275. 275.
    Howles S, Curry J, McKay I, Reynard J, Brading AF, Apostolidis A. Lack of effectiveness of botulinum neurotoxin A on isolated detrusor strips and whole bladders from mice and guinea-pigs in vitro. BJU Int. 2009;104:1524–9.Google Scholar
  276. 276.
    Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int. 2004;45:987–93.Google Scholar
  277. 277.
    Smith CP, Vemulakonda VM, Kiss S, Boone TB, Somogyi GT. Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int. 2005;47:291–7.Google Scholar
  278. 278.
    Smith CP, Gangitano DA, Munoz A, Salas NA, Boone TB, Aoki KR, et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Int. 2008;52:1068–75.Google Scholar
  279. 279.
    Hanna-Mitchell AT. AS Wolf-Johnston. Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn. 2013;34:79–84.Google Scholar
  280. 280.
    Smith CP, Franks ME. Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract. J Urol. 2003;169:1896–900.Google Scholar
  281. 281.
    Smith CP. J Nishiguchi. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology. 2005;65:37–41.Google Scholar
  282. 282.
    Yoshiyama M, Roppolo JR. Effects of LY215490, a competitive AMPA receptor antagonist, on the micturition reflex in the rat. J Pharmacol Exp Ther. 1997;280:894–904.Google Scholar
  283. 283.
    Yoshiyama M, de Groat WC. Supraspinal and spinal alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate glutamatergic control of the micturition reflex in the urethane-anesthetized rat. Neuroscience. 2005;132:1017–26.Google Scholar
  284. 284.
    Matsumoto G, Hisamitsu T, de Groat WC. Role of glutamate and NMDA receptors in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Neurosci Lett. 1995;183:58–61.Google Scholar
  285. 285.
    Yoshiyama M, Roppolo JR, de Groat WC. Alterations by urethane of glutamatergic control of micturition. Eur J Pharmacol. 1994;264:417–25.Google Scholar
  286. 286.
    Shibata T, Watanabe M, Ichikawa R, Inoue Y, Koyanagi T. Different expressions of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptor subunit mRNAs between visceromotor and somatomotor neurons of the rat lumbosacral spinal cord. J Comp Neurol. 1999;404:172–82.Google Scholar
  287. 287.
    Birder LA, de Groat WC. The effect of glutamate antagonists on c-fos expression induced in spinal neurons by irritation of the lower urinary tract. Brain Res. 1992;580:115–20.Google Scholar
  288. 288.
    Kakizaki H, Yoshiyama M. C-fos expression in spinal neurons after irritation of the lower urinary tract depends on synergistic interactions between NMDA amd AMPA glutamatergic transmission. Am J Physiol. 1996;76:215–26.Google Scholar
  289. 289.
    Kakizaki H, Yoshiyama M, Roppolo JR, Booth AM, De Groat WC. Role of spinal glutamatergic transmission in the ascending limb of the micturition reflex pathway in the rat. J Pharmacol Exp Ther. 1998;285:22–7.Google Scholar
  290. 290.
    Kawamorita N, Kaiho Y, Miyazato M, Arai Y, Yoshimura N. Roles of the spinal glutamatergic pathway activated through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and its interactions with spinal noradrenergic and serotonergic pathways in the rat urethral continence mechanisms. Neurourol Urodyn. 2014;34:475–81.Google Scholar
  291. 291.
    Tanaka H, Kakizaki H, Shibata T, Ameda K, Koyanagi T. Effects of a selective metabotropic glutamate receptor agonist on the micturition reflex pathway in urethane-anesthetized rats. Neurourol Urodyn. 2003;22:611–6.Google Scholar
  292. 292.
    Yoshiyama M, de Groat WC. Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat. Neurosci Lett. 2007;420:18–22.Google Scholar
  293. 293.
    Honda M, Yoshimura N, Hikita K, Hinata N, Muraoka K, Saito M, et al. Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats. Neurourol Urodyn. 2012;32:1026–30.Google Scholar
  294. 294.
