Skip to main content
SpringerLink
Log in

CNS Involvement in Overactive Bladder

Pathophysiology and Opportunities for Pharmacological Intervention

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

The pathophysiology of overactive bladder (OAB) syndrome is complex, and involves both peripheral and CNS factors. Several CNS disorders are associated with OAB, e.g. stroke, spinal cord injury, Parkinson’s disease and multiple sclerosis, and in each disorder the pathophysiology of OAB can be multifactorial. Irrespective of cause or pathophysiology of OAB, antimuscarinic drugs are the first line of pharmacological treatment. However, adverse effects and limited efficacy makes alternative therapeutic principles desirable. Most alternative drugs used for the treatment of OAB have a peripheral site of action, mainly affecting efferent or afferent neurotransmission or the detrusor muscle itself. New targets for pharmacological intervention may be found in the CNS.

Several CNS transmitters/transmitter systems are known to be involved in micturition control, but few drugs with a defined CNS site of action (e.g. baclofen, imipramine and duloxetine) have been used for the treatment of voiding disorders. GABA, glutamate, opioid, serotonin, noradrenaline (norepinephrine), and dopamine receptors and mechanisms are known to influence micturition, and drugs influencing these systems could potentially be developed for the treatment of OAB.

Preclinical studies in different animal models have shown that modulation of normal micturition and detrusor overactivity by drugs acting within the spinal cord or supraspinally is possible. Promising results have been obtained in such models, e.g. with drugs interfering with GABA mechanisms, serotonin 5-HT1a receptors, μ-opioid receptors and α-adrenoreceptors. However, considering the limited predictability of existing animal models for efficacy in humans, positive proof of concept studies in humans are mandatory. Such studies are scarce and further investigations are needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommittee of the International Continence Society. Neurourol Urodyn 2002; 21(2): 167–78

    Article  PubMed  Google Scholar 

  2. Steers WD. Overactive bladder (OAB): what we thought we knew and what we know today. Eur Urol Suppl 2002; 1: 3–10

    Article  Google Scholar 

  3. Andersson KE, Appell R, Awad S, et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Khoury S, Wein A, editors. Incontinence: 2nd International Consultation on Incontinence. Plymouth: Plymbridge Distributors Ltd, 2002: 479–511

    Google Scholar 

  4. Andersson KE. Treatment of the overactive bladder: possible central nervous system drug targets. Urology 2002 May; 59 (5 Suppl. 1): 18–24

    Article  PubMed  Google Scholar 

  5. Morrison J, Steers WD, Brading A, et al. Neurophysiology and neuropharmacology. In: Abrams P, Khoury S, Wein A, editors. Incontinence: 2nd International Consultation on Incontinence. Plymouth: Plymbridge Distributors Ltd, 2002: 85–161

    Google Scholar 

  6. Shefchyk SJ. Sacral spinal interneurones and the control of urinary bladder and urethral striated sphincter muscle function. J Physiol 2001 May 15; 533 Pt 1: 57–63

    Article  Google Scholar 

  7. Shefchyk SJ. Spinal cord neural organization controlling the urinary bladder and striated sphincter. Prog Brain Res 2002; 137: 71–82

    Article  PubMed  Google Scholar 

  8. de Groat WC, Booth AM, Yoshimura N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA, editor. The autonomic nervous system. Vol. 6. Nervous control of the urogenital system. London: Harwood Academic Publishers, 1993: 227–89

    Google Scholar 

  9. Andersson KE. Bladder activation: afferent mechanisms. Urology 2002 May; 59 (5 Suppl. 1): 43–50

    Article  PubMed  Google Scholar 

  10. de Groat WC, Downie JW, Levin RM, et al. Basic neurophysiology and neuropharmacology. In: Abrams P, Khoury S, Wein A, editors. Incontinence: 1st International Consultation on Incontinence. Plymouth: Plymbridge Distributors Ltd, 1999: 105–54

    Google Scholar 

  11. Taniguchi N, Miyata M, Yachiku S, et al. A study of micturition inducing sites in the periaqueductal gray of the mesencephalon. J Urol 2002 Oct; 168 (4 Pt 1): 1626–31

    Article  PubMed  Google Scholar 

  12. Holstege G, Griffiths D, de Wall H, et al. Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986 Aug 22; 250(4): 449–61

    Article  PubMed  CAS  Google Scholar 

  13. Griffiths D, Holstege G, Dalm E, et al. Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 1990; 9: 63–82

    Article  Google Scholar 

  14. Blok BF, Holstege G. Two pontine micturition centers in the cat are not interconnected directly: implications for the central organization of micturition. J Comp Neurol 1999 Jan 11; 403(2): 209–18

