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Objectives: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex., Methods: In urethane-anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM-3 (CO donor) or ZnPP (non-selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABA A receptor antagonist) or SCH50911 (GABA B receptor antagonist) on the CORM-3-induced response., Results: CORM-3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single-voided volume and bladder capacity without affecting MVP, post-voided residual volume, or voiding efficiency. The ZnPP-induced ICI shortening was reversed by CORM-3. The CORM-3-induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively., Conclusions: Brain CO can suppress the rat micturition reflex through brain γ-aminobutyric acid (GABA) receptors., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; -1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5-2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with β-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of β-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel β 3 -adrenoceptor agonist approved for the treatment of overactive bladder. However, how β 3 -adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease., Methods: In a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity., Results: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter-contraction interval (p < .05) and reduced voiding pressure (p < .01). However, no significant effects on urethral function were observed., Conclusions: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of β 3 -adrenoceptor agonists., (© 2023 John Wiley & Sons Australia, Ltd.)

We previously reported that brain α7 nicotinic acetylcholine receptors inhibited the rat micturition reflex. To elucidate the mechanisms underlying this inhibition, we focused on the relationship between α7 nicotinic acetylcholine receptors and hydrogen sulphide (H 2 S) because we found that H 2 S also inhibits the rat micturition reflex in the brain. Therefore, we investigated whether H 2 S is involved in the inhibition of the micturition reflex induced by the activation of α7 nicotinic acetylcholine receptors in the brain. Cystometry was performed in male Wistar rats under urethane anesthesia (0.8 g/kg, ip) to examine the effects of icv pre-treated GYY4137 (H 2 S donor, 1 or 3 nmol/rat) or aminooxyacetic acid (AOAA; non-selective H 2 S synthesis inhibitor, 3 or 10 μg/rat) on PHA568487 (α7 nicotinic acetylcholine receptor agonist, icv)-induced prolongation of intercontraction intervals. PHA568487 administration at a lower dose (0.3 nmol/rat, icv) had no significant effect on intercontraction intervals, while under pre-treatment with GYY4137 (3 nmol/rat icv), PHA568487 (0.3 nmol/rat, icv) significantly prolonged intercontraction intervals. PHA568487 at a higher dose (1 nmol/rat, icv) induced intercontraction interval prolongation, and the PHA568487-induced prolongation was significantly suppressed by AOAA (10 μg/rat, icv). The AOAA-induced suppression of the PHA568487-induced intercontraction interval prolongation was negated by supplementing H 2 S via GYY4137 at a lower dose (1 nmol/rat, icv) in the brain. GYY4137 or AOAA alone showed no significant effect on intercontraction intervals at each dose used in this study. These findings suggest a possible involvement of brain H 2 S in inhibiting the rat micturition reflex induced by activation of brain α7 nicotinic acetylcholine receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: This study aimed to determine whether a short-term repeated stimulation of tibial nerve afferents induces a prolonged modulation effect on the micturition reflex in a decorticated rat model., Material and Methods: Fifteen female Sprague-Dawley rats (250-350 g) were fully decorticated and paralyzed in the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 mL/min) at approximately ten-minute intervals were performed, and the micturition threshold volume (MTV) was recorded and used as a dependent variable. After four to five stable recordings, the tibial nerves of both sides were stimulated continuously for five minutes at 10 Hz and at an intensity of three times the threshold for α-motor axons. Six same stimulations were applied repeatedly, with an interval of five minutes between each stimulation. Mean MTV was calculated on the basis of several cystometries in each half-hour period before, during, and after the six repeated TNS., Results: During the experiment, all the animals survived in good condition with relatively stable micturition reflexes, and a significant increase in MTV was detected after TNS. The strongest effect (mean = 178%) was observed during the first 30 minutes after six repeated stimulations. This obvious threshold