    Igawa Y, Mattiasson A, Andersson KE. Effects of GABA-receptor stimulation and blockade on micturition in normal rats and rats with bladder outflow obstruction. J Urol. 1993;150:537–42.Google Scholar
  295. 295.
    Pehrson R, Lehmann A, Andersson KE, et al. Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats. J Urol. 2002;168:2700–5.Google Scholar
  296. 296.
    Miyazato M, Kaiho Y. Effects of duloxetine, norepinephrine and serotonin reuptake inhibitor, on the sneeze-induced urethral continence reflex in rats. BJU Int. 2007;26:700–1.Google Scholar
  297. 297.
    Pehrson R, Andersson KE. Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladder function. J Urol. 2002;167:2241–6.Google Scholar
  298. 298.
    Bushman W, Steers WD, Meythaler JM. Voiding dysfunction in patients with spastic paraplegia: urodynamic evaluation and response to continuous intrathecal baclofen. Neurourol Urodyn. 1993;12:163–70.Google Scholar
  299. 299.
    Lecci A, Giuliani S, Santicioli P, Maggi CA. Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat. J Pharmacol Exp Ther. 1992;262:181–9.Google Scholar
  300. 300.
    de Groat WC, Theobald RJ. Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents. J Physiol Lond. 1976;259:223–37.Google Scholar
  301. 301.
    Miyazato M, Sugaya K, Nishijima S, Ashitomi K, Hatano T, Ogawa Y. Inhibitory effect of intrathecal glycine on the micturition reflex in normal and spinal cord injury rats. Exp Neurol. 2003;183:232–40.Google Scholar
  302. 302.
    Shefchyk SJ. Sacral spinal interneurones and the control of urinary bladder and urethral striated sphincter muscle function. J Physiol. 2001;533:57–63.Google Scholar
  303. 303.
    Araki I. Inhibitory postsynaptic currents and the effects of GABA on visually identified sacral parasympathetic preganglionic neurons in neonatal rats. J Neurophysiol. 1994;72:2903–10.Google Scholar
  304. 304.
    Miyazato M, Sugaya K, Nishijima S, Ashitomi K, Morozumi M, Ogawa Y. Dietary glycine inhibits bladder activity in normal rats and rats with spinal cord injury. J Urol. 2005;173:314–7.Google Scholar
  305. 305.
    Miyazato M, Sasatomi K, Hiragata S, Sugaya K, Chancellor MB, de Groat WC, et al. Suppression of detrusor-sphincter dysynergia by GABA-receptor activation in the lumbosacral spinal cord in spinal cord-injured rats. Am J Physiol Regul Integr Comp Physiol. 2008;295:336–42.Google Scholar
  306. 306.
    Miyazato M, Sasatomi K, Hiragata S, Sugaya K, Chancellor MB, de Groat WC, et al. GABA receptor activation in the lumbosacral spinal cord decreases detrusor overactivity in spinal cord injured rats. J Urol. 2008;179:1178–83.Google Scholar
  307. 307.
    Zafra F, Aragon C. Glycine transporters are differentially expressed among CNS cells. J Neurosci. 1995;15:3952–69.Google Scholar
  308. 308.
    Zafra F, Gomeza J, Olivares L, Aragón C, Giménez C. Regional distribution and developmental variation of the glycine transporters GLYT1 and GLYT2 in the rat CNS. Eur J Neurosci. 1995;7:1342–52.Google Scholar
  309. 309.
    Yoshikawa S, Oguchi T, Funahashi Y, de Groat WC, Yoshimura N. Glycine transporter type 2 (GlyT2) inhibitor ameliorates bladder overactivity and nociceptive behavior in rats. Eur Urol. 2012;62:704–12.Google Scholar
  310. 310.
    Yoshimura N, Sasa M. Contraction of urinary bladder by central norepinephrine originating in the locus coeruleus. J Urol. 1988;139:423–7.Google Scholar
  311. 311.
    Yoshimura N, Sasa M. a1-Adrenergic receptor-mediated excitation from the locus coeruleus of the sacral parasympathetic preganglionic neuron. Life Sci. 1990;47:789–97.Google Scholar
  312. 312.
