Collaborative for Education on Urinary Incontinence and Women's Health (ceUIwh)

Clinical Consult

Each month, questions with a common theme will be selected and answered comprehensively by one of our Steering Committee members. Previously answered questions will be archived each month for your reference. If you wish to submit a question, click here.

This Month's Question:

What is the relationship between the central nervous system and the lower urinary tract?

Response by Karen Sasso, MSN, RN, APN, CCCN, posted 12/20/2004:

Urinary incontinence affects about 13 million people in the United States, of whom about 11 million are women.¹ Among these, approximately half suffer from stress urinary incontinence (SUI), with the highest percentage among young women.² SUI is characterized by an involuntary loss of urine during physical activities such as coughing, sneezing, laughing, lifting, or exercising. SUI may be caused by decreased urethral resistance, urethral hypermobility, and/or relaxation of the pelvic floor muscles.¹ Studies have shown that neurotransmitters – serotonin and norepinephrine – play an integral role in micturition, urine storage, and urethral sphincter activity.^1,3 Consequently, pharmacologic agents affecting these neurotransmitter pathways may be beneficial in the treatment of SUI.

Management of the lower urinary tract is mediated by multiple response pathways controlled by the brain and spinal cord.⁴ The frontal lobe of the brain, which is part of the cerebral cortex, permits conscious control over micturition.⁵ Within the brainstem, the pons contains the pontine micturition center (PMC), which coordinates voluntary relaxation of the urethral sphincter and contraction of the bladder during voiding.^5,6 Impulses reaching the lower urinary tract are mediated via nerves that originate in the thoracic-lumbar and sacral regions of the spinal cord. The spinal cord also receives sensory information from the bladder, urethra, and pelvic floor.⁵

The peripheral nervous system includes the autonomic and somatic peripheral nerves.⁶ The autonomic nervous system, which is divided into the sympathetic and parasympathetic nervous systems, manages the involuntary portion of the lower urinary tract through adrenergic pathways to urethral and bladder smooth muscle. The parasympathetic nervous system innervates the pelvic nerve to facilitate urination via relaxation of the internal urethral sphincter and contraction of the bladder muscle, or detrusor. The sympathetic nervous system innervates the hypogastric nerve to promote urine storage via contraction of the internal urethral sphincter and relaxation of the detrusor.⁶ In contrast, the somatic nervous system regulates striated muscles in the lower urinary tract under voluntary control, including the pelvic diaphragm and the external urinary sphincter (also called the rhabdosphincter).⁷ The pudendal nerve, the somatic component of the peripheral nervous system, works in conjunction with the hypogastric nerve, the sympathetic component, to store urine in the bladder.⁶ Under normal conditions, the micturition reflex is inhibited. However, stimulation of the PMC, initiated by stretch receptors activating afferent nerves in the bladder wall, overrides the sympathetic and somatic storage reflexes and triggers the micturition reflex.^7,8

Onuf's nucleus comprises a group of somatic motor neurons in the sacral spinal cord. Cholinergic axons from these motor neurons traverse the pudendal nerve and innervate the striated muscle, or rhabdosphincter.⁷ Onuf's nucleus exhibits a high density of serotonergic and noradrenergic receptors and terminals.⁹ This characteristic has led to research studies focusing on serotonergic and noradrenergic receptor agonists and antagonists.^10,12 Stimulation of these receptors increases pudendal nerve efferent activity.⁷ Glutamate is the primary excitatory neurotransmitter for pudendal sphincter motor neurons.⁷ In effect, serotonin and norepinephrine act as modulators for glutamate, which is the “on/off” switch for the storage reflex. When glutamate is “on,” the external urethral sphincter contracts (storage phase), and when it is “off,” the external urethral sphincter relaxes (voiding phase).¹³

Studies have demonstrated that a correct voluntary pelvic floor muscle contraction increases urethral closure pressure.¹⁴ In women with SUI, behavioral modifications, including lifestyle changes, bladder training, and pelvic floor muscle exercises, may be recommended. Additionally, pharmacotherapy, medical devices, and surgical intervention, either alone or in combination with behavioral modifications, may be advised.

Pharmacologic agents affecting the pathways of neurotransmitters serotonin and norepinephrine have been used in the treatment of SUI. Prescribed off-label for women with mild SUI, alpha-adrenergic agonists raise urethral closure pressure, but evidence of clinical improvement is mixed. Side effects, including elevations in blood pressure, anxiety, respiratory difficulties, and palpitations, must be balanced by modest benefits.^6,15 Also prescribed off-label for SUI, imipramine, a tricyclic antidepressant, promotes urethral sphincter closure and detrusor inhibition, primarily via peripheral mechanisms. However, imipramine has been associated with several adverse events, including alpha-adrenergic effects and anticholinergic effects (eg, dry mouth, flushing, and heat intolerance); its effectiveness in the treatment of SUI requires further evidence.^6,15

Finally, duloxetine, an investigational serotonin and norepinephrine reuptake inhibitor, has been shown to prolong the effect of naturally released serotonin and norepinephrine in the central nervous system.⁸ These neurotransmitters interact with receptors in Onuf's nucleus, which stimulates pudendal-nerve–efferent activity to increase contraction of the urethral rhabdosphincter, therefore increasing urethral resistance. Duloxetine supports bladder-sphincter synergy by providing sphincter contraction during bladder filling, but not during bladder emptying in micturition.⁸ Furthermore, duloxetine has been shown to significantly reduce incontinence episodes and is well tolerated in the clinical setting.^16-18

References

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Hunskaar S, Arnold EP, Burgio K, Diokno AC, Herzog AR, Mallet VT. Epidemiology and natural history of urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2000;11:301-319.
Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of the lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther. 1995;274:1014-1024.
Fraser MO, Chancellor MB. Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence. BJU Int. 2003;91:743-748.
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Newman DK. Managing and Treating Urinary Incontinence. Baltimore, Md: Health Professions Press; 2002:23-26.
Thor KB. Targeting serotonin and norepinephrine receptors in stress urinary incontinence. Int J Gynaecol Obstet. 2004;86(suppl 1):S38-S52.
Thor KB. Serotonin and norepinephrine involvement in the efferent pathways to the urethral rhabdosphincter: implications for treating stress urinary incontinence. Urology. 2003;62(suppl 4A):3-9.
Thor KB. Neurourology: exploring new horizons. Adv Stud Med. 2002;2:677-680.
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;946:290-297.
Danuser H, Thor KB. Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflexes in the anaesthetized cat. Br J Pharmacol. 1996;118:150-154.
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;153:1308-1312.
Chancellor MB, Yoshimura N. Neurophysiology of stress urinary incontinence. Rev Urol. 2004;6(suppl 3):S19-S28.
Bo K. Urinary incontinence, pelvic floor dysfunction, exercise and sport. Sports Med. 2004;34:451-464.
Gray M. Stress urinary incontinence in women. J Am Acad Nurse Pract. 2004 ;16:188-197.
Norton PA, Zinner NR, Yalcin I, Bump RC; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol. 2002;187:40-48.
Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I, Bump RC; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol. 2003;170(4 Pt 1):1259-1263.
Cardozo L, Drutz HP, Baygani SK, Bump RC. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol. 2004;104:511-519.