    Article  PubMed  CAS  Google Scholar 

  15. Fowler CJ. Urinary disorders in Parkinson’s disease and multiple system atrophy. Funct Neurol 2001 Jul–Sep; 16(3): 277–82

    PubMed  CAS  Google Scholar 

  16. Nour S, Svarer C, Kristensen JK, et al. Cerebral activation during micturition in normal men. Brain 2000 Apr; 123 Pt 4: 781–9

    Article  Google Scholar 

  17. Athwal BS, Berkley KJ, Hussain I, et al. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001 Feb; 124 Pt 2: 369–77

    Article  Google Scholar 

  18. Matsuura S, Kakizaki H, Mitsui T, et al. Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 2002 Nov; 168(5): 2035–9

    Article  PubMed  Google Scholar 

  19. Fowler CJ. Neurological disorders of micturition and their treatment. Brain 1999 Jul; 122 Pt 7: 1213–31

    Article  Google Scholar 

  20. Marinkovic S, Bedlani G. Voiding and sexual dysfunction after cerebrovascular accidents. J Urol 2001 Feb; 165(2): 359–70

    Article  PubMed  CAS  Google Scholar 

  21. Sakakibara R, Hattori T, Yasuda K, et al. Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI. J Neurol Sci 1996 Apr; 137(1): 47–56

    Article  PubMed  CAS  Google Scholar 

  22. Belayev L, Alonso OF, Busto R, et al. Middle cerebral artery occlusion in the rat by intraluminal suture: neurological and pathological evaluation of an improved model. Stroke 1996 Sep; 27(9): 1616–22

    Article  PubMed  CAS  Google Scholar 

  23. Yokoyama O, Yoshiyama M, Namiki M, et al. Influence of anesthesia on bladder hyperactivity induced by middle cerebral artery occlusion in the rat. Am J Physiol 1997 Dec; 273 (6 Pt 2): R1900–7

    PubMed  CAS  Google Scholar 

  24. Kaidoh K, Igawa Y, Takeda H, et al. Effects of selective beta2 and beta3-adrenoceptor agonists on detrusor hyperreflexia in conscious cerebral infarcted rats. J Urol 2002 Sep; 168(3): 1247–52

    Article  PubMed  CAS  Google Scholar 

  25. Yokoyama O, Yoshiyama M, Namiki M, et al. Role of the forebrain in bladder overactivity following cerebral infarction in the rat. Exp Neurol 2000 Jun; 163(2): 469–76

    Article  PubMed  CAS  Google Scholar 

  26. Yokoyama O, Yoshiyama M, Namiki M, et al. Glutamatergic and dopaminergic contributions to rat bladder hyperactivity after cerebral artery occlusion. Am J Physiol 1999 Apr; 276 (4 Pt 2): R935–42

    PubMed  CAS  Google Scholar 

  27. Yokoyama O, Yoshiyama M, Namiki M, et al. Changes in dopaminergic and glutamatergic excitatory mechanisms of micturition reflex after middle cerebral artery occlusion in conscious rats. Exp Neurol 2002 Jan; 173(1): 129–35

    Article  PubMed  CAS  Google Scholar 

  28. Kodama K, Yokoyama O, Komatsu K, et al. Contribution of cerebral nitric oxide to bladder overactivity after cerebral infarction in rats. J Urol 2002 Jan; 167(1): 391–6

    Article  PubMed  CAS  Google Scholar 

  29. Kanie S, Yokoyama O, Komatsu K, et al. GABAergic contribution to rat bladder hyperactivity after middle cerebral artery occlusion. Am J Physiol Regul Integr Comp Physiol 2000 Oct; 279(4): R1230–8

    PubMed  CAS  Google Scholar 

  30. Singer C. Urinary dysfunction in Parkinson’s disease. Clin Neurosci 1998; 5(2): 78–86

    PubMed  CAS  Google Scholar 

  31. Berger Y, Blaivas JG, DeLaRocha ER, et al. Urodynamic findings in Parkinson’s disease. J Urol 1987 Oct; 138(4): 836–8

    PubMed  CAS  Google Scholar 

  32. Dmochowski RR. Female voiding dysfunction and movement disorders. Int Urogynecol J Pelvic Floor Dysfunct 1999; 10(2): 144–51