    Yoshimura N, Sasa M, Yoshida O, Takaori S. Mediation of micturition reflex by central norepinephrine from the locus coeruleus in the cat. J Urol. 1990;143:840–3.Google Scholar
  313. 313.
    Espey MJ, Downie JW, Fine A. Effect of 5-HT receptor and adrenoceptor antagonists on micturition in conscious cats. Eur J Pharmacol. 1992;221:167–70.Google Scholar
  314. 314.
    Ishizuka O, Mattiasson A, Andersson KE. Role of spinal and peripheral alpha 2 adrenoceptors in micturition in normal conscious rats. J Urol. 1996;156:1853–7.Google Scholar
  315. 315.
    Ishizuka O, Mattiasson A, Steers WD, Andersson KE. Effects of spinal alpha 1-adrenoceptor antagonism on bladder activity induced by apomorphine in conscious rats with and without bladder outlet obstruction. Neurourol Urodyn. 1997;16:191–200.Google Scholar
  316. 316.
    de Groat WC, Yoshiyama M, Ramage AG, Yamamoto T, Somogyi GT. Modulation of voiding and storage reflexes by activation of alpha1-adrenoceptors. Eur Urol. 1999;36(Suppl 1):68–73.Google Scholar
  317. 317.
    Sugaya K, Nishijima S, Miyazato M, Ashitomi K, Hatano T, Ogawa Y. Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adrenergic receptor antagonists, on bladder activity in rats. Neurosci Lett. 2002;328:74–6.Google Scholar
  318. 318.
    Kadekawa K, Sugaya K, Nishijima S, Ashitomi K, Miyazato M, Ueda T, et al. Effect of naftopidil, an alpha1D/A-adrenoceptor antagonist, on the urinary bladder in rats with spinal cord injury. Life Sci. 2013;92:1024–8.Google Scholar
  319. 319.
    Yokoyama O, Ito H, Aoki Y, Oyama N, Miwa Y, Akino H. Selective alpha1A-blocker improves bladder storage function in rats via suppression of C-fiber afferent activity. World J Urol. 2009;28:609–14.Google Scholar
  320. 320.
    Kontani H, Maruyama I, Sakai T. Involvement of alpha 2-adrenoceptors in the sacral micturition reflex in rats. Jpn J Pharmacol. 1992;60:363–8.Google Scholar
  321. 321.
    Denys P, Chartier-Kastler E, Azouvi P, Remy-Neris O, Bussel B. Intrathecal clonide for refractory detrusor hyperreflexia in spinal cord injured patients: A preliminary report. J Urol. 1998;160:2137.Google Scholar
  322. 322.
    Galeano C, Jubelin B. Micturition reflexes in chronic spinalized cats: The underactive detrusor and detrusor-sphincter dyssynergia. Neurourol Urodyn. 1986;5:45–63.Google Scholar
  323. 323.
    Page ME, Valentino RJ. Locus coeruleus activation by physiological challenges. Brain Res Bull. 1994;35:557–60.Google Scholar
  324. 324.
    Rouzade-Dominguez ML, Curtis AL, Valentino RJ. Role of Barrington's nucleus in the activation of rat locus coeruleus neurons by colonic distension. Brain Res. 2001;917:206–18.Google Scholar
  325. 325.
    Koyama Y, Imada N, Kayama Y, Kawauchi A, Watanabe H. How does the distention of urinary bladder cause arousal? Psychiatry Clin Neurosci. 1998;52:142–5.Google Scholar
  326. 326.
    Valentino RJ, Chen S, Zhu Y, Aston-Jones G. Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington's nucleus. Brain Res. 1996;732:1–15.Google Scholar
  327. 327.
    Danuser H, Thor KB. Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the alpha 1 adrenergic receptor antagonist prazosin. J Urol. 1995;153:1308–12.Google Scholar
  328. 328.
    de Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol. 2001;41:691–721.Google Scholar
  329. 329.
