Basic Bladder

N e u ro p h y s i o l o g y
J. Quentin Clemens, MD, MSCI

KEYWORDS
 Neuroanatomy  Physiology  Lower urinary tract
 Pharmacology

Normal lower urinary tract function requires the low-pressure urine storage across a wide range
storage of urine at low intravesical pressure, of bladder volumes. This process is measured by
without leakage. Intermittently, this storage func- calculating the bladder compliance (change in
tion is interrupted by the voluntary and complete bladder volume/change in intravesical pressure),
expulsion of urine. These processes (storage and which is expressed in mL/cm H2O. Normal compli-
voiding) are unique in that they involve the coordi- ance is maintained throughout filling by reorienta-
nation of the peripheral autonomic, peripheral tion of the detrusor smooth muscle fibers and
somatic, and central nervous systems (CNS). connective tissue so that they are parallel to the
This article provides an overview of the basic prin- lumen, thinning of the lamina propria, and flat-
ciples that are recognized to regulate these func- tening of the urothelium.4 Bladder accommodation
tions, although many of these processes remain is a complex and poorly understood process that
poorly understood. Furthermore, much of this can be altered because of neurologic damage or
knowledge has been obtained from in vivo animal changes in the ECM content. For instance, an
models, and the relevance of these findings to increase in type III collagen has been found in
human physiology is not always clear. bladders with decreased compliance.5

BLADDER ANATOMY AND BIOMECHANICS GENERAL NEUROANATOMY

The bladder base refers to the trigone and bladder The CNS consists of the brain and spinal cord, and
neck, whereas the body consists of the supratrig- the peripheral nervous system (PNS) consists
onal portion.1 The bladder wall consists (from the of the sensory (afferent) and motor (efferent)
outside, away from the bladder lumen) of the neurons that communicate with the CNS. The
serosa, smooth muscle and extracellular matrix PNS is divided into the somatic and the autonomic
(ECM) (in approximately 50-50 distribution), the nervous systems. The somatic nervous system is
lamina propria, and the urothelium. Like other responsible for regulating structures that are under
smooth muscles, the detrusor muscle is oriented conscious control (such as the striated external
in a seemingly random fashion, is not attached to urethral sphincter and the levator muscles in the
tendon or bone, is able to maintain steady tension pelvic floor). The autonomic nervous system
over a wide range of muscle lengths, and has controls visceral and endocrine functions,
a slower contraction velocity than the skeletal including bladder contraction and relaxation. The
muscle.2,3 The detrusor muscle uses the ECM as autonomic nervous system is subdivided into the
a scaffold to generate tension, which produces parasympathetic and sympathetic nervous
a bladder contraction. systems. Sympathetic and parasympathetic are
Bladder accommodation refers to the changes anatomic terms that indicate the location from
that occur during bladder filling to permit where the nerve fibers emanate. Parasympathetic
urologic.theclinics.com

Disclosures: Merck, stock ownership; Pfizer, consultant, investigator; Lilly, consultant; Afferent Pharmaceuti-
cals, consultant; Medtronic, proctor.
Division of Neurourology and Pelvic Reconstructive Surgery, Department of Urology, University of Michigan
Medical Center, 1500 East Medical Center Drive, Taubman Center 3875, Ann Arbor, MI 48109-5330, USA
E-mail address: [email protected]

Urol Clin N Am 37 (2010) 487–494

doi:10.1016/j.ucl.2010.06.006
0094-0143/10/$ e see front matter Ó 2010 Elsevier Inc. All rights reserved.
488 Clemens