    Article  PubMed  CAS  Google Scholar 

  33. Albanese A, Jenner P, Marsden CD,et al. Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurosci Lett 1988 Apr 22; 87(1–2): 46–50

    Article  PubMed  CAS  Google Scholar 

  34. Yoshimura N, Mizuta E, Kuno S, et al. 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 Apr; 32(4): 315–21

    Article  PubMed  CAS  Google Scholar 

  35. Seki S, Igawa Y, Kaidoh K, et al. Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats. Neurourol Urodyn 2001; 20(1): 105–13

    Article  PubMed  CAS  Google Scholar 

  36. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol 1999 Mar; 161(3): 743–57

    Article  PubMed  CAS  Google Scholar 

  37. Fernandez O. Mechanisms and current treatments of urogenital dysfunction in multiple sclerosis. J Neurol 2002 Jan; 249(1): 1–8

    Article  PubMed  Google Scholar 

  38. Sirls LT, Zimmern PE, Leach GE. Role of limited evaluation and aggressive medical management in multiple sclerosis: a review of 113 patients. J Urol 1994 Apr; 151(4): 946–50

    PubMed  CAS  Google Scholar 

  39. Mizusawa H, Igawa Y, Nishizawa O, et al. A rat model for investigation of bladder dysfunction associated with demyelinating disease resembling multiple sclerosis. Neurourol Urodyn 2000; 19(6): 689–99

    Article  PubMed  CAS  Google Scholar 

  40. Downie JW. Pharmacological manipulation of central micturition circuitry. Curr Opin in CPNS Invest Drugs 1999; 1: 231–9

    CAS  Google Scholar 

  41. de Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol 2001; 41: 691–721

    Article  PubMed  Google Scholar 

  42. Chebib M, Johnston GAR. The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol 1999 Nov; 26(11): 937–40

    Article  PubMed  CAS  Google Scholar 

  43. Bowery NG. GABAB receptor pharmacology. Annu Rev Pharmacol Toxicol 1993; 33: 109–47

    Article  PubMed  CAS  Google Scholar 

  44. Rudolph U, Crestani F, Möhler H. GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharm Sci 2001 Apr; 22(4): 188–94

    Article  PubMed  CAS  Google Scholar 

  45. Coggeshall RE, Carlton SM. Receptor localization in the mammalian dorsal horn and primary afferent neurons. Brain Res Brain Res Rev 1997 Jun; 24(1): 28–66

    Article  PubMed  CAS  Google Scholar 

  46. Malcangio M, Bowery NG. GABA and its receptors in the spinal cord. Trends Pharm Sci 1996 Dec; 17(12): 457–62

    Article  PubMed  CAS  Google Scholar 

  47. Jursky F, Tamura S, Tamura A, et al. Structure, function and brain localization of neurotransmitter transporters. J Exp Biol 1994 Nov; 196: 283–95

    PubMed  CAS  Google Scholar 

  48. Borden LA, Murali Dhar TG, Smith KE, et al. Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur J Pharmacol 1994 Oct 14; 269(2): 219–24

    Article  PubMed  CAS  Google Scholar 

  49. Fink-Jensen A, Suzdak PD, Swedberg MDB, et al. The γ-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. Eur J Pharmacol 1992 Sep 22; 220(2–3): 197–201

    Article  PubMed  CAS  Google Scholar 

  50. Maggi CA, Furio M, Santicioli P, et al. Spinal and supraspinal components of GABAergic inhibition of the micturition reflex in rats. J Pharm Exp Ther 1987 Mar; 240(3): 998–1005

    CAS  Google Scholar 

  51. Maggi CA, Santicioli P, Giuliani S, et al. The effects of baclofen on spinal and supraspinal micturition reflexes in rats. Naunyn Schmiedebergs Arch Pharmacol 1987 Aug; 336(2): 197–203

    Article  PubMed  CAS  Google Scholar 

  52. Igawa Y, Mattiasson A, Andersson KE. Effects of GABAreceptor stimulation and blockade on micturition in normal rats and rats with bladder outflow obstruction. J Urol 1993 Aug; 150 (2 Pt 1): 537–42

    PubMed  CAS  Google Scholar 

  53. Pehrson R, Lehmann A, Andersson KE. Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats. J Urol 2002 Dec; 168: 2700–5

    Article  PubMed  CAS  Google Scholar 

  54. Kontani H, Kawabata Y, Koshiura R. In vivo effects of γ-aminobutyric acid on the urinary bladder contraction accompanying micturition. Jpn J Pharmacol 1987 Sep; 45(1): 45–53

