Micturition Center Research Articles

Effects of pedunculopontine nucleus stimulation on human bladder function.

The pedunculopontine nucleus (PPN) is a deep brain stimulation target for Parkinson's disease (PD). Unilateral PPN stimulation has been described in a previous case report to provoke urinary frequency, urgency and detrusor overactivity, due to probable activation of the pontine micturition center. Our aim was to evaluate the effect of bilateral PPN DBS on urodynamic parameters and to investigate the likely mechanisms using probabilistic tractography. Six male PD subjects with bilateral PPN deep brain stimulators were recruited. Urodynamic bladder filling assessments were carried out with the stimulators ON and OFF. Two subjects also had diffusion-weighted and T1-weighted MRI scans performed and probabilistic tractography was carried out to describe white matter connections with the stimulated area. Five subjects completed urodynamic testing. PPN DBS did not give rise to detrusor overactivity or lower sensory thresholds during bladder filling. However, there was a significant increase in maximal bladder capacity with stimulation: mean bladder volume at maximal capacity was 199 mL (range 103-440) ON stimulation compared with 131 mL (range 39-230) OFF stimulation. Tractography demonstrated extensive connectivity to cortical and subcortical regions, some of which have been implicated in bladder control. Fiber pathways also passed close to the vicinity of the pontine micturition center. Bilateral PPN DBS did not have a detrimental effect on urodynamic filling parameters or produce detrusor overactivity, but did slightly increase maximal capacity. Possible mechanisms include long-range connectivity or local effects at the pontine micturition center.

Barrington's nucleus: Neuroanatomic landscape of the mouse “pontine micturition center”

AbstractBarrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the “pontine micturition center.” Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium‐sized Bar neurons located medial to the locus coeruleus (LC). Bar neurons express a GFP reporter for Vglut2, develop from a Math1/Atoh1 lineage, and exhibit immunoreactivity for NeuN. Many neurons in and around this core cluster express a reporter for corticotrophin‐releasing hormone (BarCRH). Axons from BarCRH neurons project to the lumbosacral spinal cord and ramify extensively in two regions: the dorsal gray commissural and intermediolateral nuclei. BarCRH neurons have unexpectedly long dendrites, which may receive synaptic input from the cerebral cortex and other brain regions beyond the core afferents identified previously. Finally, at least five populations of neurons surround Bar: rostral‐dorsomedial cholinergic neurons in the laterodorsal tegmental nucleus; lateral noradrenergic neurons in the LC; medial GABAergic neurons in the pontine central gray; ventromedial, small GABAergic neurons that express FoxP2; and dorsolateral glutamatergic neurons that express FoxP2 in the pLC and form a wedge dividing Bar from the dorsal LC. We discuss the implications of this new information for interpreting existing data and future experiments targeting BarCRH neurons and their synaptic afferents to study micturition and other pelvic functions.

Barrington's nucleus: Neuroanatomic landscape of the mouse "pontine micturition center".

Barrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the "pontine micturition center." Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium-sized Bar neurons located medial to the locus coeruleus (LC). Bar neurons express a GFP reporter for Vglut2, develop from a Math1/Atoh1 lineage, and exhibit immunoreactivity for NeuN. Many neurons in and around this core cluster express a reporter for corticotrophin-releasing hormone (BarCRH ). Axons from BarCRH neurons project to the lumbosacral spinal cord and ramify extensively in two regions: the dorsal gray commissural and intermediolateral nuclei. BarCRH neurons have unexpectedly long dendrites, which may receive synaptic input from the cerebral cortex and other brain regions beyond the core afferents identified previously. Finally, at least five populations of neurons surround Bar: rostral-dorsomedial cholinergic neurons in the laterodorsal tegmental nucleus; lateral noradrenergic neurons in the LC; medial GABAergic neurons in the pontine central gray; ventromedial, small GABAergic neurons that express FoxP2; and dorsolateral glutamatergic neurons that express FoxP2 in the pLC and form a wedge dividing Bar from the dorsal LC. We discuss the implications of this new information for interpreting existing data and future experiments targeting BarCRH neurons and their synaptic afferents to study micturition and other pelvic functions.