fibers emerge from the cranial and sacral Preganglionic sympathetic efferent nerves exit
segments of the spinal cord, whereas sympathetic from the thoracolumbar segment of the spinal
fibers emerge from the thoracic and lumbar cord at T10 through L2. The ganglia for these
segments of the spinal cord. nerves have variable locations: some are next to
the vertebrae (paraganglia), some are between
CROSS-SECTIONAL ANATOMY OF THE the vertebrae and the target organ (preganglia),
SPINAL CORD and some are located with the end organ (periph-
eral ganglia).7 Sympathetic efferent nerves to the
Peripheral sensory information is carried via lower urinary tract are located within the hypogas-
afferent nerves fibers, which enter the dorsal tric nerve. The sympathetic efferent nerves modu-
(posterior) aspect of the spinal cord and then travel late contractions of the urethral smooth muscle
upward to the central processing centers in the and bladder outlet and inhibit parasympathetic
CNS (Fig. 1). Afferent cell bodies are located in activity that promotes bladder contraction. The
the dorsal root ganglia. The white matter of the primary neurotransmitter for postganglionic
spinal cord contains bundles of myelin-coated sympathetic fibers is norepinephrine, but the
neurons, whereas the gray matter contains the primary neurotransmitter for preganglionic sympa-
cell bodies of interneurons and efferent motor thetic fibers is ACh.
neurons. Within the gray matter, nerve cell bodies Preganglionic somatic efferent nerves exit from
are generally organized into functional clusters the sacral segment of the spinal cord at S2 through
called nuclei (such as Onuf nucleus). Axons within S4. Nerve bodies for these nerves are located in
the white matter are functionally grouped into the Onuf nucleus, along the lateral border of the
tracts. Efferent motor axons exit from the ventral ventral gray matter in the sacral region of the spinal
root of the spinal cord. cord. The nerve fibers travel within the pudendal
nerve to the external urethral sphincter, where
RELEVANT NEUROANATOMY: PNS AND they modulate striated (voluntary) sphincter
SPINAL CORD contraction.8
In humans and animals, afferent nerves have
Preganglionic parasympathetic efferent nerves been identified in the detrusor muscle and the sub-
exit from the sacral segment of the spinal cord at urothelium.9,10 The suburothelial afferent nerve
S2 through S4. The axons travel a long distance fibers form a plexus that lies immediately beneath
within the pelvic nerve to the ganglia (pelvic the urothelial lining, with some nerve terminals ex-
plexus) that are located immediately adjacent to tending into the urothelium itself. This plexus is
the end organ (bladder) (Fig. 2). These fibers more prominent in the trigone and bladder neck
modulate bladder contractions. The primary and relatively sparse in the bladder dome. Afferent
neurotransmitter for both pre- and postganglionic nerve fibers from the lower urinary tract travel
parasympathetic fibers is acetylcholine (ACh).6 within the pelvic, hypogastric, and pudendal

Fig. 1. Cross section of the sacral

segment of the spinal cord.
DRG DORSAL Sensory nerve fibers enter the
DRG
dorsal spinal cord. Cell bodies of
these sensory nerves are located
Sensory in the dorsal root ganglia (DRG).
(Afferent) In The white matter contains
bundles of neurons, whereas the
gray matter contains the cell
GRAY
MATTER bodies of interneurons and
efferent motor neurons. Motor
nerve fibers exit the ventral spinal
cord in the ventral root.

WHITE
MATTER

Motor
VENTRAL (Efferent) Out
 Basic Bladder Neurophysiology 489

Fig. 2. Parasympathetic efferent nerves exit from the sacral region of the spinal cord at S2 through S4 and travel
within the pelvic nerve. Parasympathetic activity promotes bladder emptying by causing contraction of the de-
trusor and relaxation of the bladder outlet. Sympathetic efferent nerves exit from the thoracolumbar segment
of the spinal cord at T10 through L2 and travel within the hypogastric nerve. These nerves modulate contractions
of the urethral smooth muscle and bladder outlet and inhibit parasympathetic activity that promotes bladder
contraction. Somatic efferent nerves exit from the sacral segment of the spinal cord at S2 through S4 and travel
within the pudendal nerve to the external urethral sphincter, where they modulate striated (voluntary) sphincter
contraction. Afferent nerve fibers from the lower urinary tract travel within the pelvic, hypogastric, and pudendal
nerves. Therefore, these peripheral nerves carry bidirectional (afferent and efferent) information between the
end organs and the spinal cord.