increase remained for at least five hours., Conclusions: A prolonged poststimulation modulatory effect on the micturition reflex was induced by short-term repeated TNS in decorticated rats. This study provides a theoretical explanation for the clinical benefit of TNS in patients with overactive bladder and suggests decorticated rats as a promising model for further investigation of the neurophysiological mechanisms underlying the bladder inhibitory response induced by TNS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The present study investigated the inhibitory effects of a novel minimally invasive implanted tibial nerve stimulation device on non-nociceptive bladder reflexes in cats., Materials and Methods: A wireless minimally invasive implanted nerve stimulator was implanted adjacent to the left tibial nerve in seven cats. Multiple cystometrograms (CMGs) were obtained to determine the inhibitory effects of tibial nerve stimulation (TNS) at different frequencies and intensities on the micturition reflex by infusing normal saline (NS)., Results: TNS at 6 Hz did not significantly change the bladder capacity (BC) compared to the control level at the intensity threshold (T), while TNS significantly (P < 0.05) increased the BC to 158.89 ± 20.57% of the control level at 2 T. When stimulated at 15 Hz, TNS did not significantly (P > 0.05) change the BCs at 1 T and 2 T., Conclusions: The minimally invasive implanted TNS device was shown to be effective in inhibiting the micturition reflex under physiologic conditions. Further studies are warranted to determine the inhibitory effects of TNS on nociceptive bladder reflexes.

We recently reported that hydrogen sulfide (H 2 S) is a possible relaxation factor in the rat bladder. However, there is no available information about the roles of central H 2 S in the micturition reflex, so we investigated the effects of centrally administered GYY4137 (H 2 S donor) and AOAA (H 2 S synthesis inhibitor) on the micturition reflex in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. Cystometry was performed before and after the administration of GYY4137 (3 or 10 nmol/rat, icv) or AOAA (30 or 100 μg/rat, icv). In some rats, SR95531 (GABA A receptor antagonist, 0.1 nmol/rat, icv) or SCH50911 (GABA B receptor antagonist, 0.1 nmol/rat, icv) was administered 30 min before GYY4137 administration (10 nmol/rat, icv). Centrally administered GYY4137 dose-dependently prolonged the intercontraction intervals (ICI) without altering maximum voiding pressure (MVP). On the other hand, centrally administered AOAA dose-dependently shortened ICI without altering MVP. The AOAA (30 μg/rat, icv)-induced ICI shortening was reversed in the central presence of GYY4137 (10 nmol/rat, icv). Centrally pretreated SR95531 or SCH50911 significantly attenuated the GYY4137 (10 nmol/rat, icv)-induced prolongation of ICI, respectively. These findings suggest that endogenous brain H 2 S can inhibit the rat micturition reflex via both GABA A and GABA B receptors in the brain., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mechanical stretch of the urothelium induces the release of ATP that activates bladder afferent nerves. In the rat urinary bladder, ATP is also a contractile co-transmitter in the parasympathetic innervation. In isolated preparations, ATP evokes a urothelial release of acetylcholine that substantially contributes to ATP-evoked contractile responses. Currently we aimed to further examine the interactions of ATP and acetylcholine in the rat urinary bladder in two in vivo models. In the whole bladder preparation, atropine reduced ATP-evoked responses by about 50% in intact but denervated bladders, while atropine had no effect after denudation of the urothelium. In a split bladder preparation, reflex-evoked responses of the contralateral half were studied by applying stimuli (agonists or stretch) to the ipsilateral half. Topical administration of ATP and methacholine as well as of stretch induced contralateral reflex-evoked contractions. While topical administration of atropine ipsilaterally reduced the ATP- and stretch-induced contralateral contractions by 27 and 39%, respectively, the P2X purinoceptor antagonist PPADS reduced them by 74 and 84%. In contrary, the muscarinic M2-(M4)-selective receptor antagonist methoctramine increased the responses by 38% (ATP) and 75% (stretch). Pirenzepine (M1-selective antagonist) had no effect on the reflex. In vitro, in the absence of the reflex, methoctramine did not affect the ATP-induced responses. It is concluded that urothelial ATP potently induces the micturition reflex and stimulates urothelial release of acetylcholine. Acetylcholine subsequently acts on afferents and on the detrusor muscle. While muscarinic M2 and/or M4 receptors in the sensory