    Ramage AG, Wyllie MG. A comparison of the effects of doxazosin and terazosin on the spontaneous sympathetic drive to the bladder and related organs in anaesthetized cats. Eur J Pharmacol. 1995;294:645–50.Google Scholar
  330. 330.
    Gajewski J, Downie JW, Awad SA. Experimental evidence for a central nervous system site of action in the effect of alpha-adrenergic blockers on the external urinary sphincter. J Urol. 1984;132:403–9.Google Scholar
  331. 331.
    Yashiro K, Thor KB, Burgard EC. Properties of urethral rhabdosphincter motoneurons and their regulation by noradrenaline. J Physiol. 2010;588:4951–67.Google Scholar
  332. 332.
    Downie JW, Bialik GJ. Evidence for a spinal site of action of clonidine on somatic and viscerosomatic reflex activity evoked on the pudendal nerve in cats. J Pharmacol Exp Ther. 1988;246:352–8.Google Scholar
  333. 333.
    Thor KB, Donatucci C. Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women. J Urol. 2004;172:27–33.Google Scholar
  334. 334.
    Kaiho Y, Kamo I, Chancellor MB, Arai Y, de Groat WC, Yoshimura N, et al. Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats. Am J Physiol Renal Physiol. 2007;292:639–46.Google Scholar
  335. 335.
    Miyazato M, Kaiho Y. Effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on sneeze-induced urethral continence reflex in rats. Am J Physiol Renal Physiol. 2008;295:F264–71.Google Scholar
  336. 336.
    Furuta A, Asano K, Egawa S, de Groat WC, Chancellor MB, Yoshimura N, et al. Role of alpha2-adrenoceptors and glutamate mechanisms in the external urethral sphincter continence reflex in rats. J Urol. 2009;181:1467–73.Google Scholar
  337. 337.
    Kitta T, Miyazato M, Chancellor MB, de Groat WC, Nonomura K, Yoshimura N, et al. Alpha2-adrenoceptor blockade potentiates the effect of duloxetine on sneeze induced urethral continence reflex in rats. J Urol. 2010;184:762–8.Google Scholar
  338. 338.
    McMahon SB, Spillane K. Brain stem influences on the parasympathetic supply to the urinary bladder of the cat. Brain Res. 1982;234:237–49.Google Scholar
  339. 339.
    Chen SY, Wang SD, Cheng CL, Kuo JS, De Groat WC, Chai CY. Glutamate activation of neurons in CV-reactive areas of cat brain stem affects urinary bladder motility. Am J Physiol. 1993;265:F520–9.Google Scholar
  340. 340.
    De Groat WC, Roppolo JR. Neural control of the urinary bladder and colon. In Y Taché, D Wingate and T Burks, Editors. Boca Raton, FL.: CRC Press, 1993; 167–190.Google Scholar
  341. 341.
    Ito T, Sakakibara R, Nakazawa K, Uchiyama T, Yamamoto T, Liu Z, et al. Effects of electrical stimulation of the raphe area on the micturition reflex in cats. Neuroscience. 2006;142:1273–80.Google Scholar
  342. 342.
    Fukuda H, Koga T. Midbrain stimulation inhibits the micturition, defecation and rhythmic straining reflexes elicited by activation of sacral vesical and rectal afferents in the dog. Exp Brain Res. 1991;83:303–16.Google Scholar
  343. 343.
    Steers WD, de Groat WC. Effects of m-chlorophenylpiperazine on penile and bladder function in rats. Am J Physiol. 1989;257:R1441–9.Google Scholar
  344. 344.
    Guarneri L, Ibba M. The effect of mCPP on bladder voiding contractions in rats are mediated by the 5HT2A/5-HT2C receptors. Neurourol Urodyn. 1996;15:316.Google Scholar
  345. 345.
    Espey MJ, Du HJ, Downie JW. Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats. Brain Res. 1998;798:101–8.Google Scholar
  346. 346.