nerves.11,12 Therefore, these peripheral nerves fibers appear to activate, become mechanosensi-
carry bidirectional (afferent and efferent) informa- tive, and modulate pathologic voiding reflexes.16
tion between the end organs and the spinal cord.
The sensory fibers enter the spinal cord via the RELEVANT NEUROANATOMY: BRAINSTEM
dorsal root, and the nerve cells bodies are located AND ABOVE
within the dorsal root ganglia. Afferent nerves
release numerous neurotransmitters (eg, Conclusive experimental evidence using brain-
substance P, neurokinins, calcitonin geneerelated lesioning techniques, electric stimulation, and
polypeptide, vasoactive intestinal polypeptide).13 axonal tracing studies indicate that an area of the
Most sensory innervation of the bladder and pons (the pontine micturition center [PMC] or Bar-
urethra originates in the thoracolumbar region of rington nucleus) mediates the normal micturition
the spinal cord and travels within the pelvic reflex by coordinating the activity of the detrusor
nerve.12 Within the pelvic nerve, 2 types of bladder and urethral sphincter muscles.17e20 Therefore,
afferent nerves have been identified, myelinated spinal cord lesions below this level often result in
Ad fibers and unmyelinated C fibers. The Ad fibers discoordination between the detrusor and urethral
respond to normal bladder distention and are sphincter (detrusor-sphincter dyssynergia). The
thought to be the primary functional afferent PMC receives input from multiple higher brain
nerves during normal micturition.12 Conversely, centers, including the basal ganglia, periaqueduc-
the C fibers respond to chemical irritation (noci- tal gray, thalamus, and hypothalamus.21 Brain
ception) or to cold, and most of these fibers are imaging studies in healthy volunteers suggest
inactive during normal micturition.14,15 However, a model of supraspinal bladder control, in which
during certain pathologic states (eg, inflammation, afferent signals from the lower urinary tract are
suprasacral spinal cord injury), these “silent” C received in the periaqueductal gray and relayed
490 Clemens