innervation exert inhibitory modulation, muscarinic M3 receptors cause excitation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats., Methods: Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs., Results: SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN-1, 0 µg] and 54.9% [SIN-1, 250 µg] during 15 minutes after SIN-1 administration [P < .05; η 2  = 0.59]) without affecting plasma noradrenaline or maximal voiding pressure. SIN-1 (250 µg/animal) reduced single-voided volume and bladder capacity without affecting post-voiding residual volume. The SIN-1 (250 µg/animal)-induced adrenaline elevation and ICI reduction were attenuated by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (carboxy-PTIO) (NO scavenger, icv) (ICI values; 44.7% [vehicle + SIN-1] and 77.5% [carboxy-PTIO + SIN-1] during 15 minutes after SIN-1 administration [P < .05; η 2  = 0.51]). Acute bilateral adrenalectomy abolished SIN-1-induced adrenaline elevation, while showed no effect on the SIN-1-induced ICI reduction. The ICI reduction was attenuated by MK-801 (NMDA receptor antagonist, icv) (ICI values; 47.0% [vehicle + SIN-1] and 87.6% [MK-801 + SIN-1] during 15 minutes after SIN-1 administration [P < .05; η 2  = 0.61]), but not by DNQX (AMPA receptor antagonist, icv)., Conclusion: Brain NO is involved in facilitation of the rat micturition reflex through brain NMDA receptors, independently of the sympatho-adrenomedullary outflow modulation., (© 2020 Wiley Periodicals LLC.)

Objectives: To identify the types of serotonin (5-hydroxytryptamine) receptors of the prefrontal cortex related to the micturition reflex., Methods: Female Sprague-Dawley rats and a microinjection method were used for this study. Stainless steel guide cannulas were implanted bilaterally into the prefrontal cortex, and a polyethylene catheter was inserted into the bladder. Cystometric parameters (intercontraction interval and maximum voiding pressure) were measured before and after injection of any one of six specific antagonists of 5-hydroxytriptamine receptors (5-hydroxytryptamine 1A, 5-hydroxytryptamine 2A, 5-hydroxytryptamine 2C, 5-hydroxytryptamine 3, 5-hydroxytryptamine 4 and 5-hydroxytryptamine 7) into the prefrontal cortex. The prefrontal cortex was divided into two regions, namely the prelimbic cortex and the infralimbic cortex. The experiments were carried out in conscious and free-moving rats., Results: The intercontraction interval value increased significantly after injection of the 5-hydroxytriptamine 2A receptor antagonist, MDL11939, into the prelimbic cortex of the rat prefrontal cortex (7.68 ± 1.28 vs 9.02 ± 1.41 min, P < 0.05), whereas the intercontraction interval value decreased significantly after injection of the 5-hydroxytriptamine 7 antagonist SB269970 into the prelimbic cortex (9.42 ± 0.39 vs 8.14 ± 0.71 min, P < 0.05). The intercontraction interval was unaffected by injection of either of these two antagonists into the infralimbic cortex. The other four antagonists (5-hydroxytryptamine 1A, 5-hydroxytryptamine 2C, 5-hydroxytryptamine 3 and 5-hydroxytryptamine 4) had no effect on the intercontraction interval after injection into the prelimbic cortex and the infralimbic cortex. The maximum voiding pressure was unaffected by injection of any one of the six 5-hydroxytriptamine antagonists into the prelimbic cortex and infralimbic cortex., Conclusions: In the rat prefrontal cortex5-hydroxytryptamine 2A receptors excite the micturition reflex, whereas 5-hydroxytryptamine 7 receptors inhibit this reflex., (© 2020 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Following identification as the endogenous ligand for the NOP receptor, nociceptin/orphanin FQ (N/OFQ) has been shown to control several biological functions including the micturition reflex. N/OFQ elicits a robust inhibitory effect on rat micturition by reducing the excitability of the afferent fibers. After intravesical administration N/OFQ increases urodynamic bladder capacity and volume threshold in overactive bladder patients but not in normal subjects. Moreover daily treatment with intravesical N/OFQ for 10 days significantly reduced urine leakage episodes. Different chemical modifications were combined into the N/OFQ sequence to generate Rec 0438 (aka UFP-112), a peptide NOP full agonist with high potency and selectivity and long-lasting duration of action. Rec 0438 mimicked the robust inhibitory effects of N/OFQ on rat micturition reflex; its action is solely due to NOP receptor stimulation, does not show tolerance liability after 2 weeks of treatment, and can be elicited by intravesical administration. Collectively the evidence summarized and discussed in this chapter strongly suggests that NOP agonists are promising innovative drugs to treat overactive bladder.

ATP in the suburothelial layer is released from the bladder urothelium by mechanical stimuli. ATP directly activates purinergic receptors that are expressed on primary bladder afferent neurons and induces the micturition reflex. Although ATP is also released to the bladder lumen from the bladder urothelium, the role of ATP in the bladder lumen is unknown. Recently, clinical studies have reported that urinary ATP levels are much higher in patients with an overactive bladder than healthy controls. These results suggest that ATP in the bladder lumen is also involved in the micturition reflex. In this study, we performed intravesical ATP instillation in the mouse bladder. We evaluated urinary function with novel reliable methods using improved cystometry and ultrasonography, which we previously established. We found that intravesical ATP instillation induced urinary frequency because of activation of bladder afferent nerves without inflammatory changes in the bladder or an increase in post-void residual urine. These results suggest that not only ATP in the suburothelial layer, but also ATP in the bladder lumen, are involved in enhancement of the micturition reflex., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to determine if the duration of the micturition reflex modulation could be prolonged by repeated periods of afferent stimulation in the decorticated rat., Methods: Eighteen female Sprague-Dawley rats were used for the study, 10 for intravesical electrical stimulation (IVES), and 8 for Ano-genital pudendal afferents stimulation. Repeated constant flow cystometries were performed with body-warm saline (0.06-0.1 mL/min) at about 10 min interval. The selected afferents were stimulated continuously for 5 min at maximal intensity. The same stimulation was repeated six times with a pause of 5 min between the stimulations. The mean threshold volume of cystometries performed during one hour before and each hour after the stimulation were compared., Results: After six periods of IVES, the micturition threshold volume decreased to its lowest value (62% of control) during the first hour and remained at 80% 4 h later (n = 10, P < 0.01). Ano-genital afferent stimulation produced a corresponding increase in the micturition threshold volume. The long-lasting poststimulation effect was again observed for more than 5 h. During the first hour the mean threshold volume increased to 211% of controls and it remained at about this level for the entire observation period (n = 8, P < 0.01)., Conclusions: Repeated short periods of stimulation prolonged the modulatory effect well beyond the stimulation period. The findings provide experimental evidence supporting the clinical application of IVES and ano-genital stimulation for treatment of neurogenic urinary bladder dysfunction., (© 2018 Wiley Periodicals, Inc.)

Electrical stimulation of peripheral nerves controlling the bladder is an alternative, nondestructive medical treatment for urinary incontinence and retention. In this study, we aimed to identify the most efficient sensory and motor spinal nerve roots involved in the micturition reflex. Unilateral L5-S2 dorsal and ventral roots were electrically stimulated, and bladder reflex contractions were recorded under isovolumetric conditions. Repeated stimulation of the L6 and S1 dorsal roots not only abolished bladder reflex contractions but also induced a poststimulation inhibitory effect, whereas repeated stimulation of the L5 and S2 dorsal roots had no effect. Only the L6 ventral root directly caused bladder contraction when ventral roots L5-S2 were stimulated in sequence. Upon retrograde tracing using pseudorabies virus (PRV), the sacral parasympathetic nucleus of the L6 segment had more PRV-positive cells than the other segments, though the S1 segment of the dorsal root ganglia had the highest density of PRV-positive neurons. These results suggest the L6 ventral root is most efficient in producing detrusor muscle contraction, and the S1 dorsal root best inhibits the micturition reflex., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.

Elderly patients suffering from lower urinary tract symptoms with benign prostatic hyperplasia (BPH) are widely prescribed α 1 -adrenoceptor blockers (α 1 -blockers) to improve voiding and storage symptoms. The mechanism of action for improvements in voiding symptoms is well understood; tonus of the urethra and prostate are decreased and urinary flow rate is increased by α 1 -blockers. However, the mechanisms underlying storage symptoms have remained unclear, although detrusor hyperactivity has been identified as a significant factor. Previous investigations have yielded informative results, such as amelioration of reduced blood flow and afferent C-fiber activation, and the importance of the urothelium. Recently, the fascinating role of α 1A - and α 1D -adrenoceptor subtypes have been investigated for bladder function. Furthermore, the scope of this pathology covers both the bladder and that part of the central nervous system related to the micturition reflex. This review describes the beneficial effects of α 1 -blockers on storage symptoms and the pathogenesis of storage symptoms related to BPH, discusses the mechanisms of action for α 1 -blockers with reference to results from cystometry to suggest improvements in management that suppress detrusor hyperactivity, and examines the potential influence of α 1A - and α 1D -adrenoceptor subtypes on bladder activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg)., Methods: A bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings., Results: PAG DBS at 2-2.5 V, PnO DBS at 2-2.5 V, and PPTg DBS at 1.75-2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5-5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions., Conclusion: PPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions., Significance: DBS could be a potential approach to manage bladder function under various conditions., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. Lower urinary tract symptoms in children include overactive bladder, voiding postponement, stress incontinence, giggle incontinence, and dysfunctional voiding. Gastrointestinal co-morbidities, including constipation or fecal incontinence, are commonly associated with lower urinary tract (LUT) symptoms in children, often reaching 22-34%. This review summarized the potential mechanisms underlying functional lower urinary and gastrointestinal co-morbidities in children. It also covered the current understanding of clinical pathophysiology in the pediatric population, anatomy and embryological development of the pelvic organs, role of developing neural circuits in regulation of functional co-morbidities, and relevant translational animal models., Materials and Methods: This was a non-systematic review of the published literature, which summarized the available clinical and translational studies on functional urologic and gastrointestinal co-morbidities in children, as well as neural mechanisms underlying pelvic organ 'cross-talk' and 'cross-sensitization'., Results: Co-morbidity of pediatric lower urinary and gastrointestinal dysfunctions could be explained by multiple factors, including a shared developmental origin, close anatomical proximity, and pelvic organ 'cross-talk'. Daily physiological activity and viscero-visceral reflexes between the lower gastrointestinal and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant modulatory role of the neural pathways. Recent studies have provided evidence that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs due to a phenomenon known as pelvic organ 'cross-sensitization'. Cross-sensitization between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs. Investigation of functional changes in nerve fibers and neurons sets certain limits in conducting appropriate research in humans, making the use of animal models necessary to uncover the underlying mechanisms and for the development of novel therapeutic approaches for long-term symptomatic treatment of LUTD in the pediatric population., Conclusion: Pediatric LUTD is often complicated by gastrointestinal co-morbidities; however, the mechanisms linking bladder and bowel dysfunctions are not well understood. Clinical studies have suggested that therapeutic modulation of one system may improve the other system's function. To better manage children with LUTD, the interplay between the two systems, and how co-morbid GI and voiding dysfunctions can be more specifically targeted in pediatric clinics need to be understood., (Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Aims: To investigate the role of the PFC in the micturition reflex using an in vivo microdialysis study in rats., Methods: Adult female Sprague-Dawley rats were used and microdyalysis in the PFC and cystometrography (CMG) were performed under consciousness and free movement in the present study. Experiment 1: Samples including extracellular neurotransmitters were collected by microdyalysis and analyzed by high performance liquid chromatography. At the same time, CMG were performed to measure intercontraction interval (ICI) and maximum voiding pressure (MVP).  Experiment 2: SSRI (citalopram, 1 µM) was administered into the PFC, and microdyalysis and cystometrography (CMG) were performed simultaneously. Experiment 3: Following SSRI administration, 5-HT1A agonist (8-OH-DPAT, 300 µM), which has the effect of decreasing the level of serotonin (5-HT) in the PFC, was administered into the PFC, and microdyalysis and CMG were performed simultaneously., Results: Experiment 1: Extracellular level of 5-HT in the PFC significantly increased during micturition reflex (P < 0.05), whereas levels of glutamate or dopamine were not significantly changed. Experiment 2: Local administration of SSRI in the PFC increased the 5-HT level up to approximate 600% of the basal level. It also significantly increased ICI (P < 0.05), whereas no significant change was found in MVP. Experiment 3: The extracellular level of 5-HT gradually decreased after local administration of 5-HT1A agonist, thereby ICI significantly decreased (P < 0.05)., Conclusions: The results of the present study suggest that the PFC has a suppressive effect on neural control of the micturition reflex via serotonin. Neurourol. Urodynam. 35:902-907, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Overactive bladder in women is a common chronic condition of urinary storage, affecting a significant proportion of the population. It is defined as a symptom diagnosis that indicates lower urinary tract dysfunction, in which patients experience urinary urgency, with or without urge incontinence, usually accompanied by frequency and nocturia. The diagnosis and treatment of overactive bladder are straightforward and systematic in line with national and international guidelines. However, women are required to disclose their bladder symptoms, and be motivated to make changes to their lifestyle to see improvements. This article focuses specifically on idiopathic detrusor overactivity; its diagnosis, treatment and psychological effects on women. Healthcare professionals require an understanding of the pathophysiology and treatment rationale for the condition to ensure appropriate management strategies for patients presenting to primary and secondary care are implemented.

Objectives: To elucidate the possible involvement of glutamate and serotonin (5-hydroxytryptamine) neurons in the ventrolateral midbrain periaqueductal gray during noxious stimulation., Methods: The study was carried out by evoking a noxious stimulation by acetic acid in an animal model of cystitis. Changes in glutamate and 5-hydroxytryptamine in the periaqueductal gray during the micturition reflex and acetic acid-induced cystitis were determined using in vivo microdialysis combined with cystometry in rats., Results: Extracellular glutamate levels slightly, but significantly, increased during the micturition reflex induced by saline infusion into the bladder. Intravesical infusion of acetic acid facilitated the micturition reflex characterized by increases in voiding pressure and decreases in the intercontraction interval. Glutamate levels were markedly increased by acetic acid, and this enhancement was sustained for at least 3 h. 5-Hydroxytryptamine levels, which were not altered during the micturition reflex, were increased after intravesical infusion of acetic acid., Conclusion: The results suggest that periaqueductal gray glutamate and 5-hydroxytryptamine neurons differentially participate in the modulation of both nociception and the micturition reflex. Furthermore, periaqueductal gray 5-hydroxytryptamine levels appear to reflect the nociceptive stimuli., (© 2016 The Japanese Urological Association.)

Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5(th) week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1(st) week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.

Unlabelled: A growing body of evidence suggests that 5-hydroxytryptamine (5-HT; serotonin) has both physiological and pathological functions in the lower urinary tract. A wide variety of 5-HT receptor subtypes are variably expressed in different organs, both peripheral and central. On urinary bladder smooth muscle, 5-HT1A, 5-HT2, 5-HT3, and 5-HT7 subtypes could function as postjunctional receptors. Postjunctional 5-HT2 receptors induce detrusor contraction of the bladder body. 5-HT1A is suggested to have a similar effect to 5-HT2, while 5-HT3 might suppress detrusor contraction evoked by direct muscle stimulation. Postjunctional 5-HT7 is reported to induce relaxation of the bladder neck, which might be required for efficient voiding. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes also could act as prejunctional receptors in autonomic excitatory nerve terminals. 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes facilitate the neurogenic contraction of the detrusor by enhancing cholinergic or purinergic transmission, whereas 5-HT1A receptors might inhibit the release of acetylcholine in the detrusor. Furthermore, 5-HT1D could be involved in the suppression of ATP release from the urothelium, aiding visceral sensation of the urinary bladder. In the central pathways controlling the micturition reflex, 5-HT1A, 5-HT2A, and 5-HT7 are involved in regulation of bladder and urethral sphincter activities. Their functions, especially that of 5-HT1A, vary in a species- and site (spinal or supraspinal)- dependent manner. In addition to urinary bladder, 5-HT could be involved in prostate contraction and cell proliferation. Evidence indicates that 5-HT receptor subtypes may be novel therapeutic targets for lower urinary tract symptoms., Funding: Grants-in-Aid for Scientific Research (C) (KAKENHI 23590707, 24590722, and 26460694) from the Japan Society for the Promotion of Science.

Aim: We investigated the spinal mechanism through which naftopidil inhibits the micturition reflex by comparing the effects of noradrenaline and naftopidil in rats., Methods: The following were investigated: the influence of oral naftopidil on plasma monoamine and amino acid levels, the distribution of oral 14C-naftopidil, the effects of intravenous (IV) or intrathecal (IT) injection of noradrenaline or naftopidil on isovolumetric bladder contractions, amino acid levels in the lumbosacral spinal cord after IT noradrenaline or naftopidil, and the effects of IT naftopidil and strychnine and/or bicuculline on isovolumetric bladder contractions., Key Findings: Oral naftopidil decreased the plasma adrenaline level, while it increased the serotonin and glycine levels. After oral administration, 14C-naftopidil was detected in the spinal cord and cerebrum, as well as in plasma and the prostate gland. When the bladder volume was below the threshold for isovolumetric reflex contractions, IV (0.1mg) or IT (0.1μg) noradrenaline evoked bladder contractions, but IV (1mg) or IT (0.01-1μg) naftopidil did not. When the bladder volume was above the threshold for isovolumetric reflex contractions, IV or IT noradrenaline transiently abolished bladder contractions. IT noradrenaline decreased the levels of glycine and gamma-aminobutyric acid (GABA) in the lumbosacral cord, while IT naftopidil increased the GABA level. IT strychnine and/or bicuculline blocked the inhibitory effect of IT naftopidil on bladder contractions., Significance: Naftopidil inhibits the micturition reflex by blocking α1 receptors, as well as by the activation of serotonergic, glycinergic, and GABAergic neurons in the central nervous system., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood., Experimental Approach: We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [(3) H]-ACh overflow experiments., Key Results: Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [(3) H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid., Conclusions and Implications: Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors., (© 2014 The British Pharmacological Society.)

The pontine micturition center or Barrington's nucleus (BN) - besides regulating micturition - co-regulates the activity of other pelvic viscera such as the colon and genitals. At present, this issue is gaining particular importance due to: (i) recent findings of α-synuclein in BN, (ii) known urinary dysfunction in parkinsonian patients (part of the so-called non-motor symptoms), other patients with dementia and as in very old individuals; and (iii) its proximity to the pedunculopontine nucleus, a surgical target in deep brain stimulation for Parkinson's disease (PD). The structural and functional organization of the micturition reflex comprises a coordinating action of somatic motor activity with both divisions of the autonomic nervous system, modulated by trunk encephalic and cortical centers that involve the BN as locus coeruleus and periaqueductal gray matter, among other trunk encephalic structures. The involvement of dopaminergic activity (physiologic inhibition of the micturition reflex mediated by dopaminergic D1 activity) that diminishes in Parkinsonism and leads to overactivity of the micturition reflex is also well known. In this review, the integrating role of the BN in the context of vesical and gastrointestinal behavior is revisited, and the principal morpho-functional findings that associate dysfunction with the urinary disorders that appear during the pre-motor stages of PD are summarized., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

In contrast to the well-known signaling role of urothelial ATP to control bladder function, the hypothesis that uracil nucleotides (UTP and/or UDP) also exert autocrine/paracrine actions only recently gained experimental support. Urothelial cells express UDP-sensitive P2Y6 receptors, yet their role in the control of bladder activity has been mostly neglected. This study was designed to investigate the ability of PSB0474, a stable UDP analogue which exhibits selectivity for P2Y6 receptors, to modulate urodynamic responses in the anaesthetized rat in vivo. Instillation of PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions. PSB0474-induced bladder overactivity was prevented by the selective P2Y6 antagonist, MRS2578. The increase in the VF produced by PSB0474 was also blocked by inhibitors of pannexin-1 hemichannels, (10)Panx or carbenoxolone, when these drugs were applied inside the bladder lumen but not when they were administered intravenously. Reduction of hemichannels pore permeability with H1152 also prevented PSB0474-induced bladder overactivity, but the exocytosis inhibitor, Exo-1, was inactive. PSB0474 increased by 3-fold the urinary ATP content. Implication of hemichannels permeability on PSB0474-induced ATP release was demonstrated by real-time fluorescence video-microscopy measuring the uptake of propidium iodide by intact urothelial cells in the absence and in the presence of MRS2578 or carbenoxolone. Confocal microscopy studies confirmed the co-localization of pannexin-1 and P2Y6 receptors in the rat urothelium. Data indicate that activation of P2Y6 receptors causes bladder overactivity in the anaesthetized rat indirectly by releasing ATP from the urothelium via pannexin-1 hemichannels., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Barrington's nucleus (BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre-sympathetic output (PSO) and pre-parasympathetic output (PPO) neurons in the BN using patch-clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13-L1 and S1-S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A-type K(+) currents were significantly larger in PPO than in PSO neurons. Blocking A-type K(+) channels increased the excitability more in PPO than in PSO neurons. Stimulting μ-opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABAA receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs., (© 2013 International Society for Neurochemistry.)

Objectives: Low power diode Iaser (830 nm) irradiation is a useful analgesic tool in superficial pain. Pulse laser irradiation allows us to increase the laser power because the non-irradiation time reduces heating effects and/or direct tissue damage at the irradiation area. This new irradiation device using pulse laser was applied to the dorsal skin to investigate the effects on the micturition reflex in the rat by targeting underlying sacral spinal roots., Methods: Vesical pressure measurement during the continuous infusion of the urinary bladder with saline, acetic acid (AA, 0.1%) or prostaglandin E2 (PGE2 , 10(-5) M) were performed in un-anesthetized rats. Multi-unit recording from bladder afferent nerves preformed under urethane anesthesia. Laser irradiation, either continuously at 1 W or in 10 W-pulse mode, was delivered at 830 nm from 1.5 cm above the skin at the lumbosacral joint., Results: During continuous saline infusion to the urinary bladder, neither continuous (1 W) nor pulse (10 W) laser irradiation altered the intercontraction interval and nerve firing during distention of the bladder. Pulse laser, but not continuous laser irradiation, increased the intercontraction interval with AA or PGE2 infusion and diminished nerve firing during distention of the bladder with AA or PGE2 infusion., Conclusion: These data indicate that pulse laser could diminish inflammation related nerve firing from the bladder. Since this laser irradiation did not affect the normal bladder distention elicited nerve firing, it appears capable of reducing urgency sensation without loss of the basic micturition reflex., (© 2011 Blackwell Publishing Asia Pty Ltd.)