Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury

doi:10.1016/S0079-6123(05)52005-3

Progress in Brain Research

Volume 152, 2006, Pages 59-84

https://doi.org/10.1016/S0079-6123(05)52005-3 Get rights and content

Abstract

The lower urinary tract has two main functions, the storage and periodic expulsion of urine, which are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). During urine storage the outlet is closed and the bladder is quiescent, thereby maintaining a low intravesical pressure over a wide range of bladder volumes. During micturition the outlet relaxes and the bladder contracts to promote the release of urine. This reciprocal relationship between bladder and outlet is generated by visceral reflex circuits, some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are presumably involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter functions. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. Studies in animals indicate that the recovery of bladder function after spinal cord injury is dependent in part on plasticity of bladder afferent pathways and the unmasking of reflexes triggered by capsaicin-sensitive C-fiber bladder afferent neurons. The plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons, and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.

Introduction

The functions of the lower urinary tract to store and periodically release urine are dependent upon neural circuits located in the brain, spinal cord and peripheral ganglia (Barrington, 1925; Kuru, 1965; de Groat et al., 1993; Morrison et al., 2002). This dependence on central nervous control distinguishes the lower urinary tract from many other visceral structures (e.g., the gastrointestinal tract and cardiovascular system) that maintain a certain level of function even after elimination of extrinsic neural input.

The lower urinary tract is also unusual with regard to its pattern of activity and the complexity of its neural regulation. For example, the urinary bladder has two principal modes of operation: storage and elimination. Thus many of the neural circuits exhibit switch-like or phasic patterns of activity (de Groat, 1975) in contrast to tonic patterns occurring in autonomic pathways to cardiovascular organs. In addition, micturition is under voluntary control and depends upon learned behavior that develops during maturation of the nervous system, whereas many other visceral functions are regulated involuntarily. Micturition also depends on the integration of autonomic and somatic efferent mechanisms within the lumbosacral spinal cord (Chancellor and Yoshimura, 2002; Morrison et al., 2002). This is necessary during urine storage and elimination to coordinate the activity of visceral organs (the bladder and urethra) with that of urethral striated muscles.

The dependence of lower urinary tract functions on complex central neural networks renders these functions susceptible to a variety of neurological disorders (Torrens and Morrison, 1987; Chancellor and Yoshimura, 2002). This chapter will review studies in animals and humans that have provided insights into the neural control of the lower urinary tract and the disruption of this control by spinal cord injury.

Section snippets

Anatomy and innervation

The storage and periodic elimination of urine are regulated by the activity of two functional units in the lower urinary tract: (1) a reservoir (the bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). Under normal conditions, the urinary bladder and outlet exhibit a reciprocal relationship. During urine storage, the bladder neck and proximal urethra are closed; and the bladder smooth muscle is quiescent, allowing intravesical pressure to

Reflex mechanisms controlling the lower urinary tract

The neural pathways controlling lower urinary tract function are organized as simple on–off switching circuits that maintain a reciprocal relationship between the urinary bladder and urethral outlet (Groat, Booth, & Yoshimura (1993), de Groat et al. (1981)) (Fig. 2). The principal reflex components of these switching circuits are listed in Table 1 and illustrated in Fig. 3. Intravesical pressure measurements during bladder filling in both humans and animals reveal low and slowly increasing

Sympathetic storage pathway

The integrity of the sympathetic input to the lower urinary tract is not essential for the performance of micturition (Torrens and Morrison, 1986; de Groat et al., 1993). However, physiologic experiments in animals indicate that during bladder filling, the sympathetic system does provide a tonic inhibitory input to the bladder as well as an excitatory input to the urethra. This sympathetic input is physiologically significant since surgical interruption or pharmacologic blockade of the

Supraspinal and spinal neurotransmitters controlling micturition

Various neurotransmitters at the spinal and supraspinal level are involved in regulation of micturition and continence (de Groat and Yoshimura, 2001). Glutamic acid, which is the major excitatory transmitter in the central nervous system, has an important role in the control of the micturition reflex. Experiments in rats indicate that glutamatergic transmission in the spinal cord is essential for bladder and urethral reflexes and for the spinal processing of afferent input from the bladder.