    Article  PubMed  CAS  Google Scholar 

  55. Maggi CA, Santicioli P, Grimaldi G, et al. The effect of peripherally administered GABA on spontaneous contractions of rat urinary bladder in vivo. Gen Pharmacol 1983; 14(4): 455–8

    Article  PubMed  CAS  Google Scholar 

  56. Sillén U, Persson B, Rubenson A. Involvement of central GABA receptors in the regulation of the urinary bladder function in anaesthetised rats. Naunyn Schmiedebergs Arch Pharmacol 1980 Nov; 314(2): 195–200

    Article  PubMed  Google Scholar 

  57. Zhu Q-M, Hu D-Q, Tsung S, et al. Differential effects of GABAA and GABAB receptor agonists on cystometry in conscious mice [abstract no. 157]. J Urol 2002; 4 Suppl.: 39–40

    Google Scholar 

  58. Pehrson R, Andersson K-E. Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladder function. J Urol 2002 May; 167(5): 2241–6

    Article  PubMed  CAS  Google Scholar 

  59. Blok BF, de Weerd H, Holstege G. The pontine micturition center projects to sacral cord GABA immunoreactive neurons in the cat. Neurosci Lett 1997 Sep 19; 233(2–3): 109–12

    Article  PubMed  CAS  Google Scholar 

  60. Rekling JC, Funk GD, Bayliss DA, et al. Synaptic control of motoneuronal excitability. Physiol Rev 2000 Apr; 80(2): 767–852

    PubMed  CAS  Google Scholar 

  61. Nishizawa O, Sugaya K, Shimoda N. Pontine and spinal modulation of the micturition reflex. Scand J Urol Nephrol 1995; 29 Suppl. 175: 15–9

    Google Scholar 

  62. 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(2): 163–70

    Article  PubMed  CAS  Google Scholar 

  63. Steers WD, Meythaler JM, Haworth C, et al. Effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary dysfunction due to spinal cord pathology. J Urol 1992 Dec; 148(6): 1849–55

    PubMed  CAS  Google Scholar 

  64. Taylor MC, Bates CP. A double-blind crossover trial of baclofen: a new treatment for the unstable bladder syndrome. Br J Urol 1979 Dec; 51(6): 504–5

    Article  PubMed  CAS  Google Scholar 

  65. Haubensak K. A double-blind trial with the antispasticity drug Lioresal in 15 paraplegics with upper neuron lesions. Urol Int 1977; 32(2–3): 198–201

    Article  PubMed  CAS  Google Scholar 

  66. Leyson JFJ, Martin BF, Sporer A. Baclofen in the treatment of detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1980 Jul; 124(1): 82–4

    PubMed  CAS  Google Scholar 

  67. Laporte AM, Doyen C, Nevo IT, et al. Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HT2 and 5-HT3 receptors in the aged human spinal cord. J Chem Neuroanat 1996 Jul; 11(1): 67–75

    Article  PubMed  CAS  Google Scholar 

  68. Marlier L, Teilhac JR, Cerruti C, et al. Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord. Brain Res 1991 May 31; 550(1): 15–23

    Article  PubMed  CAS  Google Scholar 

  69. Pubols LM, Bernau NA, Kane LA, et al. Distribution of 5-HT1 binding sites in cat spinal cord. Neurosci Lett 1992 Aug 17; 142(2): 111–4

    Article  PubMed  CAS  Google Scholar 

  70. Thor KB, Nickolaus S, Helke C. Autoradiographic localization of 5-hydroxytryptamine1A, 5-hydroxytryptamine1B and 5-hydroxytryptamine1C/2 binding sites in the rat spinal cord. Neuroscience 1993 Jul; 55(1): 235–52

    Article  PubMed  CAS  Google Scholar 

  71. Verge D, Daval G, Marcinkiewicz M, et al. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 1986 Dec; 6(12): 3474–82

    PubMed  CAS  Google Scholar 

  72. McMahon SB, Spillane K. Brain stem influences on the parasympathetic supply to the urinary bladder of the cat. Brain Res 1982 Feb 25; 234(2): 237–49

    Article  PubMed  CAS  Google Scholar 

  73. Sugaya K, Ogawa Y, Hatano T, et al. Evidence for involvement of the subcoeruleus nucleus and nucleus raphe magnus in urine storage and penile erection in decerebrate rats. J Urol 1998 Jun; 159(6): 2172–6