    Thor KB, Katofiasc MA, Danuser H, Springer J, Schaus JM. The role of 5-HT(1A) receptors in control of lower urinary tract function in cats. Brain Res. 2002;946:290–7.Google Scholar
  347. 347.
    Gu B, Olejar KJ, Reiter JP, Thor KB, Dolber PC. Inhibition of bladder activity by 5-hydroxytryptamine1 serotonin receptor agonists in cats with chronic spinal cord injury. J Pharmacol Exp Ther. 2004;310:1266–72.Google Scholar
  348. 348.
    Testa R, Guarneri L, Poggesi E, Angelico P, Velasco C, Ibba M. Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635. J Pharmacol Exp Ther. 1999;290:1258–69.Google Scholar
  349. 349.
    Pehrson R, Ojteg G, Ishizuka O, Andersson KE. Effects of NAD-299, a new, highly selective 5-HT1A receptor antagonist, on bladder function in rats. Naunyn Schmiedeberg's Arch Pharmacol. 2002;366:528–36.Google Scholar
  350. 350.
    Kakizaki H, Yoshiyama M, Koyanagi T, De Groat WC. Effects of WAY100635, a selective 5-HT1A-receptor antagonist on the micturition-reflex pathway in the rat. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1407–13.Google Scholar
  351. 351.
    de Groat WC. Influence of central serotonergic mechanisms on lower urinary tract function. Urology. 2002;59:30–6.Google Scholar
  352. 352.
    de Groat WC. Integrative control of the lower urinary tract: preclinical perspective. Br J Pharmacol. 2006;147(Suppl 2):S25–40.Google Scholar
  353. 353.
    de Groat WC, AM Booth. Neural control of the urinary bladder and large intestine. C. M. Brooks, K. Koizumi and A. Sato. Tokyo, Tokyo Univ. 1979; Press: 50–67.Google Scholar
  354. 354.
    Danuser H, Thor KB. Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflexes in the anaesthetized cat. Br J Pharmacol. 1996;118:150–4.Google Scholar
  355. 355.
    Miyazato M, Kaiho Y, Kamo I, Kitta T, Chancellor MB, Sugaya K, et al. Role of spinal serotonergic pathways in sneeze-induced urethral continence reflex in rats. Am J Physiol Renal Physiol. 2009;297(4):F1024–31.Google Scholar
  356. 356.
    Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther. 1995;274:1014–24.Google Scholar
  357. 357.
    Cannon TW, Yoshimura N, Chancellor MB. Innovations in pharmacotherapy for stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2003;14:367–72.Google Scholar
  358. 358.
    Castro-Diaz D, Amoros MA. Pharmacotherapy for stress urinary incontinence. Curr Opin Urol. 2005;15:227–30.Google Scholar
  359. 359.
    Ishiura Y, Yoshiyama M, Yokoyama O, Namiki M, de Groat WC. Central muscarinic mechanisms regulating voiding in rats. J Pharmacol Exp Ther. 2001;297:933–9.Google Scholar
  360. 360.
    Masuda H, Chancellor MB, Kihara K, Sakai Y, Koga F, Azuma H, et al. Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats. BJU Int. 2009;104:1163–9.Google Scholar
  361. 361.
    Masuda H, Ichiyanagi N, Yokoyama M, Sakai Y, Kihara K, Chancellor MB, et al. Muscarinic receptor activation in the lumbosacral spinal cord ameliorates bladder irritation in rat cystitis models. BJU Int. 2009;104:1531–7.Google Scholar
  362. 362.
    Masuda H, Hayashi Y, Chancellor MB, Kihara K, de Groat WC, de Miguel F, et al. Roles of peripheral and central nicotinic receptors in the micturition reflex in rats. J Urol. 2006;176:374–9.Google Scholar
  363. 363.
    Yoshikawa S, Kitta T, Miyazato M, Sumino Y, Yoshimura N. Inhibitory role of the spinal cholinergic system in the control of urethral continence reflex during sneezing in rats. Neurourol Urodyn. 2013;33:443–8.Google Scholar
  364. 364.