Neurogenic dysfunction of the lower urinary tract

Neurogenic disturbances of micturition can be classified into two general categories: failure to store and failure to eliminate urine (Wein, 2002). Problems with storage occur with differing degrees of severity, ranging from reduced bladder capacity and frequency of urination to urgency and incontinence. A common finding is that disorders affecting the brain, particularly suprapontine areas, produce hyperactive or uninhibited bladders. Cerebrovascular accidents, Parkinson's disease, tumors or

Conclusions

The lower urinary tract has two main functions: storage and periodic elimination of urine. These functions are regulated by a complex neural control system located in the brain and spinal cord. This control system performs like a simple switching circuit to maintain a reciprocal relationship between the reservoir (bladder) and outlet components (urethra and urethral sphincter) of the urinary tract. Spinal cord injury disrupts voluntary control and the normal reflex pathways that coordinate

Acknowledgments

The authors’ research is supported by NIH research grants (DK49430, DK 57267, P01 HD 39768).

References (163)

M. Abdel-Gawad et al.
Evidence of a peripheral role of neurokinins in detrusor hyperreflexia: a further study of selective tachykinin antagonists in chronic spinal injured rats
J. Urol.
(2001)
L.A. Birder et al.
Increased c-fos expression in spinal lumbosacral projection and preganglionic neurons after irritation of the lower urinary tract in the rat
Brain Res.
(1999)
J.A. Black et al.
Tetrodotoxin-resistant sodium channels Na_v 1.8/SNS and Na_v 1.9/NaN in afferent neurons innervating urinary bladder in control and spinal cord injured rats
Brain Res.
(2003)
B.F. Blok et al.
Direct projections from the periaqueductal gray to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat
Neurosci. Lett.
(1994)
A.M. Booth et al.
Regulation of urinary bladder capacity by endogenous opioid peptides
J. Urol.
(1985)
A.S. Braverman et al.
M₂ receptors in genito-urinary smooth muscle pathology
Life Sci.
(1999)
C.R. Chapple
Muscarinic receptor antagonists in the treatment of overactive bladder
Urology
(2000)
C.L. Cheng et al.
The role of capsaicin-sensitive afferent fibers in the lower urinary tract dysfunction induced by chronic spinal cord injury in rats
Exp. Neurol.
(2004)
C.L. Cheng et al.
Effect of capsaicin on micturition and associated reflexes in chronic spinal rats
Brain Res.
(1995)
F. Cruz et al.
Desensitization of bladder sensory fibers by intravesical capsaicin has long lasting clinical and urodynamic effects in patients with hyperactive or hypersensitive bladder dysfunction
J. Urol.
(1997)

W.C. de Groat

Nervous control of the urinary bladder of the cat

Brain Res.

(1975)

W.C. de Groat et al.

Developmental and injury induced plasticity in the micturition reflex pathway

Behav. Brain Res.

(1998)

W.C. de Groat et al.

Parasympathetic preganglionic neurons in the sacral spinal cord

J. Auton. Nerv. Syst.

(1982)

W.C. de Groat et al.

Mechanisms underlying the recovery of urinary bladder function following spinal cord injury

J. Auton. Nerv. Syst.

(1990)

W.C. de Groat et al.

Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine

J. Auton. Nerv. Syst.

(1981)

M.J. Espey et al.

Serotonergic modulation of cat bladder function before and after spinal transection

Eur. J. Pharmacol.

(1995)

C.J. Fowler et al.

Intravesical capsaicin for neurogenic bladder dysfunction

Lancet

(1992)

G. Geirsson et al.

Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia

J. Urol.

(1995)

G. Geirsson et al.

Positive bladder cooling test in neurologically normal young children

J. Urol.

(1994)

S.S. Hegde et al.

Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder

Life Sci.

(1999)

K.M. Ho et al.

Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the human urethral sphincter

J. Urol.

(1999)

Y. Igawa et al.

Effects of GABA-receptor stimulation and blockade on micturition in normal rats and rats with bladder outflow obstruction

J. Urol.

(1993)

O. Ishizuka et al.

Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rats

Neuroscience

(1995)

O. Ishizuka et al.

Role of spinal and peripheral alpha 2 adrenoceptors in micturition in normal conscious rats

J. Urol.

(1996)

W. Janig et al.

Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception

Prog. Brain. Res.