    Article  PubMed  CAS  Google Scholar 

  74. Raymond JR, Mukhin YV, Gelasco A, et al. Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 2001 Nov–Dec; 92(2–3): 179–212

    Article  PubMed  CAS  Google Scholar 

  75. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002 Apr; 71(4): 533–54

    Article  PubMed  CAS  Google Scholar 

  76. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999 Aug; 38(8): 1083–152

    Article  PubMed  CAS  Google Scholar 

  77. de Groat WC. Influence of central serotonergic mechanisms on lower urinary tract function. Urology 2002 May; 59 (5 Suppl. 1): 30–6

    Article  PubMed  Google Scholar 

  78. Espey MJ, Downie JW. Serotonergic modulation of cat bladder function before and after spinal transection. Eur J Pharmacol 1995 Dec 12; 287(2): 173–7

    Article  PubMed  CAS  Google Scholar 

  79. Espey MJ, Downie JW, Fine A. Effect of 5-HT receptor and adrenoceptor antagonists on micturition in conscious cats. Eur J Pharmacol 1992 Oct 6; 221(1): 167–70

    Article  PubMed  CAS  Google Scholar 

  80. Lecci A, Giuliani S, Santicioli P, et al. Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat. J Pharmacol Exp Ther 1992 Jul; 262(1): 181–9

    PubMed  CAS  Google Scholar 

  81. Pehrson R, Ojteg G, Ishizuka O, et al. Effects of NAD-299, a new, highly selective 5-HT (1A) receptor antagonist, on bladder function in rats. Naunyn Schmiedebergs Arch Pharmacol 2002 Dec; 366(6): 528–36

    Article  PubMed  CAS  Google Scholar 

  82. Ishizuka O, Gu B, Igawa Y, et al. Role of supraspinal serotonin receptors for micturition in normal conscious rats. Neurourol Urodyn 2002; 21(3): 225–30

    Article  PubMed  CAS  Google Scholar 

  83. Testa R, Guarneri L, Angelico P, et al. Effect of different 5-hydroxytryptamine receptor subtype antagonists on the micturition reflex in rats. BJU Int 2001 Feb; 87(3): 256–64

    Article  PubMed  CAS  Google Scholar 

  84. Testa R, Guarneri L, Poggesi E, et al. Effect of several 5-hydroxytryptamine (1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635. J Pharmacol Exp Ther 1999 Sep; 290(3): 1258–69

    PubMed  CAS  Google Scholar 

  85. Kakizaki H, Yoshiyama M, Koyanagi T, et al. 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 May; 280(5): R1407–13

    PubMed  CAS  Google Scholar 

  86. Rajaofetra N, Passagia JG, Marlier L, et al. Serotoninergic, noradrenergic, and peptidergic innervation of Onuf s nucleus of normal and transected spinal cords of baboons (Papio papio). J Comp Neurol 1992 Apr 1; 318(1): 1–17

    Article  PubMed  CAS  Google Scholar 

  87. Thor KB, Katofiasc MA, Danuser H, et al. The role of 5-HT (1A) receptors in control of lower urinary tract function in cats. Brain Res 2002 Aug 16; 946(2): 290–7

    Article  PubMed  CAS  Google Scholar 

  88. Leonardi A, Guarneri L, Poggesi E, et al. N-[2-[4-(2 methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-nitrophenyl) cyclohexane-carboxamide: a novel pre- and postsynaptic 5-hydroxytryptamine (1A) receptor antagonist active on the lower urinary tract. J Pharmacol Exp Ther 2001 Dec; 299(3): 1027–37

    PubMed  CAS  Google Scholar 

  89. Steers WD, Lee KS. Depression and incontinence. World J Urol 2001 Nov; 19(5): 351–7

    Article  PubMed  CAS  Google Scholar 

  90. Maggi CA, Borsini F, Lecci A, et al. Effect of acute or chronic administration of imipramine on spinal and supraspinal micturition reflexes in rats. J Pharmacol Exp Ther 1989 Jan; 248(1): 278–85

    PubMed  CAS  Google Scholar 

  91. 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 Aug; 274(2): 1014–24

    PubMed  CAS  Google Scholar 

  92. Katofiasc MA, Nissen J, Audia JE, et al. Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats. Life Sci 2002 Aug 2; 71(11): 1227–36

    Article  PubMed  CAS  Google Scholar 

  93. Norton PA, Zinner NR, Yalcin I, et al. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 2002 Jul; 187(1): 40–8

    Article  PubMed  CAS  Google Scholar 

  94. Movig KL, Leufkens HG, Belitser SV, et al. Selective serotonin reuptake inhibitor-induced urinary incontinence. Pharmacoepidemiol Drug Saf 2002 Jun; 11(4): 271–9

    Article  PubMed  CAS  Google Scholar 

  95. Kuhar MJ, Pert CB, Snyder SH. Regional distribution of opiate receptor binding in monkey and human brain. Nature 1973 Oct 26; 245(5426): 447–50

    Article  PubMed  CAS  Google Scholar 

  96. Mansour A, Fox CA, Akil H, et al. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 1995 Jan; 18(1): 22–9

    Article  PubMed  CAS  Google Scholar 

  97. Igawa Y, Andersson KE, Post C, et al. A rat model for investigation of spinal mechanisms in detrusor instability associated with infravesical outflow obstruction. Urol Res 1993; 21(4): 239–44

    Article  PubMed  CAS  Google Scholar 

  98. Igawa Y, Westerling D, Mattiasson A, et al. Effects of morphine metabolites on micturition in normal, unanaesthetized rats. Br J Pharmacol 1993 Sep; 110(1): 257–62

    Article  PubMed  CAS  Google Scholar 

  99. Pandita RK, Pehrson R, Christoph T, et al. Actions of tramadol on micturition in awake, freely moving rats. Br J Pharmacol 2003; 139(4): 741–8

    Article  PubMed  CAS  Google Scholar 

  100. Bolam JM, Robinson CJ, Hofstra TC, et al. Changes in micturition volume thresholds in conscious dogs following spinal opiate administration. J Auton Nerv Syst 1986 Aug; 16(4): 261–77

    Article  PubMed  CAS  Google Scholar 

  101. Malinovsky JM, Le Normand L, Lepage JY, et al. The urodynamic effects of intravenous opioids and ketoprofen in humans. Anesth Analg 1998 Aug; 87(2): 456–61

    PubMed  CAS  Google Scholar 

  102. Dray A, Metsch R. Opioids and central inhibition of urinary bladder motility. Eur J Pharmacol 1984 Feb 10; 98(1): 155–6

    Article  PubMed  CAS  Google Scholar 

  103. Dray A, Metsch R. Morphine and the centrally-mediated inhibition of urinary bladder motility in the rat. Brain Res 1984 Apr 9; 297(1): 191–5

    Article  PubMed  CAS  Google Scholar 

  104. Dray A, Metsch R. Inhibition of urinary bladder contractions by a spinal action of morphine and other opioids. J Pharmacol Exp Ther 1984 Nov; 231(2): 254–60

    PubMed  CAS  Google Scholar 

  105. Dray A, Nunan L. Supraspinal and spinal mechanisms in morphine-induced inhibition of reflex urinary bladder contractions in the rat. Neuroscience 1987 Jul; 22(1): 281–7

    Article  PubMed  CAS  Google Scholar 

  106. Kontani H, Kawabata Y. A study of morphine-induced urinary retention in anesthetized rats capable of micturition. Jpn J Pharmacol 1988 Sep; 48(1): 31–6

    Article  PubMed  CAS  Google Scholar 

  107. Drenger B, Magora F, Evron S, et al. The action of intrathecal morphine and methadone on the lower urinary tract in the dog. J Urol 1986; 135: 852–5

    PubMed  CAS  Google Scholar 

  108. Dray A, Nunan L, Wire W. Naloxonazine and opioid-induced inhibition of reflex urinary bladder contractions. Neuro-pharmacology 1987 Jan; 26(1): 67–74

    CAS  Google Scholar 

  109. Murray KH, Feneley RC. Endorphins: a role in lower urinary tract function? The effect of opioid blockade on the detrusor and urethral sphincter mechanisms. Br J Urol 1982 Dec; 54(6): 638–40

    Article  PubMed  CAS  Google Scholar 

  110. Dray A, Nunan L, Wire W. Central delta-opioid receptor interactions and the inhibition of reflex urinary bladder contractions in the rat. Br J Pharmacol 1985 Jul; 85(3): 717–26

    Article  PubMed  CAS  Google Scholar 

  111. Hisamitsu T, de Groat WC. The inhibitory effect of opioid peptides and morphine applied intrathecally and intracerebroventricularly on the micturition reflex in the cat. Brain Res 1984 Apr 23; 298(1): 51–65

    Article  PubMed  CAS  Google Scholar 

  112. de Groat WC, Kawatani M. Enkephalinergic inhibition in parasympathetic ganglia of the urinary bladder of the cat. J Physiol 1989 Jun; 413: 13–29

