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Mini-review Articles
2009 BJU INTERNATIONAL
SENSORY OUTPUT FROM THE BLADDER: THE CONCEPT OF AFFERENT NOISE
GILLESPIE
et al.
BJUI
On the origins of the sensory output from the
bladder: the concept of afferent noise
BJU INTERNATIONAL
James I. Gillespie*†, Gommert A. van Koeveringe‡, Stefan G. de Wachter‡ and
Jan de Vente†
*The Uro-physiology Research Group, the Medical School, the University, Newcastle upon Tyne, UK, †European
Graduate School of Neuroscience (EURON), the Department of Psychiatry and Neuropsychology, Maastricht
University, and ‡Department of Urology, Maastricht University Medical Centre, Maastricht, the Netherlands
Accepted for publication 14 November 2008
For many people a recurrent strong desire
to void, sometimes with incontinence,
diminishes their quality of life. At present
there are few insights into what underlies
these problems. The condition is described as
the ‘overactive bladder symptom complex’
but this definition is proving to be unhelpful.
It focuses on overt bladder contractions
rather than the main problem, which is
altered and heightened sensation. Also,
current approaches that describe bladder
sensations as episodic and leading to voiding
as ‘first and second sensation to void’ might
also be misleading if they are taken too
literally and used to suggest mechanisms.
INTRODUCTION
Current research is beginning to focus on
the mechanisms that generate afferent
information from the bladder and how it can
become altered. As these views develop it is
crucial that we appreciate the diversity of
the bladder afferent system and distinguish
between afferent and sensory information;
in this review we explore this underlying
complexity. The central nervous system
(CNS) receives vast amounts of information
from the bladder, which arises from different
locations, uses different fibre types and
involves different methods. The CNS is
continually being bombarded with ‘afferent
noise’. The challenge now is to understand
the nature and components of this ‘afferent
noise’ and which components are essential
to sensation. The emerging picture is
complex, but this complexity must not be
negated or oversimplified. It must be
embraced and incorporated it into thinking
when designing experiments, analysing data,
diagnosing patients and evaluating
treatment.
Bladder sensations and awareness of the
bladder are there all the time.
sent to the CNS to generate these sensations.
We also need to know where in the bladder or
urinary tract these sensations originate.
Finally, we must understand what goes wrong
to generate pathological sensations.
THE BASIC PROBLEM IN SIMPLE TERMS
For everyone, the pattern of everyday life
involves regular visits to the toilet. There is
nothing remarkable in this; we drink and we
must excrete excess fluids. It is a common
experience that as the bladder fills we begin to
notice sensations from the lower abdomen
which we interpret as the bladder filling and
then becoming full. We can empty our bladder
almost at any time, the place and social
decorum permitting. We do not need to wait
until it is absolutely full, but when it is full we
also recognize ‘strong’ sensations and the
need for immediate action to relieve the
problem. Thus, if we are introspective about
our bladder we can, if asked, estimate how
much is there. ‘Do you need to go’? ‘No, I am
fine’ . . . ‘Do you need to go’? ‘No, I can hold
on for a bit’, ‘Yes, I’d better go now while I
have the chance’, ‘Yes’! I must to go now!’
Thus, information about the bladder can be
accessed by the CNS at any time during filling.
1324
For significantly many people this basic
pattern of feelings, introspection and
behaviour is altered. Sensations associated
with the bladder occur more regularly,
perhaps constantly, and more intensely. Such
problematic symptoms are often coped with
by altering how much is drunk. Also people
with such sensations always make sure they
know where the nearest toilets are located. In
some cases these symptoms are so extreme
that they can completely change an
individual’s lifestyle. Once the problem
reaches these stages, more often than not,
medical advice is sought.
The basic problem is therefore to understand
the nature and origins of the sensations
originating from the lower urinary tract (LUT).
We need to know ‘what are the different
sensations that occur as the bladder fills
normally and in patients with urge’. We need
to know the kind of information that is being
KEYWORDS
sensation, bladder, afferent noise, overactive
bladder
DIFFICULTIES WITH ACCEPTED
DEFINITIONS AND CONCEPTS
The clinical problem has been defined by the
ICS as ‘the overactive bladder symptom
complex’ more commonly known as the
overactive bladder (OAB) [1]. It is defined as
strong sensations of ‘urgency’ as the bladder
fills. This is a poorly defined term which is
considered, in the English language, to be
different from that of ‘urge’ or need to go.
This might be an important distinction. Are
the sensations recognized in patients with
‘urgency’ the same as those of ‘urge’
experienced by normal subjects, but only
stronger? Or are the sensations totally
different, possibly, being generated by
different means? We do not know.
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2 0 0 9 B J U I N T E R N A T I O N A L | 1 0 3 , 1 3 2 4 – 1 3 3 3 | doi:10.1111/j.1464-410X.2009.08377.x
SENSORY OUTPUT FROM THE BLADDER: THE CONCEPT OF AFFERENT NOISE
FIG. 1. Depiction of the origins of sensation in the
bladder during the filling phase. A and B are taken
from [12], with permission. The diagram illustrates
one idea relating to perceived sensation as the
bladder volume increases. It shows what is described
as the ‘first sensation to void’ which occurs early
in the filling phase, and a subsequent series of
transient sensations as the bladder fills. As
presented, this diagram suggests that episodic
bursts of sensation, each perceived as having an
increasing intensity, occur as the bladder fills, the
final episodes being the most intense and the
sensations described as urgency. The episodic nature
of sensation might have a physical correlate in the
periphery (episodic afferent discharge) or it might be
a cortical phenomenon of increasing and decreasing
perception.
Bladder volume (–)
Time
Reduction in
volume voided
due to urgency
Normal
desire Urgency
to void
}
Void
(voluntary and/or
involuntary)
Presumed
normal
void volume
Intensity
Bladder volume (–)
Volume
voided
B
First
sensation
Intensity
Intensity of nomal
desire to void
Intervoid
interval
A
Reduction of
intervoid
interval
There is a further complication arising from
the term OAB; when patients with symptoms
of urgency are examined using standard
filling cystometry some show contractions of
the bladder as it fills. The detrusor is described
as ‘overactive’. Such observations led to the
idea that the sensations arose from these
‘overactive’ contractions. As a result, patients
were given drugs which should reduce the
contractions and so reduce the symptoms.
Bladder contractions are generated by
acetylcholine acting on muscarinic receptors.
So anticholinergic drugs were used to treat
the condition and, indeed, patients with urge
and frequency benefit from these drugs.
However, at the therapeutically effective
doses, these drugs have little effect of the
overactive contractions or the voiding
contraction [2,3]. Thus, we have reached the
unavoidable conclusion that, as they do not
affect contraction, they must be working on
©
other systems, possibly those generating
sensation.
THE INCIDENCE OF BLADDER ACTIVITY
DURING FILLING
Apparently, fewer than half of patients
with general urge symptoms have bladder
contractions during the filling phase, when
measured using conventional cystometry. The
remainder have the same symptoms but no
such activity [4,5]. This separation of patients
with the same symptoms but with different
bladder responses led to the older
classification of patients as having ‘motor
urge’ or ‘sensory urge’. Does this mean that
there are two forms of the same condition
or that it is the same condition but with
an unrelated aspect of unusual bladder
contractions? We do not know!
Many explanations have been proposed for
the wide variation in the incidence of bladder
contractions during the filling phase in rapidfill cystometry. These include filling rate, the
composition of the filling solutions and the
posture of the subject (see [5] for a recent
overview). The current thinking is that the
vast majority of patients with urge symptoms
probably have uncontrolled contractions
of the bladder, but these are only apparent
when urodynamic studies are carried out
under controlled conditions [5]. A further
complication arises from studies involving
ambulatory urodynamics. Using this
approach, up to 60% of normal asymptomatic
subjects have contractions of the bladder
during the filling phase. Such activity is not
pathological but physiological, and so activity
alone cannot play a part in the generations of
clinical symptoms of urge [6].
Patients with ‘sensory urgency’ benefit from
anticholinergic drug therapy as well as those
with ‘motor urgency’ [7]. Thus, contractions in
the bladder were not a good indicator of the
clinical presentation nor were they indicative
of a benefit of anticholinergic drugs.
It has also been reported that patients with
urgency and frequency can also have
spontaneous relaxations of the urethra [8,9].
These relaxations have been described as
urethral instability or urethral overactivity.
They can occur alone, in conjunction with but
not associated with spontaneous detrusor
contractions, or immediately preceding
detrusor contractions [8,9]. If the
spontaneous relaxations are restricted to the
reporting of large relaxations (>20 cmH2O or
3% of the maximum urethral pressure) they
occur more often in patients with urgency [9].
This has led to the idea that these events
might be related to urge or even underlie the
pathology [8,9].
In conclusion, the origins and nature of urge
sensations are unknown. Almost certainly,
they are not derived exclusively from large
bladder contractions during the filling phase.
They might not even originate in the bladder
but in the urethra.
SENSATIONS OF DESIRE AND URGE
The question as to the nature and origins of
bladder sensation has occupied clinicians and
scientists for centuries. Introspection tells
those of us who consider that we have normal
bladders that there are different normal
sensations: vague abdominal sensations as
the bladder fills, growing sensations
associated with a general desire to void and
strong sensations associated with imminent
micturition [10,11]. In a brief review Nathan
[10] stressed that the sensations of awareness
and then desire to micturate were different
from the sensations of imminent micturition.
The sensations of awareness and desire could
be mapped to the bladder, and involve bladder
distension and contraction, while sensations
of imminent micturition originate lower
down, possibly in the proximal urethra [10,11].
This distinction is often lost in current
thinking, where sensations central to urge are
considered to originate primarily from the
bladder.
More recent attempts to describe the normal
sensations as the bladder fills focus on the
sensations in relation to the need to void. It is
accepted, with no real justification, that the
sensations are episodic and that they
gradually increase in intensity. The changing
sensations associated with bladder filling are
currently depicted in schematic diagrams like
that illustrated in Fig. 1A [12]. In this
description, as the bladder fills, a sensation,
described as the ‘first sensation to void’,
appears. This sensation declines and is
followed by a series of further episodic
sensations of increasing intensity, ‘second
sensation’ and ‘third sensation’. The final
sensation, the strongest and sometimes called
urge, triggers the behaviour associated with
voiding and the micturition reflex. Attempts
have been made to quantify or score this
general approach (see [13,14]) Although
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G I L L E S P I E ET AL.
FIG. 2. This diagram suggests a modified view of the perceived sensations as the bladder fills. The sensations
generated during filling are considered to be a continuum, not episodic. However, within the continuum
different linked phases can be recognized, each associated with a progressive intensification of sensation.
The differences between this model and that in Fig. 1 might not initially be apparent. However, they represent
basic differences in the fundamental physiological processes that contribute to bladder sensation. If the
overall aim is to use such models to interpret clinical observations and assess the effects of drugs, it is
essential that the underlying concepts are based on the most current appreciation of the physiological,
pharmacological and psychological processes underlying bladder sensation.
A sensations
fill
pain
urge
bladder volume
possibly a convenient linguistic approach,
such a description omits certain key elements,
particularly the differences in the normal
sensations of ‘desire’ vs ‘need’ [10]. In
addition, the description suggests that the
sensations are episodic, waxing and waning
as the bladder fills. If sensation waxes and
wanes this raises questions as to the origins
of sensation and change. Does an apparent
reduction in sensation reflect a reduction
in the afferent firing from the bladder or
does it suggest a conscious (cortical)
suppression of sensation? This is an important
distinction as there will be fundamental
differences in the site, nature and origin
of the mechanisms involved, i.e. central vs
peripheral.
strong desire
desire
growing awareness
initial awareness
no sensation
B general sensations
void
fill
bladder volume
Similar diagrams have been drawn to describe
the situation in patients with ‘urge’ . In such
patients the first sensations occur at low
bladder volumes, and strong sensations, now
called ‘urgency’, are experienced at low
volume (Fig. 1B [12]). Urgency is followed
shortly after by voiding, the interval being
described as the ‘warning time’. Although such
descriptions recognize different components
including ‘desire’ and ‘need’ they do not help
to understand the nature of the origins of
sensation. Indeed, it can be argued that such a
model of ‘intermittent sensation’ might be
limiting if it is interpreted too literally,
representing fundamental processes that
others might use to construct hypotheses or
interpret results.
time
pain
C urge sensations
urge
An alternative description that might be more
useful in describing sensations emanating
from the bladder is illustrated in Fig. 2. In this
‘continuous sensation model’ the idea is that
signals are generated within the bladder at
all times during the filling phase. The key
difference between this approach and that
outlined in Fig. 1 is that it considers
sensations pertaining to the bladder to be
present throughout filling. Perhaps the first
perception is that the bladder has been
emptied and ‘no sensation’ is registered. Early
sensations, an ‘initial awareness’, are related
to a growing awareness of the bladder and a
realisation that there is something there. As
the bladder fills sensations change, increasing
in intensity, a ‘growing awareness’. Voiding
could be initiated as soon as we are aware
of the bladder but if there is no ‘need’,
no immediate action is necessary. Again,
introspection tells us that this might be the
case. With some reflection and experience we
can usually tell what is in our bladder and
1326
some general statements relating to the
interpretation of this information are
summarized in Fig. 2A. Indeed, it has been
suggested that normal voiding behaviour is
controlled and relies on such initial nonurgent sensations [15] with urge sensations
being different and occurring later [16].
MULTIPLE AFFERENT PATHWAYS: THE
SOURCES AND NATURE OF AFFERENT
NERVE IMPULSES
An important fact that must be recognized is
the difference between afferent fibres that
contribute to sensation and those which
do not, a difference first pointed out by
Sherrington in 1900 [17]. He noted that the
impulses from visceral fibres to the CNS did
not usually elicit sensation. The distinction
must therefore be made between afferent
fibres and a subset of afferent fibres that lead
to sensation, i.e. sensory fibres. The afferent
fibres in the periphery make their way to the
spinal cord, these are the primary afferent
fibres [18,19]. These fibres might make
contact with other secondary afferent
neurones in the cord which, in turn might
contact further tertiary neurones. Whether a
particular type of primary afferent fibre is
sensory almost certainly depends on these
secondary and tertiary connections in the
CNS. In the LUT it is also important to make
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SENSORY OUTPUT FROM THE BLADDER: THE CONCEPT OF AFFERENT NOISE
FIG. 3. A diagrammatic representation of the reflexes described by Barrington that might be involved in
generating and coordinating micturition. The seven reflexes originated in the bladder or urethral wall and had
specific effects on the bladder or urethra. The afferent fibres of the different reflexes projecting to three levels:
the sacral and lumbar cord and the hind brain. Adapted from [20–23].
pelvic floor). Furthermore, data from patients
with spinal cord injury, or sacral tumours,
suggest that the character of the sensation
changes with the involvement of different
peripheral nerves.
hind brain
1
2
lumbar cord
sacral cord
efferent
3
4
afferent
It is therefore important to appreciate that
afferent information from the LUT is carried
in three sets of nerves, the pudendal,
pelvic and hypogastric nerves. In general,
information from the external sphincter
is carried in the pudendal nerve while
signals from the urethra, bladder neck and
bladder body are carried in the pelvic and
hypogastric nerves. It is also likely that each
major nerve contains afferent fibres of
different types, and fibres associated with
the different reflexes (Fig. 3; see below). Thus
there are many inputs travelling in different
nerves contributing to different physiological
systems, which might or might not be
involved in sensation. The problem is to
unravel this complexity.
BARRINGTON’S REFLEXES
5
6
7
receptor
Reflex
Barrington 1
Barrington 2
Barrington 3
Barrington 4
Barrington 5
Barrington 6
Barrington 7
bladder distension
urethral flow
urethral distension
urethral flow
bladder distension
bladder distension
urethral flow
this distinction between afferent and sensory
fibres. There are different afferent signals
leaving the bladder (see below). Although not
proven, it is more than likely that within these
different populations of bladder afferent
fibres only some of these will lead to
sensation. Thus, some of the afferent systems
will be involved in local ‘unconscious’ spinal
reflexes while others pass information up the
©
effect
bladder contraction
bladder contraction
bladder contraction
urethral relaxation
urethral relaxation
urethral relaxation
bladder contraction
CNS to generate sensation. In the LUT it is not
yet clear which systems are only afferent and
which are afferent/sensory.
Sensations also change in character and
location; imminent sensation is described as
being lower in the pelvis, even in the
perineum and penis, suggesting involvement
of the pudendal nerve (proximal urethra vs
During filling and emptying of the bladder
the LUT is controlled by several different
reflexes. These pathways were described by
Barrington in the early 20th century [20–22].
Based on work primarily in the cat,
Barrington originally described seven
separate reflexes based on the origins of the
afferent limb and the connections that the
reflex arcs made in the spinal cord and brain.
A schematic diagram of Barrington’s reflexes,
with the origins of the afferent fibres, their
connections and the targets of the efferent
limbs, are illustrated in Fig. 3 [20–23]. It
is suspected that some of Barrington’s
reflexes do not operate or are difficult to
characterize in man, specifically reflexes 2
and 7 [23], although this point is
controversial. However, it is clear from
Barrington’s work that afferent fibres from
the LUT can be considered in different
groups depending on which reflex they
contribute to and where the projections go
in the CNS. Once again, care is needed to
distinguish which of these fibres are afferent
and which are afferent/sensory, and be
aware that different sensations could arise
from different regions of the urinary tract.
The distribution of Barrington’s reflexes
originating in different regions of the LUT
further emphasizes the point that afferent
output and possibly sensation is derived
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G I L L E S P I E ET AL.
FIG. 5. Different patterns of response in afferent fibres from the cat and rat bladder. (A) illustrates some of the
different types of response emanating from different regions of the rat bladder during filling. There are
different patterns of response: Fibres that respond maximally half way through filling (a); fibres responding
to their greatest extent at maximum bladder capacity (b); and fibres that show phasic activity linked to
rhythmic variations in bladder pressure during filling (c). With permission from [26]. (B) also shows data from
the rat (from [33], with permission). These data illustrate fibres responding during bladder filling; (b) shows a
further example of a fibre which has its maximum firing rate part way through the bladder fill. This firing also
responds to the phasic rises in bladder pressure with bursts of impulses. (C) and (D) show afferent nerve
activity from the bladder of the cat. (C) shows the response in a rapidly adapting mechanosensitive fibre in an
isovolumetric bladder. The lower panels shows that the fibre is only active during the rising phase of a phasic
bladder contraction (from [24], with permission). (D) shows compound nerve activity from several fibres
which are all responding to the phasic contractions of the bladder (from [48], with permission).
A 25 (a) body
A
10
0
50
mmHg
all units
n = 100
5
mechanoreceptors
n = 61
0
5
∗
0
chemoreceptors
n=8
∗
0
0
5
10
conduction velocity, m/sec
C
15
0
Aδ
C
10 5.0 3.3 2.5 2.0 1.6 1.4 1.25 1.1 1.0 0.9
mL 45
40
20
mmHg 0
0
50
mmHg
conduction velocity, m/sec
20
D
cmH2O
0
25
(d) RF not found
1
imp/sec
from different anatomical locations. Thus,
sensations might be felt from different
regions and at different times throughout the
filling and emptying cycle. Different locations
could even signal different sensations or
degrees of sensation [10].
(c) base
imp/sec
25
B
(b) uvj
0
50
unexcited units
n = 31
5
25
imp/sec
5
0
mmHg
number of units
0
10
(b)
(a)
B
imp/sec
FIG. 4. The different types of afferent fibres in the
pelvic nerve of the rat bladders (from [26], with
permission). (A) illustrates the three types of fibre
seen in the rat bladder; mechanosensitive,
chemosensitive or neither, with the distribution of
conduction velocities for individual fibres within
each of the three categories. (B) shows a typical
compound action potential emanating from a
population of afferent, fibres measured at the distal
end of the pelvic nerve after stimulation of the
proximal end of the L6 dorsal root. Fibres with high
conduction velocities (>2 m/s, Aδ fibres) and low
conduction velocities (<2 m/s, C fibres) can be seen.
The arrow indicates the time of stimulation.
Conduction velocity is calculated as the distance
between stimulation and response/time taken.
0
80
µV
AFFERENT FIBRE TYPES
The afferent axons that leave the LUT and the
bladder in particular can be divided broadly
into two types, i.e. small myelinated fibres
(Aδ) and unmyelinated fibres (C). These
different nerves can also be distinguished
functionally by the conduction velocities of
the impulses they carry; Aδ fibres conduct
impulses at 3–10 m/s while the C fibres
conduct at <2 m/s (Fig. 4; [24–28]). However,
there might be no functional difference
between Aδ and C fibres.
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mmHg
0
75
0
10s
Morphologically there are different types of
bladder afferents. Fibres, presumably sensory
fibres associated with the urothelium, can
express different markers [29]. For example,
fibres co-expressing neurofilament protein,
calcitonin gene-related peptide and substance
P form one population of fibres, while fibres
expressing choline acetyl-transferase are
another [29]. Almost certainly a similar
heterogeneity of afferent fibre type will be
found associated with the muscle layers of the
LUT. It is also well known that the density of
sensory fibres differs in different regions. It
was reported that the bladder neck and trigone
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SENSORY OUTPUT FROM THE BLADDER: THE CONCEPT OF AFFERENT NOISE
FIG. 6. Possible interactions between the urothelium and suburothelial nerves, and the smooth muscle and
suburothelial nerves. The basic ideas underlying this system are that stimuli acting upon the urothelial
epithelium (stretch or H+ acting via vallinoid receptors (VR1)) cause the release of active agents (NO, ATP,
prostaglandin and acetylcholine) which modulate the activity of afferent nerve fibres in the suburothelial
layer (see [31] for an overview, reprinted with permission). In addition there is the possibility that deformation
of the urothelium directly affects the afferent nerve activity. Also, substances released from the smooth
muscle layer, e.g. tachykinins or growth factors, might affect the afferent nerves. The diagram also
incorporates the possible involvement of specialized cells in within the lamina propria (myofibroblasts:
see also [41,42]). These cells are closely apposed to the afferent nerves. It has been suggested that the
myofibroblasts might contract in the presence of urothelial-derived agents, such as ATP, so activating the
nerve endings by deformation so modulating sensation.
Efferent nerve
VR1
H+
P2X3
ATP
P2X1
sGC
Force
NO
ATP
ACh
M3
Interstitial Cells
This heterogeneity and complexity is also seen
in the dorsal root ganglia that contain the cell
bodies of the bladder afferents. There, the
neuronal cell bodies can be classified on
the basis of their size and the conduction
velocities of their axons, as well as the
expression of specific markers such as
neurofilament protein [28].
Thus, within each of the general classifications
based ion function (conduction velocity, Aδ and
C) subtypes of each can be identified based on
the expression of neuronal markers. Probably
conduction velocity is the least important of the
different functions. More important is the
location of the ending inside the bladder wall
(dome, neck, lateral parts; urothelium,
suburothelium,muscle,serosa)andthepresence
of receptors and neurotransmitters.
Afferent nerve
VR1
receive a higher density of sensory innervation
than the lateral wall and dome [30,31].
Stretch
FUNCTIONAL SUBTYPES
PAIN
M2
Urothelium
Smooth Muscle
Suburothelial space
FIG. 7. Non-voiding activity: the motor component of motor/sensory noise. Panel (A) is taken from [54], and
shows the responses seen in the first measurements from the bladder. Recording of respiration (R), bladder
activity (V), blood pressure (P) and a time marker are illustrated. Note the rhythmic bladder activity. (B) shows
a typical recording of the phasic activity in the cat (taken from [55], with permission). This activity was first
seen in 1892 and attributed to intrinsic activity being generated from within the bladder wall (Sherington,
1892) [45]. Note the changes in the frequency of the activity as the bladder fills, reaching a maximum just
before micturition occurs (M). (C) illustrates a recording on nonvoiding activity in the conscious rat. Different
patterns of activity can be seen at different times during the filling cycle, with increases in both frequency
and rate (taken from [56], with permission).
A
C
R
void
sensation
phase 0
phase II
phase I
phase III
V
P
T
B
VC
©
4 HD
M
5 cm H2O
vesicle pressure
1 HD 3 HD
cm H2O
30
15
400 sec
0
0
20
40
60 min
Some of the small unmyelinated afferent
fibres (C fibres) responded to excessive
stretch, cold and noxious stimuli (i.e. pain).
Distinct populations of C fibres have been
described that have a low threshold to stimuli
(LT fibres), high threshold fibres (HT fibres) and
fibres that do not respond to any apparent
stimuli, silent fibres [25,26,32]. These fibres
are generally considered to be signalling the
sensations related to pain.
MECHANOSENSITIVE FIBRES
In the 1950s Iggo [24] described afferent
fibres from the bladder that responded
responses to bladder distension (Fig. 5) [24].
These fibres appear to be mechanoreceptors
and are thought to be involved in signalling
bladder volume. The properties of these fibres
are complex. Some have been shown to
respond only at low volumes and some only
at high volume. In addition, some fibres
respond differently when the bladder is
filled at different rates [26,33]. The
relative importance of these different
mechanosensitive fibres is not known, but the
variety of sensitivities might function to
provide the integration centres in the CNS
with a wealth of information on bladder
volume and rate of urine accumulation.
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G I L L E S P I E ET AL.
A
B
300 nMαβMATP
300 nM arecaidine
10 cm H2O
30
cm H2O
20
10
100 sec
0
0.12
0.10
0.08
0.06
0.04
0.02
0
C
Fint
Fss
Bladder pressure cm H2O
More recent work described a complex
interaction between the urothelium and
afferent fibres. Upon stretch the urothelium
releases a range of substances: prostaglandin
[33], ATP [34], nitric oxide [35] and
acetylcholine [36], all recently reviewed [35].
The reason why the urothelium releases so
many different substances is unclear.
However, it has been shown that ATP can
modulate directly the firing of afferent
bladder nerves [37]. Although there is no
direct evidence, it has been argued that nitric
oxide can similarly modulate afferent nerve
activity [38]. Evidence in support of a
cholinergic modulation of afferent firing has
come from the observation that M3-specific
muscarinic antagonists influence voiding
frequency via a mechanism that does not
rely on receptors in the detrusor [2,3].
The mechanism is thought to involve
an acetylcholine-dependent activation of
afferent nerves [2]. Indeed it was shown that
the M3-specific antagonists tolterodine and
darifenacin can reduce bladder afferent firing
[39,40]. Thus, the current thinking is that this
urothelial system is involved in stretchinduced modulation of bladder afferent firing
and so sensations (Fig. 6) [41,42]. Such
mechanisms can be grouped together as
‘chemical’ modulators of afferent nerve
activity.
FIG. 8. Elements of the pharmacology of the mechanisms involved in the generation and modulation of
phasic activity in the isolated whole bladder. Upper panel: in the isolated unstimulated bladder, small
spontaneous transient rises in pressure occur, i.e. autonomous activity. Panel (A) shows that the autonomous
activity is dramatically modulated by cholinergic stimulation. Application of the cholinergic agonist
arecaidine produces an initial burst of high-frequency high-amplitude activity. After this burst there is a
period of reduced activity followed by a period of slow high-amplitude sustained activity [49], with
permission. The initial burst of activity is inhibited by subnanomolar concentration of M3-specific
antagonists, implying a central role for type M3 muscarinic receptors. Panels (B) and (C) illustrate that this
sustained activity can be influenced by ATP and adrenergic stimulation [51,52], with permission. The lower
panel is taken from [49] and shows diagrammatically the proposed subtypes and arrangement of interstitial
cells proposed to be involved in the generation and modulation of phasic activity in the bladder wall.
Transients/sec
UROTHELIAL ‘CHEMICALLY’
MODULATED FIBRES
5
10 µM noradrenaline
10
0
200 400 600
800 1000 1200 sec
5
0
0 200 400 600 800 1000 1200 sec
MYOFIBROBLAST-LINKED SENSORY FIBRES
M 3 > M2
Nerve fibres are found throughout the lamina
propria close to a cell type described as a
myofibroblast [41]. The myofibroblasts are
thought to have contractile properties such
that activation will result in movement and
stimulation of the local nerves [41]. These
myofibroblasts appear to form a syncitium
with cells connected via gap junctions [42].
Such an arrangement has been considered to
represent a further sensory system in the
bladder contributing to afferent outflow
(Fig. 6) [31,35,41,43]. However, how this
system operates in vivo remains to be
understood.
MOTOR/SENSORY FIBRES
There are also afferent fibres that adapt
rapidly to mechanical stretch (Fig. 5C) [24].
These fibres adapt so rapidly that they are
unable to signal slow changes in bladder
volume, such as occur during normal filling
1330
pacemaker
M2 > M3
cable network
N
M3
outer muscle layer
[24]. However, they are ideally suited to
respond to rapid stretches of the bladder wall.
Such activity occurs in the normal and
pathological bladder where local contractions
generate small pressure changes
accompanied by local stretches (Fig. 7)
[17,25,44]. It is this phasic motor activity that
generates phasic afferent discharges (Fig. 5)
[25,26,32]. The idea that such a motor/sensory
system existed in the bladder was first
proposed in the early part of the 20th century
[45,46]. It has also been know for some time
that this motor/sensory system has the
capacity to be modulated by different inputs.
Data from the cat showed that the amplitude
and frequency of this activity can be
influenced by sympathetic nerve inputs
[47,48]. Furthermore, data from the isolated
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JOURNAL COMPILATION
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2009 BJU INTERNATIONAL
SENSORY OUTPUT FROM THE BLADDER: THE CONCEPT OF AFFERENT NOISE
FIG. 9.
The concept of afferent noise: A
schematic diagrams illustrating
the major elements and specific
components of the mechanisms
involved in the generation of
afferent noise.
cortex
medulla
HT fibres
LT fibres
Silent fibres
1 Pain
Pain C fibres
2 Static mechanical
Stretch receptors Aδ/C
Strectch receptors
3 Chemical
Urothelial modulation
4 Mechanical
Myofirboblasts
cord
5 Motor/sensory Motor/sensory
CNS
Detrusor contraction
FIG. 10.
The details of the component
systems contributing to afferent
noise. Each element (1–5)
illustrates the component parts
of the systems involved: pain,
mechanosensitive, urothelial,
myofibroblasts and motor/
sensory. Also, the locations where
there is processing of information
are indicated (a–d), i.e. the
intramural ganglia, the spinal
cord, medulla and cortex.
CNS
3
urothelium
sub-urothelial
interstitial cells
PG
a
ganglia
ACh
NO
ATP
myofibroblasts
d
medulla
c
C afferents
1
C afferents
cord
Aδ and C afferents
b
in parallel – in series receptors
inhibitory
cortex
4
afferent
collaterals
volume
local
stretch
contraction
pacemaker
2
5
excitatory
cable network
muscarinic
muscle layer
M M
1
4
bladder suggest more complex regulatory
mechanisms associated with local inputs from
within the bladder, involving acetylcholine,
prostaglandins, ATP, noradrenaline, substance
P and calcitonin gene-related peptide [49–53]
(Fig. 8). Thus, this motor/sensory system has
the capacity to function as a modulated
system having both excitatory and inhibitory
input mechanisms.
THE CONCEPT OF AFFERENT NOISE
Together, these observations suggest that
there are different components to afferent
discharge: signals emanating from noxious
stimuli (pain); stretch-mediated signals
(mechanical, free nerves and those coupled to
myofibroblasts); signals modulated by
chemical release from the urothelium
(chemical); and signals generated in a
modulated motor sensory system (Fig. 9). We
now know a considerable amount about the
©
M3
different elements; some of the key factors
are elaborated in Fig. 10.
CONCLUSIONS
The volume of afferent information leaving
the bladder is potentially enormous and
consequently the CNS is constantly inundated
with what we now describe as ‘afferent noise’.
The outflow appears to come from different
sources that can be categorized based on the
mechanisms which underlie their generation,
modulation or function. They could equally be
categorized structurally and by the expression
of fibre-specific markers. How and when
the CNS chooses to use these different
components of afferent noise to trigger the
micturition reflexes or contribute to sensation
is unclear. Answering such questions
constitute the next series of challenges facing
functional urology.
This overview states the obvious: ‘the origins,
nature and modulation of the afferent output
from the bladder are complex’. We cannot
negate or oversimplify these complexities; we
must incorporate them when designing
experiments, analysing data, diagnosing
patients and devising and evaluating
treatment. If we do not we will not
understand how the bladder works and what
goes wrong.
Afferent information is available to the CNS
during both filling and voiding. Which aspects
of this afferent noise reach consciousness is
unclear, but introspection suggests that we
can probably access this peripheral input at
any time during filling to gauge bladder
volume. When this afferent noise reaches an
particular extent the sensations grow in
intensity and we interpret them as awareness,
desire, strong desire, urge and eventually pain.
We can use any of these sensations to start
seeking a place to void and then trigger the
micturition reflexes. In this view sensation is
constant but ever-increasing. The description
of ‘first sensation to void’, ‘second sensation
to void’ and ‘urge’ represents particular
sensations within this continuum, and
probably not the generation of a ‘pulse’ of
sensation from the periphery. This is an
important distinction, as it indicates perhaps
a better understanding of the mechanisms
generating bladder sensation. The key to this
apparent episodic sensation is the CNS, which
might choose to ‘put into the back of one’s
mind’ bladder sensations from the bladder so
as to concentrate on something else. Thus
sensation is generated in the periphery but
can be modulated centrally. Sensory outflow
from the bladder is available to the CNS
throughout filling, and so information on
bladder volume is constantly available to the
consciousness if we choose to be
introspective.
There are several points that should then be
emphasized:
• The CNS is constantly being inundated with
afferent noise during both the storage and
voiding phases of the micturition cycle.
• This afferent noise, useful in analysing the
state of the LUT, emanates from the length of
the tract, including specific regions within
the bladder wall, the bladder neck, trigone,
proximal urethra, urethra and the sphincters.
• Only a fraction of the afferent noise
will be used to generate sensation, other
components contribute to the plethora of
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G I L L E S P I E ET AL.
reflexes coordinating bladder filling, sphincter
regulation and voiding.
• Different systems involving afferent noise
are apparent: pain, mechanosensitive,
chemical and motor/sensory.
• Elements of the afferent noise-generating
systems can be altered by chemical and
environmental factors with the potential
to modulate peripheral sensation or the
sensitivity of reflex arcs. It is very likely that
sacral neuromodulation addresses and alters
this system.
Within this complexity must lie the answers
to fundamental questions about how the
bladder works and the origin of bladder
pathology, specifically clinical urge.
Importantly, it will be through an
understanding of this complexity that we will
eventually be able to better diagnose the
different elements of the condition and treat
it effectively for all patients.
4
5
6
7
8
9
ACKNOWLEDGEMENTS
Part of this work was supported by a BJU Int
Collaborative Research Award to GA van
Koeveringe and JI Gillespie. We are very
grateful to the BJU Int for their generous
support. We are also indebted to Professor
Karl-Erik Andersson for long and valued
discussion regarding the physiology and
pharmacology underlying sensation in the
bladder.
10
11
12
CONFLICT OF INTEREST
None declared.
13
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Correspondence: James I. Gillespie, The
Uro-physiology Research Group, Institute
of Cellular Medicine, The Medical School,
The University, Newcastle upon Tyne,
NE2 4HH, UK.
e-mail: [email protected]
Abbreviations: LUT, lower urinary tract; OAB,
overactive bladder.
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