    Dray A, Metsch R. Inhibition of urinary bladder contractions by a spinal action of morphine and other opioids. J Pharmacol Exp Ther. 1984;231:254–60.Google Scholar
  365. 365.
    Pandita RK, Pehrson R, Christoph T, Friderichs E, Andersson KE. Actions of tramadol on micturition in awake, freely moving rats. Br J Pharmacol. 2003;139:741–8.Google Scholar
  366. 366.
    Kamo I, Cannon TW, Conway DA, Torimoto K, Chancellor MB, de Groat WC, et al. The role of bladder-to-urethral reflexes in urinary continence mechanisms in rats. Am J Physiol Renal Physiol. 2004;287:F434–41.Google Scholar
  367. 367.
    Chen ML, Shen B, Wang J, Liu H, Roppolo JR, de Groat WC, et al. Influence of naloxone on inhibitory pudendal-to-bladder reflex in cats. Exp Neurol. 2010;224:282–91.Google Scholar
  368. 368.
    Mally AD, Matsuta Y, Zhang F, Shen B, Wang J, Roppolo JR, et al. Role of opioid and metabotropic glutamate 5 receptors in pudendal inhibition of bladder overactivity in cats. J Urol. 2012;189:1574–9.Google Scholar
  369. 369.
    Tai C, Larson JA, Ogagan PD, Chen G, Shen B, Wang J, et al. Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats. Am J Physiol Renal Physiol. 2012;302:F1090–7.Google Scholar
  370. 370.
    Hou XH, Hyun M, Taranda J, Huang KW, Todd E, Feng D, et al. Central control circuit for context-dependent micturition. Cell. 2016;167:73–86. e12Google Scholar
  371. 371.
    Kruse MN, Noto H, Roppolo JR, de Groat WC. Pontine control of the urinary bladder and external urethral sphincter in the rat. Brain Res. 1990;532:182–90.Google Scholar
  372. 372.
    Mallory BS, Roppolo JR, de Groat WC. Pharmacological modulation of the pontine micturition center. Brain Res. 1991;546:310–20.Google Scholar
  373. 373.
    Matsuura S, Downie JW, Allen GV. Micturition evoked by glutamate microinjection in the ventrolateral periaqueductal gray is mediated through Barrington's nucleus in the rat. Neuroscience. 2000;101:1053–61.Google Scholar
  374. 374.
    Rocha I, Burnstock G, Spyer KM. Effect on urinary bladder function and arterial blood pressure of the activation of putative purine receptors in brainstem areas. Auton Neurosci 2001; 88:6–15.Google Scholar
  375. 375.
    Chen SY, Chai CY. Coexistence of neurons integrating urinary bladder activity and pelvic nerve activity in the same cardiovascular areas of the pontomedulla in cats. Chin J Physiol. 2002;45:41–50.Google Scholar
  376. 376.
    Naka H, Nishijima S, Kadekawa K, Sugaya K, Saito S. Influence of glutamatergic projections to the rostral pontine reticular formation on micturition in rats. Life Sci. 2009;85:732–6.Google Scholar
  377. 377.
    Nishijima S, Sugaya K, Kadekawa K, Ashitomi K, Yamamoto H. Effect of chemical stimulation of the medial frontal lobe on the micturition reflex in rats. J Urol. 2012;187:1116–20.Google Scholar
  378. 378.
    Sugaya K, Nishijima S. Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats. J Urol. 2014;192:1278–85.Google Scholar
  379. 379.
    Guo YX, Li DP, Chen SR, Pan HL. Distinct intrinsic and synaptic properties of pre-sympathetic and pre-parasympathetic output neurons in Barrington's nucleus. J Neurochem. 2013;126:338–48.Google Scholar
  380. 380.
    Yokoyama O, Ootsuka N, Komatsu K, Kodama K, Yotsuyanagi S, Niikura S. Forebrain muscarinic control of micturition reflex in rats. Neuropharmacology. 2001;41:629–38.Google Scholar
  381. 381.