    PubMed  Google Scholar 

  113. Shimizu I, Kawashima K, Ishii D, et al. Effects of (+)-pentazocine and 1,3-di-o tolylguanidine (DTG), sigma (sigma) ligands, on micturition in anaesthetized rats. Br J Pharmacol 2000 Oct; 131(3): 610–6

    Article  PubMed  CAS  Google Scholar 

  114. Shimizu I, Kawashima K, Ishii D, et al. Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats. Eur J Pharmacol 2001 Jan 26; 412(2): 171–9

    Article  PubMed  CAS  Google Scholar 

  115. Herman RM, Wainberg MC, delGiudice PF, et al. The effect of a low dose of intrathecal morphine on impaired micturition reflexes in human subjects with spinal cord lesions. Anesthesiology 1988 Sep; 69(3): 313–8

    Article  PubMed  CAS  Google Scholar 

  116. Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci 1999 Jan; 20(1): 19–26

    Article  PubMed  CAS  Google Scholar 

  117. Raffa RB, Friderichs E. The basic science aspect of tramadol hydrochloride. Pain Rev 1996; 3: 249–71

    CAS  Google Scholar 

  118. Lehmann KA. Le tramadol dans les douleurs aiguës. Drugs 1997; 53: 25–33

    Article  PubMed  Google Scholar 

  119. Pehrson R, Andersson KE. Tramadol inhibits detrusor overactivity due to dopamine receptor stimulation. J Urol 2003 Jul; 170(1): 272–5

    Article  PubMed  CAS  Google Scholar 

  120. Pehrson R, Stenman E, Andersson KE. Effects of tramadol on rat detrusor overactivity induced by experimental cerebral infarction. Eur Urol 2003 Oct; 44(4): 495–9

    Article  PubMed  CAS  Google Scholar 

  121. Kontani H, Inoue T, Sakai T. Dopamine receptor subtypes that induce hyperactive urinary bladder response in anesthetized rats. Jpn J Pharmacol 1990 Dec; 54(4): 482–6

    Article  PubMed  CAS  Google Scholar 

  122. Jackson DM, Westlind-Danielsson A. Dopamine receptors: molecular biology, biochemistry and behavioural aspects. Pharmacol Ther 1994; 64(2): 291–370

    Article  PubMed  CAS  Google Scholar 

  123. van Dijken H, Dijk J, Voom P, et al. Localization of dopamine D2 receptor in rat spinal cord identified with immuno-cytochemistry and in situ hybridization. Eur J Neurosci 1996 Mar; 8(3): 621–8

    Article  PubMed  Google Scholar 

  124. Hurd YL, Suzuki M, Sedvall GC. D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J Chem Neuroanat 2001 Jul; 22(1–2): 127–37

    Article  PubMed  CAS  Google Scholar 

  125. Gerfen CR. Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci 2000; 23: S64–70

    Article  PubMed  CAS  Google Scholar 

  126. Pavlakis AJ, Siroky MB, Goldstein I, et al. Neurourologic findings in Parkinson’s disease. J Urol 1983 Jan; 129(1): 80–3

    PubMed  CAS  Google Scholar 

  127. Sakakibara R, Shinotoh H, Uchiyama T, et al. SPECT imaging of the dopamine transporter with [(123)I]-beta-CIT reveals marked decline of nigrostriatal dopaminergic function in Parkinson’s disease with urinary dysfunction. J Neurol Sci 2001 Jun 15; 187(1–2): 55–9

    Article  PubMed  CAS  Google Scholar 

  128. Wolters EC, Tissingh G, Bergmans PL, et al. Dopamine agonists in Parkinson’s disease. Neurology 1995 Mar; 45 (3 Suppl. 3): S28–34

    Article  PubMed  CAS  Google Scholar 

  129. Finazzo AE, Peppe A, Parisi AI, et al. Effect of L-DOPA on lower urinary tract behaviour in Parkinson’s disease patients. Proceedings of the International Continence Society 32nd Annual Meeting; 2002 Aug 28–30; Heidelberg, 225–6

  130. Christmas TJ, Kempster PA, Chappie CR, et al. Role of subcutaneous apomorphine in parkinsonian voiding dysfunction. Lancet 1988 Dec 24–31; 2(8626–8627): 1451–3

    Article  PubMed  CAS  Google Scholar 

  131. Yoshimura N, Mizuta E, Yoshida O, et al. 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 Jul; 286(1): 228–33

    PubMed  CAS  Google Scholar 

  132. Elam M, Thoren P, Svensson TH. Locus coeruleus neurons and sympathetic nerves: activation by visceral afferents. Brain Res 1986 Jun 4; 375(1): 117–25

    Article  PubMed  CAS  Google Scholar 

  133. Smith MS, Schambra UB, Wilson KH, et al. Alphal-adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alphal-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res 1999 Jan 8; 63(2): 254–61

    Article  PubMed  CAS  Google Scholar 

  134. 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 Apr; 153(4): 1308–12

    Article  PubMed  CAS  Google Scholar 

  135. 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 Dec 29; 294(2–3): 645–50

    Article  PubMed  CAS  Google Scholar 

  136. Ishizuka O, Persson K, Mattiasson A, et al. Micturition in conscious rats with and without bladder outlet obstruction: role of spinal alpha 1-adrenoceptors. Br J Pharmacol 1996 Mar; 117(5): 962–6

    Article  PubMed  CAS  Google Scholar 

  137. Gu BJ, Ishizuka O, Igawa Y, et al. Role of supraspinal alpha1 adrenoceptors for voiding in conscious rats with and without bladder outlet obstruction. J Urol 2002 Apr; 167(4): 1887–91

    Article  PubMed  CAS  Google Scholar 

  138. Steers WD, Clemow DB, Persson K, et al. The spontaneously hypertensive rat: insight into the pathogenesis of irritative symptoms in benign prostatic hyperplasia and young anxious males. Exp Physiol 1999 Jan; 84(1): 137–47

    PubMed  CAS  Google Scholar 

  139. Persson K, Pandita RK, Spitsbergen JM, et al. Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998 Oct; 275 (4 Pt 2): R1366–73

    PubMed  CAS  Google Scholar 

  140. Yoshiyama M, Yamamoto T, de Groat WC. Role of spinal alpha (1)-adrenergic mechanisms in the control of lower urinary tract in the rat. Brain Res 2000 Nov 3; 882(1–2): 36–44

    Article  PubMed  CAS  Google Scholar 

  141. Yoshiyama M, De Groat WC. Role of spinal alpha1-adrenoceptor subtypes in the bladder reflex in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 2001 May; 280(5): R1414–9

    PubMed  CAS  Google Scholar 

  142. Day HE, Campeau S, Watson Jr SJ, et al. Distribution of alpha 1a-, alpha 1b- and alpha 1d adrenergic receptor mRNA in the rat brain and spinal cord. J Chem Neuroanat 1997 Jul; 13(2): 115–39

    Article  PubMed  CAS  Google Scholar 

  143. Smith MS, Schambra UB, Wilson KH, et al. Alpha 2-Adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding alpha 2-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res 1995 Dec 1;34(1): 109–17

    Article  PubMed  CAS  Google Scholar 

  144. Stone LS, Broberger C, Vulchanova L, et al. Differential distribution of alpha2A and alpha2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 1998 Aug 1; 18(15): 5928–37

    PubMed  CAS  Google Scholar 

  145. Shi TJ, Winzer-Serhan U, Leslie F, et al. Distribution of alpha2-adrenoceptor mRNAs in the rat lumbar spinal cord in normal and axotomized rats. Neuroreport 1999 Sep 9; 10(13): 2835–9

    Article  PubMed  CAS  Google Scholar 

  146. Ishizuka O, Mattiasson A, Andersson KE. Role of spinal and peripheral alpha 2 adrenoceptors in micturition in normal conscious rats. J Urol 1996 Nov; 156(5): 1853–7

    Article  PubMed  CAS  Google Scholar 

  147. Kontani H, Tsuji T, Kimura S. Effects of adrenergic alpha2-receptor agonists on urinary bladder contraction in conscious rats. Jpn J Pharmacol 2000 Dec; 84(4): 381–90

    Article  PubMed  CAS  Google Scholar 

  148. Andersson KE. Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alpha-adrenoceptor antagonists. World J Urol 2002 Apr; 19(6): 390–6

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Swedish Medical Research Council (grant no. 6837). The authors have no conflicts of interest directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Lund University Hospital, Lund, S-221 85, Sweden

    Karl-Erik Andersson & Rikard Pehrson

Authors
  1. Karl-Erik Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rikard Pehrson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl-Erik Andersson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andersson, KE., Pehrson, R. CNS Involvement in Overactive Bladder. Drugs 63, 2595–2611 (2003). https://doi.org/10.2165/00003495-200363230-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200363230-00003

Keywords

Search

Navigation