via the thalamus to the insula (which makes the by acetylcholinesterase. ACh is released from
sensations accessible to conscious awareness).22 postganglionic parasympathetic neurons, pregan-
According to this model, the cortex (via the ante- glionic autonomic neurons (sympathetic and para-
rior cingulate gyrus) monitors and controls micturi- sympathetic), and somatic neurons. Two main
tion reflexes and also makes voluntary voiding types of cholinergic receptors exist: nicotinic and
decisions (via the prefrontal cortex). muscarinic. Nicotinic receptors (which are respon-
sive to ACh and nicotine) are ligand-gated ion
NEURAL CONTROL OF THE LOWER URINARY channels and are found on the skeletal muscle
TRACT motor end plates, on the autonomic ganglia, and
in the CNS. The nicotinic receptors seem to have
During the storage phase of micturition, bladder a limited role in the control of micturition. Musca-
filling activates myelinated Ad afferent nerve fibers rinic receptors (which are responsive to ACh and
in the bladder wall. This afferent input results in muscarine) are G proteinecoupled receptors that
stimulation of sympathetic efferent activity (via activate ion channels via second-messenger
the hypogastric nerve), leading to contraction of cascades. These receptors are found on all auto-
smooth muscles in the bladder base and proximal nomic effector cells (eg, bladder, sweat glands,
urethra (via activation of a-adrenergic receptors) bowel) and in the CNS. Five subtypes of musca-
and relaxation of the detrusor (via activation of rinic receptors (M1 through M5) have been identi-
b-adrenergic receptors in the bladder body). fied, and the M2 and M3 subtypes predominate in
Somatic efferent activity (via the pudendal nerve) the bladder.28 Although M2 receptors are the
also increases, resulting in increased tone of the most plentiful in the detrusor (70% M2 vs 30%
striated external urethral sphincter. These M3 receptors), in vitro studies indicate that the
responses occur by spinal reflex pathways orga- M3 receptors are responsible for detrusor muscle
nized in the lumbosacral region of the spinal cord contraction.29e32 The functions of the detrusor
and represent guarding reflexes, which promote M2 receptors are less clear. Muscarinic receptors
continence.23e25 The parasympathetic system is are also found on presynaptic nerve terminals in
largely inactive during urine storage, which may the bladder and elsewhere, where they may play
partly be because of the sympathetic inhibition of a regulatory role via feedback inhibition.33,34
parasympathetic transmission at the ganglia level.
The voiding phase of micturition is initiated Excitation-contraction Coupling
voluntarily by signals from the cerebral cortex.
The initial event is relaxation of the striated Excitation-contraction coupling refers to the
external urethral sphincter, caused by inhibition process whereby binding of a ligand to a receptor
of somatic efferent activity. There is inhibition of causes force generation (muscle contraction)
sympathetic efferent activity, with concomitant (Fig. 3).35 In the detrusor smooth muscle, the
activation of parasympathetic outflow to the ligand is ACh and the receptor is the M3 receptor.
bladder and urethra.26 Bladder contraction is At rest, there is a very low concentration of free
mediated via muscarinic receptors in the bladder calcium ions (Ca21) in the smooth muscle cell.
body, and urethral smooth muscle relaxation is Binding of ACh to the M3 receptor triggers a G pro-
mediated through the release of nitric oxide teinemediated process, which causes Ca21
(NO).27 Maintenance of the voiding reflex is release from the sarcoplasmic reticulum as well
a complicated phenomenon that is mediated via as Ca21 influx from transmembrane ion channels.
communication between the spinal cord and the The free Ca21 binds to calmodulin, and the
pons (spinobulbospinal reflex), with the involve- Ca21-calmodulin complex then activates the
ment of midbrain structures such as the periaque- enzyme myosin light chain kinase, which phos-
ductal gray.21 phorylates the light chain of the contractile protein,
myosin. This phosphorylation causes the myosin
light chain to change shape and interact with actin,
PHARMACOLOGY OF THE LOWER URINARY
causing force generation.35 Alongside this
TRACT
process, alternate methods are at work to facilitate
Cholinergic Mechanisms
subsequent muscle relaxation. The Ca21-calmod-
In certain neurons of the CNS and PNS, the neuro- ulin complex activates transmembrane Ca21
transmitter ACh is synthesized from the essential pumps to remove free Ca21 from the cell, the
nutrient choline by the enzyme choline acetyltrans- ligand-receptor complex is degraded, and excess
ferase. In response to various stimuli, ACh is extracellular ACh is degraded by acetylcholines-
released into the synaptic cleft, where it either terase. This enzyme is abundant in the synaptic
binds to cholinergic receptors or is broken down cleft, and its role in rapidly clearing free ACh
 Basic Bladder Neurophysiology 491

Nerve Terminal
ACh ACh
ACh
ACh
ACh ACh ACh ACh

Ca2+
ACh

G Protein M3 PLC

IP3 Ca2+

CONTRACTION

SR

Actin
Ca2+
MLCK
Ca2+
My osin
Calmodulin

Fig. 3. Excitation-contraction coupling. Ach is released from postganglionic parasympathetic nerve terminals into
the synaptic cleft, where it binds to the M3 receptor. This ligand-receptor complex triggers a cascade of signaling
events that involves a G protein, phospholipase C (PLC), and inositol triphosphate (IP3). This signaling cascade
leads to the release of free calcium (Ca21) into the cytosol by the sarcoplasmic reticulum (SR) as well as a direct
influx of Ca21 via transmembrane ion channels. The free Ca21 binds with calmodulin, and the resulting
Ca21-calmodulin complex activates the enzyme myosin light chain kinase (MLCK). The MLCK causes changes in the
structure of the myosin molecule, which allows the myosin to interact with actin, leading to a muscle contraction.