(1986)

Y.H. Kim et al.

The role of oxybutynin in spinal cord injured patients with indwelling catheters

J. Urol.

(1997)

M.N. Kruse et al.

Influence of spinal cord injury on the morphology of bladder afferent and efferent neurons

J. Auton. Nerv. Syst.

(1995)

M.N. Kruse et al.

Pontine control of the urinary bladder and external urethral sphincter in the rat

Brain Res.

(1990)

H.Y. Lee et al.

Distribution of P2X receptors in the urinary bladder and the ureter of the rat

J. Urol,

(2000)

B.S. Mallory et al.

Pharmacological modulation of the pontine micturition center

Brain Res.

(1991)

G. Matsumoto et al.

Non-NMDA glutamatergic excitatory transmission in the descending limb of the spinobulbospinal micturition reflex pathway of the rat

Brain Res.

(1995)

G. Matsumoto et al.

Role of glutamate and NMDA receptors in the descending limb of the spinobulbospinal micturition reflex pathway of the rat

Neurosci. Lett.

(1995)

S. Matsuura et al.

Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study

J. Urol.

(2002)

S.B. McMahon et al.

Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets

Neuron

(1994)

A. Miura et al.

Effect of pituitary adenylate cyclase activating polypeptide on lumbosacral preganglionic neurons in the neonatal rat spinal cord

Brain Res.

(2001)

C. Morgan et al.

Location of bladder preganglionic neurons within the sacral parasympathetic nucleus of the cat

Neurosci. Lett.

(1979)

K.E. Andersson

Pharmacology of lower urinary tract smooth muscle and penile erection tissues

Pharmacol. Rev.

(1993)

K.E. Andersson et al.

Urinary bladder contraction and relaxation: physiology and pathology

Physiol. Rev.

(2004)

I. Araki

Inhibitory postsynaptic currents and the effects of GABA on visually identified sacral parasympathetic preganglionic neurons in neonatal rats

J. Neurophysiol.

(1994)

I. Araki et al.

Unitary excitatory synaptic currents in preganglionic neurons mediated by two distinct groups of interneurons in neonatal rat sacral parasympathetic nucleus

J. Neurophysiol.

(1996)

I. Araki et al.

Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord

J. Neurosci.

(1997)

B.S. Athwal et al.

Brain activity associated with the urge to void and bladder fill volume in normal men: preliminary data from a PET study

BJU Int.

(1999)

B.S. Athwal et al.

Brain responses to changes in bladder volume and urge to void in healthy men

Brain

(2001)

E. Bahns et al.

Functional characteristics of lumbar visceral afferent fibers from the urinary bladder and urethra in the cat

Eur. J. Physiol.

(1998)

F.J.F. Barrington

The effect of lesions of the hind-and mid-brain on micturition in the cat

J. Exp. Physiol.

(1925)

B.S. Beattie et al.

Motoneurons innervating the external anal and urethral sphincters of the female cat have different patterns of dendritic arborization

Neurosci. Lett.

(1990)

C.D. Betts

Bladder and sexual function in multiple sclerosis

L.A. Birder et al.

Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder

Am. J. Physiol.

(1998)

L.A. Birder et al.

Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium

Am. J. Physiol.

(2003)

L.A. Birder et al.

Induction of c-fos gene expression in spinal neurons of the rat by nociceptive and non-nociceptive stimulation of the lower urinary tract

Am. J. Physiol.

