P
atients with an unstable bladder are defined urodynamically as demon-strating an uninhibitable elevation in intravesical pressure during bladder filling. These patients often share common symptoms, including urgency, frequency, urge incontinence, and nocturia, regardless of etiology. Urodynamics fails to discriminate among idiopathic, myogenic, and neuropathic causes. Moreover, 10%–45% of individuals with unstable bladder contractions may be asymptomatic.1Pathophysiology of Overactive
Bladder and Urge Urinary
Incontinence
William D. Steers, MD, FACS
Department of Urology, University of Virginia, Charlottesville, VA
Storage symptoms such as urgency, frequency, and nocturia, with or without urge
incontinence, are characterized as overactive bladder (OAB). OAB can lead to urge
incontinence. Disturbances in nerves, smooth muscle, and urothelium can cause
this condition. In some respects the division between peripheral and central
causes of OAB is artificial, but it remains a useful paradigm for appreciating
the interactions between different tissues. Models have been developed to mimic
the OAB associated with bladder instability, lower urinary tract obstruction,
neuropathic disorders, diabetes, and interstitial cystitis. These models share
the common features of increased connectivity and excitability of both detrusor
smooth muscle and nerves. Increased excitability and connectivity of nerves
involved in micturition rely on growth factors that orchestrate neural plasticity.
Neurotransmitters, prostaglandins, and growth factors, such as nerve growth
factor, provide mechanisms for bidirectional communication between muscle
or urothelium and nerve, leading to OAB with or without urge incontinence.
[Rev Urol
. 2002;4(suppl 4):S7–S18
]
© 2002 MedReviews, LLC
The bladder may be capable of only a limited repertoire of behaviors in response to disease. If that is the case, very different pathologic mech-anisms may manifest as the same symptom. Yet the similarity of the symptoms suggests that common factors may underlie the instability. Shared traits exhibited by unstable bladders from humans and those from animals include increased spontaneous myogenic activity, fused tetanic contractions, altered responsiveness to stimuli, and char-acteristic changes in smooth muscle ultrastructure (Figure 1). Examination of the peripheral innervation and the micturition reflex in models of OAB reveals consistent changes that include patchy denervation of the bladder, enlarged sensory neurons, hypertrophic ganglion cells, and an enhanced spinal micturition reflex. These shared features make it plausi-ble that regardless of the etiology, the underlying causative mechanisms are similar.
Electrical Properties of Unstable Detrusor
Smooth muscle from unstable bladders often shows enhanced spontaneous contractile activity. This has been documented in human bladder strips from obstructed unstable bladders2 and those patients with neuropathy.3 Altered responses are also seen to stimulation of the unstable detrusor
with agonists and to electrical stimu-lation. Yet there are subtle differences depending on etiology in the pat-terns exhibited in tissues from unsta-ble bladders. Obstructed bladders are supersensitive to muscarinic ago-nists and potassium chloride (KCl) (Figure 2). On the other hand, the obstructed detrusor has reduced con-traction on nerve stimulation.2,4,5 In idiopathic instability, bladder strips
show supersensitivity to KCl but not to muscarinic agonists, and reduced contractile response to electrical stimulation.6 Unstable strips may even be more easily activated by direct electrical stimulation of the smooth muscle,7showing contractions elicited by stimulation of nerves that are resistant to the nerve-blocking action of tetrodotoxin (TTX).
Smooth muscle bundles in normal detrusor are not as well coupled elec-trically as those in most viscera. Absent coupling implies that in vivo electrical activity can traverse the length of individual cells without the risk of inadvertently spreading and raising intravesical pressure. To com-pensate for the absence of coupling, dense innervation allows synchro-nous activation of the muscle and a rise in intravesical pressure during volitional voiding.
Compared to normal bladders, unstable bladders are better coupled electrically. This allows spontaneous electrical activity to spread and initiate synchronous contractions through-out the detrusor, which explains the fused tetanic contractions seen in unstable bladder strips. In the whole bladder, the increased excitability and greater connectivity of the smooth muscle create foci of electrical activity that could propagate and generate an uninhibited contraction.
Morphologic Changes in the Detrusor
Regardless of the etiology, unstable detrusor develops common changes in the macroscopic structure of the bladder. Unstable human bladders frequently show patchy denervation of the muscle bundles. Some muscle Smooth muscle from unstable bladders often shows enhanced spontaneous contractile activity.
Figure 1. Bladder smooth muscle from patients in unstable bladder demonstrates increased myogenic activity, with fused tetanic contractions and changes in structure. Increased connective tissue between muscle fascicles is reminiscent of that seen with aging, obstruction, and apoptosis due to ischemia. Thus, myogenic changes are commonly seen in the OAB with or without urge incontinence. Reprinted from Morrison J, Steers WD, Brading A, et al. Neurophysiology and neuropharmacology. In: Khoury S, Abrams P, Wein A (eds). Incontinence, 2nd ed. Plymouth, UK: Health Publication Ltd; 2002.
Enhanced coupling, tetanic contractions
fascicles may be completely dener-vated, while neighboring bundles appear normal. Other regions may show intermediate innervation.6–9 The areas of reduced innervation become infiltrated with connective tissue.7–9After complete denervation, hypertrophy of the smooth muscle cells occurs.9 At an ultrastructural level, a common feature in unstable detrusor is the presence of protrusion junctions and ultra-close abutments between the myocytes. This picture is rare in the normal detrusor and may represent the morphologic correlate to increased electrical coupling in unstable bladders.
Neuroplasticity
While myogenic mechanisms are in place to ensure that an inadvertent neural impulse does not trigger a detrusor contraction, the nervous system is designed to ensure that transmission occurs across synapses with a high degree of efficiency. Furthermore, the default mode seems to be to empty the bladder in response to injury or disease, consis-tent with a role in eliminating toxic waste. The ability of the nervous sys-tem to change transmitters, reflexes, or synaptic transmission with disease, injury, or changes in the environ-ment involves neuroplasticity. On the one hand, plasticity may shift the balance toward voiding. However, coexistent conditions such as ischemia may injure nerves so sensation is lost or damage to smooth muscle results in impaired contractility. The net effect could be clinical scenarios such as detrusor hyperactivity with impaired contractility (DHIC) or unstable contractions in the absence of sensation of urgency.
The concept of such a relationship among ischemia, obstruction, aging, and OAB is supported by a recent investigation demonstrating that blood flow to the detrusor smooth
muscle was reduced in proportion to the level of decompensation.10 Ischemia, aside from initiating apop-tosis of smooth muscle cells, damages intrinsic nerves. Neurons are more susceptible to ischemia than smooth muscle, and such damage is irre-versible. Neuronal degeneration is common in obstructed unstable blad-ders and may contribute to instability. The patchy denervation suggests the death of some of the intrinsic bladder neurons. Bladder ischemia may occur with severe obstruction or from peripheral vascular disease.4,6In the hypertrophied detrusor following
obstruction, increased metabolic
demands11 combined with reduced
blood flow can produce anoxia, triggering neuronal death. This could result from obstruction due to benign prostatic hyperplasia (BPH), urethral stricture, or detrusor-sphinc-ter dyssynergia.
Spinal cord transection and ure-thral obstruction produce bladder instability and an increase in size of both the afferent neurons in the dorsal root ganglia (DRG)12 and the efferent neurons in the pelvic plexus (after obstruction).13,14 After spinal injury, electrophysiologic measure-Cell membrane G-p G-p SR Ca2+ CAMP PIP IP3 DAG
ACh
Nerve terminal ACh AC Ca2+M2
M3
PLC Increased sensitivityFigure 2. Altered responses to stimuli occur in unstable bladders. Obstructed bladders demonstrate hypersensitivity to cholinergic agonists acting at muscarinic (M2or M3) receptors and increased contractions due to potassium chloride, but reduced electrical evoked contractions. Detrusor tissue from idiopathic instability patients shows increased electrical evoked contractions but normal sensitivity to muscarinic agonists (M3and M2). Denervated bladders show increased M3receptor expression. Acetylcholine released from parasympathetic nerves supplying the bladder cause activation of M3receptors responsible for bladder contraction in humans. The M3elicited contraction is due to a rise in cytosolic calcium (Ca+2) from intracellular stores. Ca+2is released from these stores following M
3-coupled activation of G-protein (G-p) mediated phospholipase C (PLC) breakdown. Inositol triphosphate (IP3) triggers Ca+2 release from sacroplasmic reticulum (SR). M2activation causes a fall in cyclic adenosine monophosphate (cAMP), preventing relaxation. Newer anticholinergics selectively target M3receptors in the hope of reducing side effects and perhaps increasing efficacy. Reprinted from Morrison J, Steers WD, Brading A, et al. Neurophysiology and neurophar-macology. In: Khoury S, Abrams P, Wein A (eds). Incontinence, 2nd ed. Plymouth, UK: Health Publication Ltd; 2002.
ments reveal a shorter delay in the central transmission of the micturi-tion reflex.15,16The micturition pathway is reorganized from a spinobulbospinal loop to a predominantly spinal net-work. Silent C-fiber (unmyelinated) afferents can trigger micturition in unstable bladders, although not in normal bladders. Such reorganization probably occurs in humans, because the ice water test that activates spe-cific cold-sensitive C-fibers fails to evoke micturition in normal subjects but does so in obstructed and neuro-pathic patients.17,18Moreover, intraves-ical administration of selective C-fiber neurotoxins such as capsaicin and resiniferatoxin often eliminates insta-bility.19It is plausible that the changes associated with OAB are the result of alterations in activity in the nerves controlling the detrusor.
Clinical observations provide a hint that urgency is a separate sensation from that of bladder fullness. Recordings from afferents during bladder filling and contraction20,21 have shown increased activity in a unimodal population of small
myeli-nated and unmyelimyeli-nated (A-delta and C) fibers in response to intravesical pressure and contraction (Table 1). This implies that there are in-series stretch receptors in the bladder wall whose activity correlates with the sensations of bladder filling and full-ness. However, it seems unlikely that fibers with such properties normally mediate the sensation of urgency. Normally the urgent desire to void disappears once voiding begins. Unstable pressure rises may also appear in the absence of sensation. It has been postulated that urgency is triggered by local distortions in the bladder wall, caused by heterogenous activity in some muscle bundles.22 This scenario could develop in normal bladders if a few low-threshold post-ganglionic parasympathetic neurons were activated by autonomous reflex at the termination of filling. Poor coupling between bundles in normal bladder ensures that such diffuse activity does not raise intravesical pressure. However, it might elicit enough local distortions to activate a subset of nerves that specifically
transduce the sensation of urgency. Enhanced coupling in the unstable bladder might permit a wave of dif-fuse activity, causing urgency and culminating in an involuntary con-traction. If coupling is absent, then urgency exists without an intravesical pressure deviation. This hypothesis would explain the efficacy of antimuscarinic drugs in urge incon-tinence. If only a fraction of ganglia were activated directly by the sensory nerves, suppression of their effects could eliminate both urgency at low volumes and the unstable contrac-tions. Urgency could also result from a lowering of the threshold or spon-taneous firing of afferents, as seen in interstitial cystitis (IC) and sensory urgency.
The molecular trigger for changes in the afferents or synaptic transmis-sion in the central nervous system (CNS) may be nerve growth factor (NGF), in addition to other neu-rotrophins (brain-derived neurotrophic factor, neurotrophins 3 and 4, glial-derived neurotrophic factor [GDNF]) and cytokines (Figure 3). NGF is
Table 1
Voltage-Gated Sodium Channel Subtypes in Nerves
Channel Previous Gene Chromosome Pharmacology KO Phenotype Abundance in
Name Symbol (human) Adult DRG
Nav1.1 Type I SCN1A 2q24 TTX-s Present
Nav1.2 Type II SCN2A 2q23–24 TTX-s Lethal Present
Nav1.3 Type II SCN3A 2q24 TTX-s Up-regulated
in axotomy
Nav1.4 SkM SCN4A 17q23–25 TTX-s Absent
Nav1.5 Cardiac SCN5A 8p21 TTX-r Absent
Nav1.6 NaCh6 SCN8A 12q13 TTX-s Abundant
Nav1.7 PN1 SCN9A 2q24 TTX-s Abundant
Nav1.8 SNS/PN3 SCN10A 3p21–24 TTX-r Partial analgesia Abundant
Nav1.9 NaN SCN11A 3p21–24 TTX-r Abundant
Nax NaG SCN6A/7A 2q21–23 TTX-? Altered salt intake Present
responsible for the growth and main-tenance of sympathetic and sensory neurons and has been shown to be responsible for neuronal regrowth after injury. NGF is elevated in the bladders of some models of OAB and in those of patients with BPH or IC and idiopathic detrusor instability. In animal models of partial urethral obstruction, chemical cystitis, and spinal cord injury (SCI), pretreatment with antibodies against NGF or its receptor prevents urinary frequency and unstable contractions (Figures 4 and 5). Conversely, intravesical NGF causes unstable detrusor contrac-tions. Gene therapies delivering NGF reverse sensory defects in animal models of diabetes. Blockade of NGF also prevents shared features of neu-roplasticity, such as enhanced reflex activity, increased growth-associated protein 43 (GAP-43) expression in the dorsal horn of the spinal cord, and hypertrophy of DRG neurons, in these models. Taken together, these observations suggest that NGF orchestrates some of the neuronal events leading to OAB.
Molecular Basis for Plasticity Due to NGF: Sodium Channel Isoforms
How could NGF produced by a target tissue, as in SCI, obstruction, and inflammation, and then retrogradely transported to the DRG lead to OAB? Recent data suggest that membrane conductance and thus excitability of DRG neurons are altered in models
associated with increased access to NGF. This altered conductance is postulated to result from changes in the structure or combination of pro-tein subunits of sodium (Na+) and
potassium (K+) channels in the cell membrane. A change in Na+ channel isoform appears sufficient to change the properties of afferents. NGF is known to lower the threshold for fir-ing of bladder neurons (hypothetical lower volume threshold for voiding) and induce spontaneous and burst firing (hypothetical unstable
contrac-tions, urgency).23The site of abnormal ectopic firing has been determined to be the DRG, and the firing appears to be due to changes in the isoforms for voltage-gated Na+ channels, which
causes spontaneous ectopic discharges. Voltage-gated Na+channels generate currents during the upstroke of the nerve action potential and are involved in the propagation of the nerve impulse.
TTX binds to and inactivates volt-age-gated Na+channels. Most voltage-gated Na+ channels exhibit rapid inactivation kinetics and sensitivity to nanomolar concentrations of TTX. These Na+channels are termed TTX-sensitive (TTX-S) (Table 1). Small bladder sensory neurons in the L6-S1 DRG show two types of Na+currents, a rapidly inactivating TTX-S sodium current (INa) and a slowly inactivating
TTX-resistant (TTX-R) INa.
As neurons switch from a quies-cent state to high-frequency firing,
UROTHELIUM URINE Neurokinin A Inflammatory Mediators Smooth Muscle P2X3 ATP trk-A Force Stretch NO VR1 Capsaicin H+ VR1 NGF NK-2
Figure 3. The urothelium directly communicates with suburothelial afferents acting as luminal sensors. Increased sensitivity of these afferents may lead to overactive bladder (OAB). Low pH, high potassium concentration in the urine, and increased osmolality can influence sensory nerves through mediators such as nitric oxide (NO) and neurokinin A, which acts through NK-2 receptors. H+ions activate vanilloid (VR-1) receptors, causing pain. Adenosine triphosphate (ATP) can activate purinergic P2X3receptors and modulate sensation. Mice lacking the P2X3receptor exhibit enlarged bladders and reduced sensation. Inflammatory cytokines and nerve growth factor (NGF) acting at tyrosine kinase A (trk A) receptors can influence the growth, transmitter synthesis, and function of neurons. Sensitization of suburothelial afferents without changes in smooth muscle may result only in urgency. If afferents are sensitized (lower thresholds, spontaneous burst firing) and smooth muscle coupling is enhanced, urgency with unstable contractions may result. Vanilloid, neurokinin, and purinergic antagonists are being examined as possible therapies for OAB and urge incontinence. Reprinted from Morrison J, Steers WD, Brading A, et al. Neurophysiology and neuropharmacology. In: Khoury S, Abrams P, Wein A (eds). Incontinence, 2nd ed. Plymouth, UK: Health Publication Ltd; 2002.
Recent data suggest that membrane conductance and thus excitability of DRG neurons are altered in models associated with increased access to NGF.
as with reawakening of C-fibers, they use their Na+ channels differently. But does DRG express a different repertoire of Na+ channels? There is extensive evidence to suggest that subunits forming the pore of the Na+ channel change in response to envi-ronmental conditions and changes in access to NGF. This scenario has been called environmental plasticity
associated with channelopathy. Afferents are the early warning system for the bladder. Yet a sub-stantial number fail to respond to normal environmental stimuli: 61% of sensory nerves innervating the rat bladder are unmyelinated C-fibers, according to findings based on con-duction velocities of single dorsal root fibers. The remaining nerves are
lightly myelinated A-delta fibers. While 61% of bladder afferents (both A-delta and C) respond to distention of the bladder, no less than a third fail to respond to any mechanical or chemical stimuli. It is tempting to speculate that some forms of OAB derive from recruitment of silent C-fiber afferents. The early warning system is put on full alert. Understanding the switch from quies-cent to activated afferents may be the key to understanding OAB and why anticholinergic drugs are not uni-formly effective in treating urgency, frequency, and urge incontinence.
Thirty percent of DRG neurons give rise to A-delta fibers that exhibit pre-dominantly TTX-S Na+ currents and are responsible for normal voiding. These cells show low thresholds and short-duration action potentials. At least 60% of bladder DRG neurons are capsaicin sensitive and express the vanilloid receptor (VR-1) (Table 2). Of these DRG neurons, 95% give rise to C-fibers.24The TTX-R Na+currents are present in small DRG neurons that are immunoreactive for
sub-Spinal cord injury
NGF Detrusor overactivity Obstruction Inflammation NGF antibody prevents plasticity Altered Na channel expression/function C-fiber reawakening Figure 5. After transient environmental (ie, intravesical)
changes such as inflammation or temporary obstruction, afferents may revert to normal activity. However, if patient is genomically predisposed to OAB (eg, exhibits familial urge incontinence or chronic pain syndromes such as interstitial cystitis, irritable bowel syndrome, or fibromyalgia) or long-term environmental changes occur, nerve growth factor (NGF) may alter afferents irreversibly. Antibody to NGF or fusion protein against the NGF receptor prevents overactive bladder (OAB) in animal models coincident with alterations in afferents. NGF’s long-term actions may rely on changes in sodium (Na+) channel isoforms expressed by afferents that influence excitability. Most unmyelinated (C-fiber) afferents are not responsive to normal stimuli such as distention or pres-ence of intravesical contents. However, following spinal cord injury, obstruction, or inflammation, activation of the silent C-fibers occurs. The reawakening of silent C-fibers may correspond to changes in Na+channel expression. Novel approaches to OAB in the future may target the mechanisms leading to these long-term changes. Reprinted from Morrison J, Steers WD, Brading A, et al. Neurophysiology and neuropharmacology. In: Khoury S, Abrams P, Wein A (eds). Incontinence, 2nd ed. Plymouth, UK: Health Publication Ltd; 2002.
Afferent plasticity
bladder
Irritated, obstructed Sacral spinal cord
Dorsal horn interneuron Preganglionic neuron Parasympathetic postganglionic neuron
Enhanced synaptic transmission
Recruitment of lower-threshold, spontaneously firing afferent
Figure 4. Sensitization of bladder afferents such as occurs following obstruction or inflammation may lead to enhanced transmission involv-ing second-order neurons in the sacral spinal cord. If pre-ganglionic neurons are not activated, then urgency and frequency without unstable contractions may result. Reprinted from Morrison J, Steers WD, Brading A, et al. Neurophysiology and neu-ropharmacology. In: Khoury S, Abrams P, Wein A (eds).
Incontinence, 2nd ed. Plymouth, UK: Health Publication Ltd; 2002.
stance P and calcitonin gene-related peptide (SP/CGRP), express trk-A, and give rise to C-fibers supplying the bladder.24,25More than 85% of Na+ currents in small-diameter (C-fiber) DRG neurons corresponding to blad-der retrogradely labeled cells exhibit predominantly TTX-R currents. These TTX-R cells demonstrate high thresh-olds and long-duration action poten-tials and likely contribute to the higher thresholds for C-fibers. After SCI, obstruction, or cystitis, enhancement of spinal reflexes has been confirmed by abolishment with capsaicin and a positive ice-water test clinically.26 Plasticity occurs in
TTX-S and TTX-R Na+ channels as
well as in potassium (K+) channels in DRG neurons after SCI, obstruction, or cystitis. With SCI, 60% of dissoci-ated bladder DRG neurons exhibit
TTX-S Na+ currents, compared to
30% of such neurons in intact rats.27 IA K+ (low-conductance potassium) currents are also postulated to be reduced, preventing membrane relaxation. These two changes lead to enhanced excitability of C-fibers coinciding with development of a spinal micturition reflex. With cyclophosphamide cystitis, slowly inactivating IA currents in TTX-R
neurons are reduced, possibly leading to OAB.27 As further evidence for a channelopathy contributing to OAB, antisense but not sense deoxy-oligonucleotides against the (Nav1.8)
Na+ channel (TTX-resistant) reduce urinary frequency and unstable con-tractions in cyclophosphamide cystitis and bladder outlet obstruction and, in a model of idiopathic instability/ attention deficit disorder/hyperten-sion, the spontaneously hypertensive
rate (SHR).28,29 It is tempting to spec-ulate that the cellular basis for this plasticity is a change in Na+currents. The molecular basis for this plasticity may be a change in the expression or function of Na+ and K+ channel iso-forms. The trigger for plasticity may be NGF or other signaling molecules. There is clinical evidence that Na+ channels play a role in OAB and can be manipulated to treat urgency and frequency. The local anesthetic and
nonselective Na+ channel blocker lidocaine can be used to reduce the symptoms of OAB in a variety of conditions, including BPH. Intravesical lidocaine blocks sensory nerve trans-mission from the human bladder; like subcutaneous lidocaine, it may preferentially act on C-fibers. These are the afferents that give rise to pathologic reflexes such as the ice-water test.30 Intravesical lidocaine increases bladder capacity and
reduces involuntary contractions. In a small, uncontrolled study of elderly patients with detrusor instability, the oral Na+ channel blocker mexiletine improved or cured urge incontinence.31 The effects of these agents vary with the disease. Perhaps alterations in Na+ channel expression within nerves are limited to certain types of conditions leading to OAB. Differences in degree of innervation or access to drug could explain differential actions of nonselective local anesthetics that
block Na+ channels. In children
with neurogenic bladders due to myelodysplasia, Lapointe and col-leagues32 found that intravesical lidocaine decreased involuntary con-tractions in 58% of patients, but increased capacity in 71% of subjects by nearly 60%. Lidocaine increases bladder capacity to the greatest degree in spinal cord–injured patients (230%) compared to its effect in supraspinal neurologic conditions and BPH.33 The first of these condi-tions is associated with a C-fiber reflex. A reduction in involuntary detrusor contractions is seen only in the first two conditions but not in
Table 2
Unmyelinated C-Fiber Terminals in Spinal Cord
Peptidergic Nonpeptide
NF –
NF-60% bladder C-fibers 10% bladder C-fibers
IB4 – IB4/FRAP +
SP/CGRP
Trk A-NGF responsive Trk B-BNDF responsive
VR1 VR1/P2X3
Laminae I/II Inner laminae II
Projection 2ndorder to 2ndorder interneurons in
brainstem/thalamus spinal cord
NF, neurofilament; IB isolectin; SP, substance P; CGRP, calcitonin gene-related peptide; VR, vanilloid receptor; FRAP, fluorescent acid phosphatase; Trk, tyrosine kinase receptor; P2X3, P2X3 purinergic receptor; BDNF, brain-derived neu-rotrophic factor; NGF, nerve growth factor.
A substantial number of afferent neurons fail to respond to normal envi-ronmental stimuli.
BPH. In contrast, Reuther and col-leagues34 found that elimination of detrusor instability in BPH patients after intravesical lidocaine was pre-dictive of cure of symptoms after transurethral resection of the prostate. In rabbits with obstructed bladders, intravesical lidocaine but not anticholinergics, potassium channel openers, or calcium channel antagonists inhibited hyperreflexia.35 Lidocaine eliminates pain associated with intravesical capsaicin, indicating its ability to inhibit VR-1–expressing afferents found beneath the urotheli-um. In contrast, intravesical TTX fails to block intravesical capsaicin-induced abdominal licking (a behavioral manifestation of bladder pain) in rats, implying that VR-1–expressing
bladder afferents are TTX-R.36
However, targeting Na+ channels
expressed by suburothelial nerves may not be as effective as blocking those expressed by spinal nerves. Na+ channels may congregate at points of contact with second-order neu-rons in the spinal cord. Intrathecal lidocaine and especially bupivacaine eradicate urinary urgency and increase bladder capacity.37 These varied susceptibilities to Na+ block-ade suggest that manipulation of Na+ channels expressed by spinal nerves or afferents could influence some disorders of micturition.
Specific Conditions Outlet Obstruction
The development of a spinal micturi-tion reflex with subsequent OAB occurs in other conditions besides SCI. Bladder outlet obstruction elicits enhancement of a spinal reflex.38 In humans with obstructed bladders, a capsaicin-sensitive spinal reflex can be detected using the ice-water test.39 Urethral obstruction stimulates increased expression of GAP-43, associated with axonal sprouting fol-lowing injury (Figure 4).40 These
observations imply de novo develop-ment of new spinal circuits following obstruction. Conversely, relief of obstruction is associated with the reduction of urinary frequency and reversal of these neural changes.40,41 This neuroplasticity persists in ani-mals that fail to revert to normal voiding after relief of obstruction.41 Nevertheless, these findings are not mutually exclusive of changes in bladder smooth muscle that are also likely to participate in the develop-ment of OAB.42
Bladder outlet obstruction initiates morphologic and electrophysiologic plasticity in afferents via NGF. NGF content is elevated in obstructed bladders in animals and humans, as well as in those with idiopathic instability.43,44 The increase in NGF content precedes the enlargement of bladder neurons and the development of urinary frequency.44 Moreover, blockade of NGF in obstructed ani-mals using autoantibodies prevents neural plasticity and urinary frequency (Figure 5).44
Inflammation
NGF has been shown to be increased in the bladders and urine of patients with IC and also in models of bladder inflammation in animals.45–47 Because NGF orchestrates events during the growth, maturation, and function of visceral afferents, one might antici-pate that inflammation of the urinary bladder would be accompanied by neuroplasticity in sensory nerves. Repeated inflammatory stimuli elicit enlargement of bladder DRG neurons.48 Inflammation reduces the activation threshold for bladder afferents.49 Likewise, intravesical NGF lowers the threshold for bladder afferents. Plasticity within the spinal cord may also occur. Chemical or mechanical inflammation of the urinary bladder increases expression of the early-immediate gene C-fos within the
lumbosacral spinal cord (Figure 4)50–52 in addition to overexpression of nitric oxide synthase in bladder DRG neurons.
Bladder overactivity induced by inflammation can be inhibited by a fusion protein that prevents interac-tion between NGF and its tyrosine kinase-A (trk-A) receptor (Figure 5).53 Hence, the neuroplasticity and the potential involvement of NGF in inflammatory conditions resemble those seen in obstruction.
Spinal Cord Injury
Insight into the mechanism underly-ing the increased mechanosensitivity of C-fibers after SCI has been gained by examining the DRG cells supplying the bladder. Plasticity in these affer-ents is manifested by enlargement of these cells54 and increased electrical excitability.55A shift in expression of Na+ channels from a high-threshold TTX-resistant type to a low-threshold TTX-sensitive type occurs after SCI.
Plasticity in bladder afferents after SCI may involve the retrograde transport of substances from either the spinal cord or the bladder to the DRG neuron. Bladder DRG neurons are responsive to a variety of neu-rotrophins, especially NGF, which has been associated with hypertrophy of bladder DRG cells in a variety of conditions. Indeed, prevention of increased NGF levels in SCI rats pre-vents hyperreflexia. Alternatively, GDNF may be especially important because a small population of DRG neurons giving rise to C-fibers is nonresponsive to NGF but responds to GDNF.56 It is worth noting that other neurogenic disorders associated with urge incontinence respond to intravesical capsaicin therapy, sug-gesting that plasticity in C-fiber afferents could form the neurogenic basis for bladder overactivity.57,58,26 The emergence of a spinal reflex cir-cuit activated by C-fiber bladder
afferents represents a positive feedback mechanism that may be unresponsive to voluntary control by higher brain centers. The net effect is involuntary urine leakage.
Depression, Anxiety, Attention Deficit Disorder, and OAB
It is probably too simplistic to view OAB with urge UI as just a myogenic or afferent disorder. Certain individ-uals seem predisposed to OAB. Circumstantial evidence suggests individuals with depression, anxiety, and attention deficit disorder may experience symptoms of OAB more often than the general population. Wolfe and colleagues59 suggested that depression, anxiety, feeding dis-turbances, pain, irritable bowel syn-drome, fibromyalgia, and changes in voiding are associated with distur-bances in brain circuits using specific neurotransmitters, in particular sero-tonin (5-hydroxytryptamine, or 5-HT). Fibromyalgia and irritable bowel syndrome are conditions seen more often in patients with IC than the general population,59–63 and these conditions are associated with OAB and possibly with depression, which provides a potential link with 5-HT metabolism. Perhaps the strongest evidence for diminished 5-HT function in depressed patients is the remarkable efficacy of selective serotonin uptake inhibitors (SSRIs) in this group of patients. In addition, neuropharma-cologic evidence indicates that some forms of depression are associated with abnormalities in the promoter for the serotonin transporter gene.64,65 5-HT also modulates pain and bladder function. Neurons originat-ing in the brainstem raphe nucleus synapse on visceral afferents and preganglionics in the thoracolumbar and sacral spinal cord. These neurons release 5-HT. Stimulation of raphe nuclei in the brain stem inhibits reflex bladder contractions.66 5-HT
and its precursors, uptake blockers, or 5-HT analogs inhibit bladder activity in a variety of species.67The actions of 5-HT are complex and mediated by over 13 different recep-tors. Some data suggest that 5-HT has a facilitating effect on voiding via modulation of bladder afferents, but intrathecal antagonists of 5-HT2
and 5-HT3 receptors reduce the
vol-ume threshold for voiding.68The lat-ter data suggest that descending 5-HT pathways tonically depress blad-der afferent input to the sacral spinal cord. Moreover, the 5HT2C agonists
MCPP and MK212 inhibit isovolu-metric rhythmic bladder contrac-tions.69,70Taken together, the pharma-cologic data suggest that 5-HT acting at some of the 13 receptors in the CNS inhibits micturition reflex path-ways. By analogy, a genomic pro-clivity toward reduced 5-HT neuro-transmission in the CNS may enhance bladder activity.
Because 5-HT influences both emotional states and bladder func-tion, are there shared conditions in which this monoamine is altered? An association between depression and bladder complaints has been report-ed. Zorn and colleagues71studied 156 consecutive patients presenting to an incontinence clinic and compared their rates of depression to those of a cohort of continent patients. Only 13% of patients with stress inconti-nence had depression, equivalent to the control cohort. In contrast, 42% of patients with mixed or urge incontinence had depression by his-tory and/or Beck Depression Inventory (BDI) scoring. Most notably, 60% of patients with idio-pathic urge incontinence had either undergone treatment for depression prior to the development of inconti-nence or scored in the depressive range on the BDI. In a cross-section-al population-based study of 133 incontinent women, Melville and
colleagues72 found that nearly a quarter of those with urge UI or mixed UI had depression but only 2% of those with stress incontinence did. These reports suggest that the association of depression with mixed or urge incontinence is significant, but not that with stress urinary incontinence. In the same study by Melville and associates,72 nearly a third of incontinent women had anx-iety or panic disorder, compared to none of those with stress UI.
Animal models for depression and anxiety demonstrate OAB. The spon-taneously hypertensive rat (SHR) is a useful animal model for studying hypertension, anxiety, and attention deficit disorder. SHRs void three times as frequently as genetic controls. Awake cystometrograms (CMGs) in SHRs demonstrates unstable contrac-tions. In humans, hypertension is reputedly a risk for OAB due to BPH.73 In addition, a significant proportion of probands with the genetic polymorphism for anxiety disorder have interstitial cystitis.74 Furthermore, many children with attention deficit disorder exhibit diurnal enuresis.75
5-HT can be depleted in the brain by neonatal treatment with clomipramine. Several months after this treatment, rats demonstrate behavioral responses consistent with depression. These animals also void more frequently and have more unstable contractions than controls do. In the clomipramine-treated and SHR models of depression and anxiety, respectively, reduced levels of 5-HT in the brain are associated with low-ered volume thresholds for voiding, with unstable bladder contractions. Interestingly, OAB persists in females but not in males following puberty in clomipramine-treated animals. These data support a link among altered 5-HT, emotional disorders, and OAB.
Gender
Recent reviews suggest that OAB and urge incontinence are more common in women than in men and that both conditions are more prevalent at times of changing hormonal levels in women.76Hormonally induced differ-ences in neurotransmitter systems (eg, by 5-HT) may explain this sexual difference in OAB in the nonelderly. Genetic, psychosocial and biologic factors seem to account for this sexual dichotomy. Estrogen and progesterone appear to influence bladder contrac-tions and voiding frequency.77Female hormones may also influence nerves. One target of estrogens in the CNS may be 5-HT neurons. This could again link 5-HT, emotional disorders, and OAB in the context of differ-ences between men and women. The serotonergic system plays a major role in depression, although there are other neurotransmitters involved. Differences in 5-HT function may explain why depression is more com-mon in women. Women may be pre-disposed to both OAB and depression in part because levels of 5-HT in the brain are substantially lower in women than in men.78When rates of 5-HT synthesis were measured in the human brain using PET, the mean rate of synthesis in normal males
was found to be 52% higher than in normal females.
By virtue of reduced 5-HT in the CNS, there may be fewer inhibitory mechanisms for autonomic events such as voiding. This could result in some women in a predisposition to OAB, depression, anxiety, eating dis-orders, and chronic pain states such as IC, fibromyalgia, and irritable bowel syndrome. The model is too simplistic to provide a universal explanation for all instances of OAB, but the pharmacogenomic basis for these shared traits merits further study.
Conclusion
Alterations in smooth muscle excitability and changes in bladder innervation orchestrated by neu-rotrophins manufactured by the detrusor are temporally linked with OAB. Direct proof in humans is diffi-cult to obtain, but circumstantial evidence is compelling. The ability of local anesthetics, intravesical afferent neurotoxins, and destruction of afferent nerves in the bladder neck and prostate to reduce urgency, fre-quency, and urge incontinence indi-cates an important role for afferent evoked reflexes.79 The detection of a spinal reflex (positive ice-water test) in patients with neurogenic bladders44
and obstruction24 suggests a shared underlying plasticity in nerves sup-plying the bladder. The molecular basis for this plasticity may be a channelopathy. In addition, genetic or hormonally induced discrepancies may explain the preponderance of OAB and urge UI in middle-aged women and in certain men. The real-ization that OAB may arise from nerves supplying the smooth muscle with a proclivity toward increased coupling with the detrusor or from altered urothelial function with dis-ease offers an avenue for therapeutic intervention.
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