from the synapse is essential for proper muscle where they cause detrusor smooth muscle
function. relaxation.38

Receptor Distribution in the Lower Urinary

Adrenergic Mechanisms Tract
Adrenergic receptors are G proteinecoupled The actions of the various neurotransmitters on the
receptors that bind catecholamines (most lower urinary tract are largely a function of receptor
commonly norepinephrine and epinephrine) that location.39,40 There is a higher density of musca-
are released from postganglionic sympathetic rinic receptors in the bladder body than in the
neurons. Stimulation of a-adrenergic receptors base, and therefore activation of these receptors
causes vasoconstriction and smooth muscle results in detrusor contraction. Adrenergic recep-
contraction, whereas stimulation of b-adrenergic tors are distributed such that a-adrenergic recep-
receptors causes increased myocardial contrac- tors (muscle contraction) predominate in the
tility and smooth muscle relaxation. There exists bladder base and urethra, whereas b-adrenergic
multiple subtypes of adrenergic receptors. receptors (muscle relaxation) predominate in the
a-Adrenergic receptors were initially divided into bladder body. Therefore, activation of the sympa-
a1 (postsynaptic) and a2 (presynaptic) receptors, thetic nervous system promotes urine storage
but a2 receptors were subsequently also found in (relaxation of the bladder body and contraction
postsynaptic locations. There are 3 subtypes of of the outlet).
a1 receptors (a1A, a1B, and a1D). The a1A subtype
is the primary subtype in the prostate and urethra,
Nonadrenergic Noncholinergic Mechanisms
where it mediates contraction of the bladder
of Bladder Excitation
outlet.36,37 The role of a2 receptors in the lower
urinary tract is not clear. There are 3 subtypes of In various mammalian species, complete blockage
b-adrenergic receptors (b1, b2, and b3). b1 Recep- of cholinergic receptors with atropine does not
tors are located in the heart, whereas b2 and b3 pre-vent detrusor muscle contraction,27 indicating
receptors are located in the lower urinary tract, that nonadrenergic noncholinergic (NANC)
492 Clemens

mechanisms exist, which at least partially mediate SENSORY ROLE OF THE UROTHELIUM
bladder contractions. In these nonhuman
mammals, there is good evidence that the trans- The urothelium has traditionally been viewed as
mitter responsible for the NANC component of a passive barrier that prevents passage of urinary
detrusor contraction is adenosine triphosphate toxins into the underlying bladder interstitium.
(ATP) acting on purinergic receptors.41,42 However, there is increasing evidence that the ur-
However, the component of NANC activation in othelium also has sensory and signaling properties
the normal human detrusor seems to be small. It that allow it communicate with nearby nerve and
is possible, however, that NANC mechanisms muscle tissue, suggesting that it is actively
may become more predominant in certain patho- involved in the storage and voiding phases of
logic states (eg, bladder outlet obstruction, over- micturition.50,51 For instance, the urothelium has
active bladder, neurogenic bladder, interstitial been shown to release chemical mediators (ATP,
cystitis).43,44 ACh, and NO) and to express numerous receptors
(eg, muscarinic, adrenergic, purinergic, and tachy-
Nitric Oxide kinin receptors).35,52 The mechanisms responsible
for urothelial ATP release have been the subject of
Stimulation of cholinergic receptors in the urethra considerable study because intravesical adminis-
causes contraction, rather than relaxation, of the tration of ATP induces detrusor overactivity and
urethral smooth muscle.45 Therefore, parasympa- mice deficient in the ATP receptor P2X3 exhibit
thetic pathways that promote voiding must elicit decreased voiding frequency and increased
urethral relaxation via noncholinergic mecha- bladder capacity.53,54 Therefore, further under-
nisms. Experimental studies indicate that NO, standing of these findings may provide additional
released from postganglionic parasympathetic therapeutic targets for lower urinary tract
nerves, is the major inhibitory neurotransmitter disorders.
that causes the urethral smooth muscle relaxation
during voiding.46,47 The mechanism of relaxation is
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