(1993)

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Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice.
We used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 μg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K⁺ currents, the sensitivity of each neuron to capsaicin was evaluated.
In capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K⁺ (K_A) and sustained delayed rectifier-type K⁺ (K_DR) currents were significantly reduced by SCI. The reduction of K_A, but not K_DR, current density was reversed by the treatment with p38 MAPK inhibitor.
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Spinal cord injury invariably leads to severe dysfunction of the lower urinary tract; patients develop urinary incontinence, recurrent urinary tract infections, incomplete bladder emptying and high bladder pressures. Reliance on catheters to empty the bladder is virtually universal. Established therapies for lower urinary tract dysfunction due to spinal cord injury focus on preventing and managing complications rather than on restoring function. Spinal Neuromodulation offers a diametrically different approach to classic therapies for neurogenic bladder: by delivering low-intensity sub-motor threshold electrical pulses directly to the spinal cord, Spinal Neuromodulation activates lumbar neural networks rendered dysfunctional by the spinal cord injury and restores communication between the lower urinary tract and higher neural centers responsible for micturition control. Spinal neuromodulation improves bladder capacity, diminishes urinary incontinence and, remarkably, restores bladder sensation even in individuals, whose spinal cord injury is considered clinically complete.
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The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinate the activity of smooth and striated muscles of the bladder and urethral outlet. Although the neural units that can induce contraction and relaxation of the bladder and urethra are located in the lumbosacral spinal cord and peripheral nervous pathways, the coordination between different components of the lower urinary tract necessary for efficient micturition requires a hierarchical neural system, in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Then, voluntary micturition depends on suprapontine inputs from the forebrain that modulate the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the reflex micturition is a spinobulbospinal pathway that has essential connections between the lumbosacral spinal cord and brainstem structures such as the periaqueductal gray matter and Pontine micturition center, which can induce bladder contractions and reciprocal urethral relaxation during voiding. However, these suprapontine and spinobulbospinal pathways, which are responsible for voluntary and reflex voiding, respectively, are still immature in infants and young children, resulting in involuntary voiding, and are often impaired in adults due to diseases or injuries of the nervous system, leading to reemergence of involuntary micturition and urinary incontinence. This chapter summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling voluntary and reflex micturition.
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Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury

Abstract

Introduction

Section snippets

Anatomy and innervation

Reflex mechanisms controlling the lower urinary tract

Sympathetic storage pathway

Supraspinal and spinal neurotransmitters controlling micturition

Neurogenic dysfunction of the lower urinary tract

Conclusions

Acknowledgments

J. Urol.

Brain Res.

Brain Res.

Neurosci. Lett.

J. Urol.

Life Sci.

Urology

Exp. Neurol.

Brain Res.

J. Urol.

Brain Res.

Behav. Brain Res.

J. Auton. Nerv. Syst.

J. Auton. Nerv. Syst.

J. Auton. Nerv. Syst.

Eur. J. Pharmacol.

Lancet

J. Urol.

J. Urol.

Life Sci.

J. Urol.

J. Urol.

Neuroscience

J. Urol.

Prog. Brain. Res.

J. Urol.

J. Auton. Nerv. Syst.

Brain Res.

J. Urol,

Brain Res.

Brain Res.

Neurosci. Lett.

J. Urol.

Neuron

Brain Res.

Neurosci. Lett.

Pharmacology of lower urinary tract smooth muscle and penile erection tissues

Pharmacol. Rev.

Urinary bladder contraction and relaxation: physiology and pathology

Physiol. Rev.

Inhibitory postsynaptic currents and the effects of GABA on visually identified sacral parasympathetic preganglionic neurons in neonatal rats

J. Neurophysiol.

Unitary excitatory synaptic currents in preganglionic neurons mediated by two distinct groups of interneurons in neonatal rat sacral parasympathetic nucleus

J. Neurophysiol.

Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord

J. Neurosci.

Brain activity associated with the urge to void and bladder fill volume in normal men: preliminary data from a PET study

BJU Int.

Brain responses to changes in bladder volume and urge to void in healthy men

Brain

Functional characteristics of lumbar visceral afferent fibers from the urinary bladder and urethra in the cat

Eur. J. Physiol.

The effect of lesions of the hind-and mid-brain on micturition in the cat

J. Exp. Physiol.

Motoneurons innervating the external anal and urethral sphincters of the female cat have different patterns of dendritic arborization

Neurosci. Lett.

Bladder and sexual function in multiple sclerosis

Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder

Am. J. Physiol.

Feline interstitial cystitis results in mechanical hypersensitivity and altered ATP release from bladder urothelium

Am. J. Physiol.

Induction of c-fos gene expression in spinal neurons of the rat by nociceptive and non-nociceptive stimulation of the lower urinary tract

Am. J. Physiol.