    Ishizuka O, Gu BJ, Yang ZX, Nishizawa O, Andersson KE. Functional role of central muscarinic receptors for micturition in normal conscious rats. J Urol. 2002;168:2258–62.Google Scholar
  382. 382.
    Nakamura Y, Ishiura Y, Yokoyama O, Namiki M, De Groat WC. Role of protein kinase C in central muscarinic inhibitory mechanisms regulating voiding in rats. Neuroscience. 2003;116:477–84.Google Scholar
  383. 383.
    Sillén U, Rubenson A, Hjälmås K. Central cholinergic mechanisms in L-DOPA induced hyperactive urinary bladder of the rat. Urol Res. 1982;10:239–43.Google Scholar
  384. 384.
    Sugaya K, Nishijima S, Miyazato M, Oda M, Ogawa Y. Chemical stimulation of the pontine micturition center and the nucleus reticularis pontis oralis. Neurourol Urodyn. 1987; 6:143–144.Google Scholar
  385. 385.
    Lee KS, Na YG, Dean-McKinney T, Klausner AP, Tuttle JB, Steers WD. Alterations in voiding frequency and cystometry in the clomipramine induced model of endogenous depression and reversal with fluoxetine. J Urol. 2003;170:2067–71.Google Scholar
  386. 386.
    O'Donnell PD. Brookover T, Hewett M, al-Juburi AZ. Continence level following radical prostatectomy. Urology. 1990;36:511–2.Google Scholar
  387. 387.
    Kanie S, Yokoyama O, Komatsu K, Kodama K, Yotsuyanagi S, Niikura S, et al. GABAergic contribution to rat bladder hyperactivity after middle cerebral artery occlusion. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1230–8.Google Scholar
  388. 388.
    Matsuta Y, Yusup A, Tanase K, Ishida H, Akino H, Yokoyama O. Melatonin increases bladder capacity via GABAergic system and decreases urine volume in rats. J Urol. 2010;184:386–91.Google Scholar
  389. 389.
    Albanese A, Jenner P, Marsden CD, Stephenson JD. Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurosci Lett. 1988;87:46–50.Google Scholar
  390. 390.
    Kontani H, Inoue T, Sakai T. Dopamine receptor subtypes that induce hyperactive urinary bladder response in anesthetized rats. Jpn J Pharmacol. 1990;54:482–6.Google Scholar
  391. 391.
    Yoshimura N, Sasa M, Yoshida O, Takaori S. Inhibitory effects of Hachimijiogan on micturition reflex via the locus coeruleus. Nihon Yakurigaku Zasshi. 1992;99:161–6.Google Scholar
  392. 392.
    Yoshimura N, Mizuta E, Kuno S, Sasa M, Yoshida O. The dopamine D1 receptor agonist SKF 38393 suppresses detrusor hyperreflexia in the monkey with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuropharmacology. 1993;32:315–21.Google Scholar
  393. 393.
    Yoshimura N, Erdman SL. Effects of spinal cord injury on neurofilament immunoreactivity and capsaicin sensitivity in rat dorsal root ganglion neurons innervating the urinary bladder. Neuroscience. 1998;83:633–43.Google Scholar
  394. 394.
    Yoshimura N, Kuno S, Chancellor MB, De Groat WC, Seki S. Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Br J Pharmacol. 2003;139:1425–32.Google Scholar
  395. 395.
    Yokoyama O, Yoshiyama M, Namiki M, de Groat WC. Glutamatergic and dopaminergic contributions to rat bladder hyperactivity after cerebral artery occlusion. Am J Phys. 1999;276:R935–42.Google Scholar
  396. 396.
    Seki S, Igawa Y, Kaidoh K, Ishizuka O, Nishizawa O, Andersson KE. Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats. Neurourol Urodyn. 2001;20:105–13.Google Scholar
  397. 397.
    Hashimoto K, Oyama T, Sugiyama T, Park YC, Kurita T. Neuronal excitation in the ventral tegmental area modulates the micturition reflex mediated via the dopamine D1 and D2 receptors in rats. J Pharmacol Sci. 2003;92:143–8.Google Scholar
  398. 398.