P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice

The role of the P2Y6 receptor in bladder function has recently attracted a great deal of attention in lower urinary tract research. We conducted this study to determine contributions of the P2Y6 receptor in lower urinary tract function of normal phenotypes by comparing P2Y6-deficient mice and wild-type mice. In in vivo experiments, P2Y6-deficient mice had more frequent micturition with smaller bladder capacity compared to wild-type mice; however, there was no difference between these groups in bladder-filling pressure/volume relationships during cystometry under decerebrate, unanaesthetized conditions. Analysis of in vivo bladder contraction revealed significant difference between the 2 groups, with P2Y6-deficient mice presenting markedly shorter bladder contraction duration but no difference in peak contraction pressure. However, analysis of in vitro experiments showed no P2Y6 involvements in contraction and relaxation of bladder muscle strips and in ATP release by mechanical stimulation of primary-cultured urothelial cells. These results suggest that the P2Y6 receptor in the central nervous system, dorsal root ganglion, or both is involved in inhibition of bladder afferent signalling or sensitivity in the pontine micturition centre and that the receptor in the detrusor may be implicated in facilitation to sustain bladder contraction force.

MP82-11 THE MOLECULAR BIOLOGIC STUDY ABOUT THE CIRCADIAN RHYTHMIC CONTROL OF MICTURITION FUNCTION

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology II1 Apr 2017MP82-11 THE MOLECULAR BIOLOGIC STUDY ABOUT THE CIRCADIAN RHYTHMIC CONTROL OF MICTURITION FUNCTION Su Jin Kim, Young Sam Cho, and Khae Hawn Kim Su Jin KimSu Jin Kim More articles by this author , Young Sam ChoYoung Sam Cho More articles by this author , and Khae Hawn KimKhae Hawn Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2558AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We investigate the relationship between circadian rhythm and water metabolism and expression of circadian clock gene in peripheral bladder and central micturition centers. METHODS Normal mouse (C57BL/6J male; WT) and circadian gene knock-out mouse (per1-/-per2-/-; PDK) was used. Water intake and urine output according to the circadian rhythm was checked using metabolic cage in 12:12 LD photoperiodic cycle (LD cycle) and constant dark cycle (DD cycle) in both WT and PDK. Circadian clock gene expression rhythm in bladder was evaluated with the activation of Per2 promotor. Circadian expression of representative clock gene was analysed; Bmal1 and Rev-erba and rhythmic expression of circadian clock gene was analysed according to time in three main functional tissue related with micturition (detrusor smooth muscle, sphincter smooth muscle and urothelium) in both WT and PDK. Expression of clock gene in central micturition center was analysed; lumbar spinal cord, pontine micturition center (PMC) and ventrolateral periaqueductal gray (vlPAG), real-time RT-PCR was used in every 3 hours for 24 hours in DD cycle in both WT and PDK. RESULTS Water intake and urine output was increased in night-time of WT in LD and DD cycle. However this tendency was disappeared to PDK. Water intake and urine output was increased in night-time of WT in LD cycle and DD cycle was disappeared in PDK and this means that circadian rhythm is due to endogenous circadian rhythm not outside environment. We can observe the activation of Per2 promotor approximately 24 hours of rhythm. And this finding represents that bladder peripheral clock was well functioned. In case of WT, characteristic circadian expression pattern of clock gene in all three tissues. On the contrary, 24 hours of promoter activated rhythm was not observed in PDK. In spinal level, unlike PDK, clock gene expression rhythm was observed in WT. But, there was no definite rhythmicity of circadian expression pattern of clock gene in the upper region of central micturition center like PMC and vlPAG. CONCLUSIONS Endogenous circadian rhythm in water intake and urine output is exist approximately 24 hours. Bladder peripheral clock gene is existed in main functional tissue related with micturition. But in terms of central micturition center, we can find circadian clock gene expression only in lumbar spinal cord. Further study about the reason why absence of circadian clock in upper central micturition center and finding other circadian control mechanism in upper micturition center is needed. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1101 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Su Jin Kim More articles by this author Young Sam Cho More articles by this author Khae Hawn Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP85-06 BRAIN NETWORKS CONTROLLING BLADDER FILLING AND VOIDING

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction I1 Apr 2017MP85-06 BRAIN NETWORKS CONTROLLING BLADDER FILLING AND VOIDING Hanneke Verstegen, John Mathai, Mark Zeidel, and Joel Geerling Hanneke VerstegenHanneke Verstegen More articles by this author , John MathaiJohn Mathai More articles by this author , Mark ZeidelMark Zeidel More articles by this author , and Joel GeerlingJoel Geerling More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2668AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lower urinary tract symptoms (LUTS) are common and poorly understood; treatment is often ineffective. Failure of neural control of bladder function likely contributes to LUTS symptoms in many patients. Prior studies have shown that the pontine micturition center (PMC) directly controls voiding. Within the PMC corticotropin releasing hormone neurons (PMCCRH) project axons directly to spinal sacral cord nuclei that control bladder contraction. Here we show that PMCCRH neurons are critical for voiding, and identify neurons, particularly in the ventrolateral periaqueductal gray (PAGVL) which directly modulate PMCCRH and alter voiding. METHODS We inject adeno-associated viruses expressing proteins in a Cre-dependent fashion into anatomically defined regions of mice expressing Cre recombinase in specific neural types, to cause highly selective expression of these probes in target neuron populations. We monitor conscious voiding with micturition video thermography (MVT), and CMG under anesthesia while monitoring/stimulating specific neuron groups. RESULTS Stimulating PMCCRH neurons using designer receptors exclusively activated by designer drugs (DREADDs) produces urinary frequency in awake mice and on anesthetized CMG. Also, ablating PMCCRH neurons by selective expression of diphtheria toxin A disrupts normal voiding and the normal CMG voiding reflex. To identify neurons which provide input to PMCCRH, we used modified rabies virus and cholera toxin B labeling of PMCCRH and confirmed our results with viral anterograde tracing. Afferents to PMCCRH are located in PAGVL, the preoptic area, the lateral hypothalamic area, and other sites. Because sacral afferents sensing bladder filling project to PAGVL we determined the impact of stimulating Glutamatergic or GABA-ergic neurons (PAGVLGLUT or PAGVLGABA) in this region. Chemogenetic or optogenetic stimulation of PAGVLGLUT neurons leads to voiding and detrusor contraction. By contrast, chemogenetic or optogenetic activation of PAGVLGABAinhibits voiding and delays detrusor contraction on CMG. CONCLUSIONS 1. PMCCRH are driver neurons for detrusor contraction/voiding. 2. PAGVLGLUT project to PMCCRH, and when fired drive voiding/detrusor contraction. 3. PAGVLGABA project to PMCCRH and inhibit voiding/detrusor contraction. PAGVL, which receives bladder-based sacral afferents, likely controls bladder filling, and is a potential target in efforts to control urge incontinence and urgency symptoms of LUTS. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1150 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hanneke Verstegen More articles by this author John Mathai More articles by this author Mark Zeidel More articles by this author Joel Geerling More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP85-07 FUNCTIONAL NEUROIMAGING OF URINE STORAGE AND VOIDING IN MICE

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction I1 Apr 2017MP85-07 FUNCTIONAL NEUROIMAGING OF URINE STORAGE AND VOIDING IN MICE Bryce MacIver, Aaron Grant, Timothy Pagliaro, David Alsop, John Mathai, and Mark Zeidel Bryce MacIverBryce MacIver More articles by this author , Aaron GrantAaron Grant More articles by this author , Timothy PagliaroTimothy Pagliaro More articles by this author , David AlsopDavid Alsop More articles by this author , John MathaiJohn Mathai More articles by this author , and Mark ZeidelMark Zeidel More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2669AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lower urinary tract symptoms (LUTS) are common and poorly understood; treatment is often ineffective. Failure of neural control of bladder function likely contributes to LUTS symptoms in many patients. Mice are continent and serve as excellent models of LUTS, in part because they can be manipulated genetically. To relate what is learned in mice to humans, we have developed functional MRI methods for mice which mirror those in humans. Such methods will allow us to compare directly the activation patterns of mouse and human brains during bladder filling and voiding, in normal and disease states. METHODS Mice are anesthetized with urethane and a catheter is implanted in the bladder dome. Blood Oxygen Level Detection Magnetic Resonance Imaging (BOLD-MRI) is carried out in a Bruker 9.4T magnet with a 4 element mouse brain phased array coil. A series of 2D multislice gradient echo-planar images are acquired every 2s, while the mouse undergoes cystometry. 25 slices are acquired with slices of 500µm, interslice distance 600µm and in-plane resolution of 250µm. Imaging occurs over a 45 minute time frame during which the mouse undergoes 10-15 voiding cycles (CMG). Data are analyzed with Statistical Parameter Mapping (SPM12) software using mouse brain adaptations. Linear modeling proceeds in 2 stages; first by providing a statistical map of the brain of individual animals and second by combining results across all animals in a group. RESULTS Preliminary results on female C57BL6/J (n =5) with a fixed effects analysis identified candidate regions across the brain with clear activation in the right Pontine Micturition Center (PMC) observed, which was confirmed by a region based random effects analysis. Negative contrast identified more extensive regions such as the periaqueductal gray and inferior colliculus with an indication that these regions are ″switched off″ during the transition to voiding. CONCLUSIONS Although technically challenging due to the small size, BOLD-MRI on mice is feasible and reveals regions of brain activation related to voiding cycles. Development of this technique along with fine mapping of brain circuits related to voiding will help define mechanisms of LUTS in mouse models that should be translatable to human disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1150 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Bryce MacIver More articles by this author Aaron Grant More articles by this author Timothy Pagliaro More articles by this author David Alsop More articles by this author John Mathai More articles by this author Mark Zeidel More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD70-01 EFFECTS OF WATER AVOIDANCE STRESS ON PERIPHERAL AND CENTRAL RESPONSES DURING BLADDER FILLING IN THE RAT

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology III1 Apr 2017PD70-01 EFFECTS OF WATER AVOIDANCE STRESS ON PERIPHERAL AND CENTRAL RESPONSES DURING BLADDER FILLING IN THE RAT Huiyi Harriet Chang, Zhuo Wang, Yunliang Gao, Rong Zhang, Daniel P Holschneider, and Larissa V Rodriguez Huiyi Harriet ChangHuiyi Harriet Chang More articles by this author , Zhuo WangZhuo Wang More articles by this author , Yunliang GaoYunliang Gao More articles by this author , Rong ZhangRong Zhang More articles by this author , Daniel P HolschneiderDaniel P Holschneider More articles by this author , and Larissa V RodriguezLarissa V Rodriguez More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3155AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chronic emotional stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitivity syndromes, such as interstitial cystitis/bladder painful syndrome (IC/BPS), which manifest as urinary frequency and bladder hyperalgesia, which have been shown to be highly responsive to stress. Given the significant overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function and its effects on regional brain activation during bladder filling. METHODS 16 adult female Wistar-Kyoto rats were randomized to 10-day WAS (n=8) or handled controls (n=8). On day 11, rats were evaluated by visceromotor reflex (VMR) for bladder hyperalgesia. VMR was obtained during isotonic bladder distention (0-40 cmH2O) with urethral occlusion. Cerebral perfusion was assessed during bladder distention (20 cmH2O) using [14C]-iodoantipyrine autoradiography with regional cerebral blood flow-related tissue radioactivity (rCBF) analyzed in 3-D reconstructed brains with statistical parametric mapping. RESULTS At 20 cmH2O, VMR significantly increased in WAS compared to controls. WAS animals compared to controls showed greater activation in cortical regions of the central micturition circuit, with seed analysis showing increased functional connectivity of the cingulate to the parabrachial/Barrington nucleus complex (PBN), of the PBN to the thalamus and somatosensory and retrosplenial cortices, and of posterior insula to anterior secondary motor cortex. CONCLUSIONS The current study demonstrates how stress exacerbation of symptoms seen in the majority of patients with IC/PBS may be centrally mediated and gives us anatomic sites to further evaluate the biological mechanisms by which stress may induce or maintain bladder hyperalgesia and urinary frequency as well as a translational model to evaluate the molecular changes behind the brain differences seen in patients with IC/BPS. Collectively, our physiologic and brain mapping results suggest hypersensitivity during bladder filing in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency and the perception of bladder fullness, including viscerosensory perception and its relay to motor regions coordinating imminent bladder contractions. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1349 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Huiyi Harriet Chang More articles by this author Zhuo Wang More articles by this author Yunliang Gao More articles by this author Rong Zhang More articles by this author Daniel P Holschneider More articles by this author Larissa V Rodriguez More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effects of Combination Treatment of Alpha 1-Adrenergic Receptor Antagonists on Voiding Dysfunction: Study on Target Organs in Overactive Bladder Rats.

PurposeOveractive bladder (OAB) causes urinary urgency, usually accompanied by frequency and nocturia. Alpha 1-adrenergic receptor (α1-AR) antagonists are known to improve lower urinary tract symptoms associated with OAB. The α1-AR antagonists constitute a variety of drugs according to the receptor subtype affinity. This study investigated the efficacy of tamsulosin, naftopidil, and a combination of the two on OAB rats.MethodsThe OAB rat model was induced by an intraperitoneal injection of cyclophosphamide for 14 days. The experimental groups were divided into 5 groups: control group, OAB-induction group, OAB-induction and tamsulosin monotherapy group, OAB-induction and naftopidil monotherapy group, and OAB-induction and tamsulosin-naftopidil combination therapy group. For the drug-treated groups, each drug was administrated for 14 days after the OAB induction. Cystometry for urodynamic evaluation and immunohistochemical stain for c-Fos and nerve growth factor (NGF) expressions in the central micturition centers were performed.ResultsIncreased contraction pressure and time with enhanced c-Fos and NGF expressions in the central micturition centers were found in the OAB rats. Tamsulosin suppressed contraction pressure and time while inhibiting c-Fos and NGF expressions. Naftopidil showed no significant effect and combination therapy showed less of an effect on contraction pressure and time. Naftopidil and combination therapy exerted no significant effect on the c-Fos and NGF expressions.ConclusionsTamsulosin showed the most prominent efficacy for the treatment of OAB compared to the naftopidil and combination. The combination of tamsulosin with naftopidil showed no synergistic effects on OAB; however, further studies of addon therapy might provide opportunities to find a new modality.

Central Control Circuit for Context-Dependent Micturition

Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior.

Effects of Panax ginseng on the nerve growth factor expression in testosterone induced benign prostatic hyperplasia

The prostatic hyperplasia in benign prostatic hyperplasia (BPH) leads to obstructive micturition symptoms. Previous studies showed that pontine micturition center (PMC), ventrolateral periaqueductal gray (vlPAG), and medial preopticnucleus (MPA) regions in the brain have been known to regulate the urinary bladder function. The present study shows the influences of Panax ginseng on nerve growth factor (NGF) expressions in PMC, vlPAG, and MPA regions in the brain. Wistar rats were used for the present study. The rats split into four groups; 4 groups (n = 6) in control group, BPH-induced group, BPH-induced and P. ginseng-treated group, and BPH-induced and finasteride-treated group. BPH in rats was induced by testosterone and the animals were evaluated for NGF expression in PMC, vlPAG, and MPA regions in the brain. The NGF expression was identified using immunohistochemistry (IHC). The NGF expression by IHC showed spots with dark brown color. In our results, NGF expressions in PMC, vlPAG, and MPA regions in the brainstem of the BPH-induced group showed increase than the control animal. These increased NGF expressions in three regions were decreased using treatment with P. ginseng (200 mg/kg). These results suggest that P. ginseng has therapeutic effects on the symptoms of BPH and is associated with the regulation of NGF expression in the brain. In conclusion, the administration of P. ginseng helps nerve growth factor activation.

Central control of visceral pain and urinary tract function.

Afferent input from Aδ and C-fibres innervating the urinary bladder are processed differently by the brain, and have different roles in signaling bladder sensation. Aδ fibres that signal bladder filling activate a spino-bulbo-spinal loop, which relays in the midbrain periaqueductal grey (PAG) and pontine micturition centre (PMC). The excitability of this circuitry is regulated by tonic GABAergic inhibitory processes. In humans and socialised animals micturition is normally under volitional control and influenced by a host of psychosocial factors. Higher nervous decision-making in a social context to 'go now' or 'do not go' probably resides in frontal cortical areas, which act as a central control switch for micturition. Exposure to psychosocial stress can have profoundly disruptive influence on the process and lead to maladaptive changes in the bladder. During sleeping the voiding reflex threshold appears to be reset to a higher level to promote urinary continence. Under physiological conditions C-fibre bladder afferents are normally silent but are activated in inflammatory bladder states and by intense distending pressure. Following prolonged stimulation visceral nociceptors sensitise, leading to a lowered threshold and heightened sensitivity. In addition, sensitization may occur within the central pain processing circuitry, which outlasts the original nociceptive insult. Visceral nociception may also be influenced by genetic and environmental influences. A period of chronic stress can produce increased sensitivity to visceral pain that lasts for months. Adverse early life events can produce even longer lasting epigenetic changes, which increase the individual's susceptibility to developing visceral pain states in adulthood.

New pharmacological approaches against chronic bowel and bladder problems in paralytics.

Spinal cord injury (SCI) leads generally to an irreversible loss of sensory functions and voluntary motor control below injury level. Cures that could repair SCI and/or restore voluntary walking have not been yet developed nor commercialized. Beyond the well-known loss of walking capabilities, most SCI patients experience also a plethora of motor problems and health concerns including specific bladder and bowel dysfunctions. Indeed, chronic constipation and urinary retention, two significant life-threatening complications, are typically found in patients suffering of traumatic (e.g., falls or car accidents) or non-traumatic SCI (e.g., multiple sclerosis, spinal tumors). Secondary health concerns associated with these dysfunctions include hemorrhoids, abdominal distention, altered visceral sensitivity, hydronephrosis, kidney failure, urinary tract infections, sepsis and, in some cases, cardiac arrest. Consequently, individuals with chronic SCI are forced to regularly seek emergency and critical care treatments when some of these conditions occur or become intolerable. Increasing evidence supports the existence of a novel experimental approach that may be capable of preventing the occurrence or severity of bladder and bowel problems. Indeed, recent findings in animal models of SCI have revealed that, despite paraplegia or tetraplegia, it remains possible to elicit episodes of micturition and defecation by acting pharmacologically or electrically upon specialized lumbosacral neuronal networks, namely the spinal or sacral micturition center (SMC) and lumbosacral defecation center (LDC). Daily activation of SMC and LDC neurons could potentially become, new classes of minimally invasive treatments (i.e., if orally active) against these dysfunctions and their many life-threatening complications.

Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats.

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.

Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury

Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)+ neurons in the autonomic nuclei and superficial dorsal horn in L6–S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)− and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH+ neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D2-like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH+ neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non-voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH+ cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH+ neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI.

Urological disturbance and its neuroanatomical correlate in patients with chronic brainstem stroke.

Few studies have depicted urological disturbances among patients with chronic brainstem stroke, and little is known about the exact location of the micturition center or its role in humans. The aim of the present study was to retrospectively investigate urological disturbances and their neuroanatomical correlates among consecutively admitted patients with chronic brainstem stroke. Urodynamic studies, brain images, and urological symptoms questionnaires were reviewed from consecutive patients suffering from brainstem stroke, who had been admitted to a stroke unit at a rehabilitation hospital between June 1, 2013 and January 31, 2015. For further comparison, consecutive data from urodynamic studies of patients with upper cervical spinal cord injury (admitted to a hospital between January 1, 2008 and January 31, 2015) were reviewed. Patients with chronic pontine stroke manifested more frequent detrusor underactivity, lower maximal detrusor pressure, and higher compliance than patients with upper cervical spinal cord injury. The most frequently involved lesions associated with detrusor underactivity were located around the central portion of the bilateral pons along the entire sagittal level. Urinary incontinence and symptoms associated with lower urinary tract dysfunction were reported in 10% and 95% of patients with brainstem stroke, respectively. No difference was found between genders or stroke subtypes in patients with brainstem stroke. The present study identified a relationship between chronic pontine stroke and detrusor underactivity. Thus, detrusor underactivity might be associated with lesions localized to central portions of the bilateral pons. The prevalence of lower urinary tract symptoms was also revealed to be high among patients with chronic brainstem stroke. Neurourol. Urodynam. 36:136-141, 2017. © 2015 Wiley Periodicals, Inc.

Gentle Mechanical Skin Stimulation Inhibits Micturition Contractions via the Spinal Opioidergic System and by Decreasing Both Ascending and Descending Transmissions of the Micturition Reflex in the Spinal Cord.

Recently, we found that gentle mechanical skin stimulation inhibits the micturition reflex in anesthetized rats. However, the central mechanisms underlying this inhibition have not been determined. This study aimed to clarify the central neural mechanisms underlying this inhibitory effect. In urethane-anesthetized rats, cutaneous stimuli were applied for 1 min to the skin of the perineum using an elastic polymer roller with a smooth, soft surface. Inhibition of rhythmic micturition contractions by perineal stimulation was abolished by naloxone, an antagonist of opioidergic receptors, administered into the intrathecal space of the lumbosacral spinal cord at doses of 2–20 μg but was not affected by the same doses of naloxone administered into the subarachnoid space of the cisterna magna. Next, we examined whether perineal rolling stimulation inhibited the descending and ascending limbs of the micturition reflex. Perineal rolling stimulation inhibited bladder contractions induced by electrical stimulation of the pontine micturition center (PMC) or the descending tract of the micturition reflex pathway. It also inhibited the bladder distension-induced increase in the blood flow of the dorsal cord at L5–S1, reflecting the neural activity of this area, as well as pelvic afferent-evoked field potentials in the dorsal commissure at the lumbosacral level; these areas contain long ascending neurons to the PMC. Neuronal activities in this center were also inhibited by the rolling stimulation. These results suggest that the perineal rolling stimulation activates the spinal opioidergic system and inhibits both ascending and descending transmissions of the micturition reflex pathway in the spinal cord. These inhibitions would lead to the shutting down of positive feedback between the bladder and the PMC, resulting in inhibition of the micturition reflex. Based on the central neural mechanisms we show here, gentle perineal stimulation may be applicable to several different types of overactive bladder.

A novel intracerebral hemorrhage-induced rat model of neurogenic voiding dysfunction: Analysis of lower urinary tract function

Neurogenic lower urinary tract dysfunction (NLUTD) is a major problem in patients with various neurological disorders, and may result in debilitating symptoms and serious complications, including chronic renal failure and recurrent urinary tract infections. Clinically, stroke is associated with voiding dysfunction. However, lower urinary tract function evaluation in an intracerebral hemorrhage (ICH) model has not, to the best of our knowledge, been reported. Therefore, in the present study, lower urinary tract function in ICH-induced rats was investigated and the results were compared with those obtained in normal rats. The effects of ICH on peripheral bladder function and central micturition centers [medial preoptic area, ventrolateral gray, pontaine micturition center and spinal cord (lumbar 4 (L4)-L5)] were also examined. Adult female Sprague-Dawley rats were divided into two groups: Control ICH-induced. Induction of ICH in the hippocampal CA1 region was performed using a stereotaxic frame and type IV collagenase. The effects of ICH on the central micturition centers were investigated by simultaneously determining the extent of neuronal activation (c-Fos) and nerve growth factor (NGF) expression, and assessing voiding function (urodynamically using cystometry). The results revealed that induction of ICH significantly enhanced bladder contraction pressure and time, while simultaneously reducing voiding pressure and time. Furthermore, the c-Fos and NGF expression levels in the neuronal voiding centers were significantly increased in the rats with induced ICH as compared with the control rats. Therefore, this ICH-induced NLUTD rat model may be a more appropriate method to analyze NLUTD in stroke patients than a cerebral infarction model, as the former more accurately reflects the nature of the hemorrhage in the two types of stroke.

MP12-09 A NOVEL INTRACEREBRAL HEMORRHAGE-INDUCED RAT MODEL OF NEUROGENIC VOIDING DYSFUNCTION: ANALYSIS OF LOWER URINARY TRACT FUNCTION

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research II1 Apr 2015MP12-09 A NOVEL INTRACEREBRAL HEMORRHAGE-INDUCED RAT MODEL OF NEUROGENIC VOIDING DYSFUNCTION: ANALYSIS OF LOWER URINARY TRACT FUNCTION Young Sam Cho, Kwan Joong Joo, Heung Jae Park, and Chil Hun Kwon Young Sam ChoYoung Sam Cho More articles by this author , Kwan Joong JooKwan Joong Joo More articles by this author , Heung Jae ParkHeung Jae Park More articles by this author , and Chil Hun KwonChil Hun Kwon More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.784AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clinically, stroke is known to be associated with voiding dysfunction. However, lower urinary tract function evaluation in an intracerebral hemorrhage (ICH) model has not been reported. Therefore, we investigated lower urinary tract function in ICH-induced rats and compared the results to those obtained in normal rats. METHODS Adults female Sprague-Dawley rats were divided into two groups: a control group and an ICH-induced group. Induction of ICH in the hippocampal CA1 region was performed using a stereotaxic frame and type IV collagenase. After induction of ICH, we examined the effects of ICH on peripheral bladder function and central micturition centers (medial preoptic area; MPA, ventrolateral gray; PAG, pontaine micturition center; PMC, and spinal cord [L4-L5]). For this study, we simultaneously investigated the effects of ICH on central micturition centers by determining the degree of neuronal activation (c-Fos) and nerve growth factor (NGF) expression and assessing voiding function (urodynamic study using cystometry). RESULTS Induction of ICH significantly enhanced bladder contraction pressure and time, while simultaneously decreasing voiding pressure and time (Fig. 1). Moreover, c-Fos and NGF expression in the neuronal voiding centers was increased by induction of ICH compared to control rats (Fig. 2). CONCLUSIONS We confirmed that ICH clearly induced NLUTD like as other overactive bladder animal models, including a spontaneous hypertensive rat model, a rat model of dopaminergic brain lesions, and a cerebral infarction model. We suggest that our ICH-induced NLUTD rat model is a more appropriate method to study NLUTD in stroke patients than a cerebral infarction model, because the former animal model more accurately reflects the nature of the hemorrhage in both type of stroke. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e131 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Young Sam Cho More articles by this author Kwan Joong Joo More articles by this author Heung Jae Park More articles by this author Chil Hun Kwon More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD10-06 THE TENSION FREE VAGINAL TAPE VERSUS THE PUBOVAGINAL SLINGS FOR WOMEN WITH NEUROGENIC STRESS URINARY INCONTINENCE

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Neurogenic Voiding Dysfunction II1 Apr 2015PD10-06 THE TENSION FREE VAGINAL TAPE VERSUS THE PUBOVAGINAL SLINGS FOR WOMEN WITH NEUROGENIC STRESS URINARY INCONTINENCE Ahmed El-Azab and Sherif El-Nashar Ahmed El-AzabAhmed El-Azab More articles by this author and Sherif El-NasharSherif El-Nashar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.946AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There are little data in the literature about the use of the minimally invasive midurethral slings (MUS) in women with neurogenic stress incontinence (nSUI) due to spinal pathologies at or below sacral micturition center. We designed this clinical trial to compare the efficacy and safety of TVT and rectus fascia Pubovaginal sling (PVS) in treating SUI in women with LMNL presenting with SUI. METHODS This is a pilot nonrandomized clinical trial including women with SUI associated with pathology at below S2 spinal segment. Women were non randomly assigned into TVT or PVS groups. Failure was defined as leakage of urine during cough test at 250 mL bladder volume. Primary outcome was time to treatment failure based on positive cough stress test. Other outcomes included UDI6 IIQ7 and Urodynamics. Regression models were utilized to adjust for confounders. Time to failure was the endpoint for that outcome and Kaplan Meier curves were used to calculate the cumulative failure rate in each group. RESULTS 40 women were included; 20 TVT and 20 PVS. For primary outcome, 7 out of 40 (17.5%) women had positive cough stress test and were considered treatment failures. 4 (20%) in the TVT group and 3 (15%) in PVS group. The time to treatment failure in TVT group was comparable to the PVS group with an unadjusted hazard ratio of 2.90 (95%CI, 0.61, 15.42, long-rank test P value=0.154). At 2 year, the cumulative objective failure rate was 5.9% in TVT group compared to 0% at the PVS group. At 4 years, cumulative failure rate was 41.8% in TVT group compared to 25.4% in the PVS group. In both groups, there were significant reductions in UDI-6 and the IIQ-7 total scores. IWhile all patients in PVS group had PVR >150 mL after surgery and required CIC, 8 patients (53%) in TVT group had PVR <150 mL and did not require CIC after surgery. Out of the remaining 12 patients in the TVT group, 5 patients were utilizing CIC before surgery. The remaining 7 had De novo increased PVR (PVR>150) and required CIC after surgery. The prevalence of De novo urge urinary incontinence was significantly higher after TVT (30% n=6 women) than after PVS (10%, n=2). Urodynamics 1 year after operation in those patients with De novo urge symptoms reveal low compliance in 2 patients and unstable bladder contractions in 6 patients (4 in TVT and 2 in PVS group). CONCLUSIONS Both PVS and TVT can be used effectively and safely to treat women with nSUI associated with spinal pathology. While postoperative CIC is needed in all patients after PVS, de novo postoperative CIC after TVT can be avoided in 50% of patients. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e202 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed El-Azab More articles by this author Sherif El-Nashar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...