    Ogawa T, Sakakibara R. Prevalence and treatment of LUTS in patients with Parkinson disease or multiple system atrophy. Nat Rev Urol. 2016;14:79–89.Google Scholar
  399. 399.
    Yoshimura N, Mizuta E, Yoshida O, Kuno S. Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys. J Pharmacol Exp Ther. 1998;286:228–33.Google Scholar
  400. 400.
    Sakakibara R, Nakazawa K, Shiba K, Nakajima Y, Uchiyama T, Yoshiyama M, et al. Firing patterns of micturition-related neurons in the pontine storage centre in cats. Auton Neurosci. 2002;99:24–30.Google Scholar
  401. 401.
    Yamamoto T, Sakakibara R, Hashimoto K, Nakazawa K, Uchiyama T, Liu Z, Ito T, Hattori T. Striatal dopamine level increases in the urinary storage phase in cats: an in vivo microdialysis study. Neuroscience. 2005;135:299–303.Google Scholar
  402. 402.
    Ogawa T, Seki S, Masuda H, Igawa Y, Nishizawa O, Kuno S, et al. Dopaminergic mechanisms controlling urethral function in rats. Neurourol Urodyn. 2006;25:480–9.Google Scholar
  403. 403.
    Kitta T, Chancellor MB, de Groat WC, Kuno S, Nonomura K, Yoshimura N. Suppression of bladder overactivity by adenosine A2A receptor antagonist in a rat model of Parkinson disease. J Urol. 2012;187:1890–7.Google Scholar
  404. 404.
    Kitta T, Yabe I, Takahashi I, Matsushima M, Sasaki H, Shinohara N. Clinical efficacy of istradefylline on lower urinary tract symptoms in Parkinson's disease. Int J Urol. 2016;23:893–4.Google Scholar
  405. 405.
    Chiba H, Mitsui T, Kitta T, Ohmura Y, Moriya K, Kanno Y, et al. The role of serotonergic mechanism in the rat prefrontal cortex for controlling the micturition reflex: An in vivo microdialysis study. Neurourol Urodyn. 2015;35:902–7.Google Scholar
  406. 406.
    de Groat WC, Griffiths D. Neural control of the lower urinary tract. Compr Physiol. 2015;5:327–96.Google Scholar
  407. 407.
    Shimizu T, Shimizu S, Higashi Y, Nakamura K, Yoshimura N, Saito M. A Stress-Related Peptide Bombesin Centrally Induces Frequent Urination through Brain Bombesin Receptor Types 1 and 2 in the Rat. J Pharmacol Exp Ther. 2016;356:693–701.Google Scholar
  408. 408.
    Shimizu T, Shimizu S, Wada N, Takai S, Shimizu N, Higashi Y, et al. Brain serotoninergic nervous system is involved in bombesin-induced frequent urination through brain 5-HT7 receptors in rats. Br J Pharmacol. 2017;174(18):3072–80.Google Scholar
  409. 409.
    Dray A, Metsch R. Opioids and central inhibition of urinary bladder motility. Eur J Pharmacol. 1984;98:155–6.Google Scholar
  410. 410.
    Hisamitsu T, de Groat WC. The inhibitory effect of opioid peptides and morphine applied intrathecally and intracerebroventricularly on the micturition reflex in the cat. J Physiol Soc Japan. 1984;46:499.Google Scholar
  411. 411.
    Noto H, Roppolo JR. Opioid modulation of the micturition reflex at the level of the pontine micturition center. Urol Int. 1991;47:19–22.Google Scholar
  412. 412.
    Nagasaka Y, Yokoyama O, Komatsu K, Ishiura Y, Nakamura Y, Namiki M. Effects of opioid subtypes on detrusor overactivity in rats with cerebral infarction. Int J Urol. 2007;14:226–31; discussion 232.Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Naoki Yoshimura
    • 1
    Email author
  • Eiichiro Takaoka
    • 1
  • Takahisa Suzuki
    • 1
  • Joonbeom Kwon
    • 1
  1. 1.Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations