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Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder inflammation characterized by the main symptoms of urinary frequency, urgency, and pelvic pain. The hypersensitivity of bladder afferent neurons is considered a significant pathophysiologic mechanism in IC/PBS. Serotonin (5-HT, 5-hydroxytryptamine) receptors are known to be involved in the regulation of the micturition reflex and hyperalgesia, but the effect of 5-HT receptors on cystitis remains unknown. In this study, a rat model of interstitial cystitis induced by intraperitoneal injection of cyclophosphamide (CYP) was used to investigate the role of 5-HT receptors on cystitis. The histology and urodynamics exhibited chronic cystitis and overactive bladder in CYP-treated rats. Notably, among 5-HT1A, 5-HT2A and 5-HT7 receptors, the expression of 5-HT2A receptor was significantly increased in bladder afferent neurons in CYP-treated rats. Intrathecal administration of the 5-HT2A receptor antagonist M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis rats. Neuronal calcium imaging of bladder afferent neurons revealed increased calcium influx induced by the 5-HT2A receptor agonist or capsaicin in cystitis rats, which could be inhibited by M100907. Moreover, RNA sequencing indicated that differentially expressed genes were enriched in inflammation-related pathways and cellular calcium homeostasis. These findings suggest that the 5-HT2A receptor is involved in the hypersensitivity of bladder afferent neurons in CYP-induced cystitis, and M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis by inhibiting neuronal hypersensitivity in the afferent pathways. The 5-HT2A receptor may be a potential therapeutic target for the treatment of IC/BPS., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurogenic lower urinary tract dysfunction (NLUTD) is a frequent consequence of spinal cord injury (SCI), leading to symptoms that significantly impact quality of life. Although many life-saving techniques are available, current treatment strategies for managing NLUTD still exhibit limitations and drawbacks. Here, we introduce a new electrical neuromodulation strategy involving electrical stimulation of the major pelvic ganglion (MPG) to initiate bladder contraction, in conjunction with innovative programmable (IPG) electrical stimulation on the pudendal nerve (PN) to induce external urethral sphincter (EUS) relaxation in freely moving or anesthetized SCI mice. Furthermore, we conducted the void spot assay, and cystometry coupled with EUS electromyography (EMG) recordings to evaluate voiding function, and monitor bladder pressure and EUS activity. Our findings demonstrate that our novel electrical neuromodulation approach effectively triggers coordinated bladder muscle contraction and EUS relaxation, effectively counteracting SCI-induced NLUTD. Additionally, this electrical neuromodulation method enhances voiding efficiency, closely resembling natural reflexive urination in SCI mice. Thus, our study offers a promising electrical neurostimulation approach aimed at restoring physiological coordination and potentially offering personalized treatment for improving voiding efficiency in individuals with SCI-associated NLUTD., (© 2024. The Author(s).)

Neurogenic bladder often occurs after pelvic ganglia injury. Its symptoms, like severe urinary retention and incontinence, have a significant impact on individuals' quality of life. Unfortunately, there are currently no effective treatments available for this type of injury. Here, we designed a fiber-enhanced tissue bandage for injured pelvic ganglia. Tight junctions formed in tissue bandages create a mini tissue structure that enhances resistance in an in vivo environment and delivers growth factors to support the healing of ganglia. Strength fibers are similar to clinical bandages and guarantee ease of handling. Furthermore, tissue bandages can be stored at low temperatures over 5 months without compromising cell viability, meeting the requirements for clinical products. A tissue bandage was applied to a male rat with a bilateral major pelvic ganglia crush injury. Compared to the severe neurogenic bladder symptoms observed in the injury and scaffold groups, tissue bandages significantly improved bladder function. We found that tissue bandage increases resistance to mechanical injury by boosting the expression of cytoskeletal proteins within the major pelvic ganglia. Overall, tissue bandages show promise as a practical therapeutic approach for ganglia repair, offering hope for developing more effective treatments for this thorny condition., (© 2024. The Author(s).)

Spinal cord injury (SCI) above the lumbosacral spinal cord induces loss of voluntary control over micturition. Spinal cord transection (SCT) was the gold standard method to reproduce SCI in rodents, but its translational value is arguable and other experimental SCI methods need to be better investigated, including spinal cord contusion (SCC). At present, it is not fully investigated if urinary impairments arising after transection and contusion are comparable. To explore this, we studied bladder-reflex activity and lower urinary tract (LUT) and spinal cord innervation after SCT and different severities of SCC. Severe-contusion animals presented a longer spinal shock period and the tendency for higher residual volumes, followed by SCT and mild-contusion animals. Urodynamics showed that SCT animals presented higher basal and peak bladder pressures. Immunostaining against growth-associated protein-43 (GAP43) and calcitonin gene-related peptide (CGRP) at the lumbosacral spinal cord demonstrated that afferent sprouting is dependent on the injury model, reflecting the severity of the lesion, with a higher expression in SCT animals. In LUT organs, the expression of GAP43, CGRP cholinergic (vesicular acetylcholine transporter (VAChT)) and noradrenergic (tyrosine hydroxylase (TH)) markers was reduced after SCI in the LUT and lumbosacral cord, but only the lumbosacral expression of VAChT was dependent on the injury model. Overall, our findings demonstrate that changes in LUT innervation and function after contusion and transection are similar but result from distinct neuroplastic processes at the lumbosacral spinal cord. This may impact the development of new therapeutic options for urinary impairment arising after spinal cord insult., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relates to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction. This study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam, and outcome measures and questionnaires to further study outcomes., Ethics and Dissemination: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences., Trial Registration: ClinicalTrials.gov NCT04734847. Registered on February 1, 2021., (© 2024. The Author(s).)

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1 + nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased ( P ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. Trpv1 knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg- Kit w-sh ) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction. NEW & NOTEWORTHY Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

Purpose: Increasing importance has been attributed in recent years to the preservation of the pelvic autonomic nerves during rectal resection to achieve better functional results. In addition to improved surgical techniques, intraoperative neuromonitoring may be useful., Methods: This single-arm prospective study included 30 patients who underwent rectal resection performed with intraoperative neuromonitoring by recording the change in the tissue impedance of the urinary bladder and rectum after stimulation of the pelvic autonomic nerves. The International Prostate Symptom Score, the post-void residual urine volume and the Low Anterior Resection Syndrome Score (LARS score) were assessed during the 12-month follow-up period., Results: A stimulation-induced change in tissue impedance was observed in 28/30 patients (93.3%). In the presence of risk factors such as low anastomosis, neoadjuvant radiotherapy and a deviation stoma, an average increase of the LARS score by 9 points was observed 12 months after surgery (p = 0,04). The function of the urinary bladder remained unaffected in the first week (p = 0,7) as well as 12 months after the procedure (p = 0,93)., Conclusion: The clinical feasibility of the new method for pelvic intraoperative neuromonitoring could be verified. The benefits of intraoperative pelvic neuromonitoring were particularly evident in difficult intraoperative situations with challenging visualization of the pelvic nerves., (© 2024. The Author(s).)

Aims: The nitric oxide (NO•)/soluble guanylate cyclase/cyclic-GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders., Methods: This review summarizes a workshop held under the auspices of ICI-RS with a view to address these questions., Results: Four areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed., Conclusions: Several potential NO•-dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

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.)

Aim: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research., Methods: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society., Results: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation., Conclusion: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Following colonic inflammation, the uninjured bladder afferent neurons are also activated. The mechanisms and pathways underlying this sensory neuron cross-activation (from injured neurons to uninjured neurons) are not fully understood. Colonic and bladder afferent neurons reside in the same spinal segments and are separated by satellite glial cells (SGCs) and extracellular matrix in dorsal root ganglia (DRG). SGCs communicate with sensory neurons in a bidirectional fashion. This review summarizes the differentially regulated genes/proteins in the injured and uninjured DRG neurons and explores the role of SGCs in regulation of sensory neuron crosstalk in visceral cross-organ sensitization. The review also highlights the paracrine pathways in mediating neuron-SGC and SGC-neuron coupling with an emphasis on the neurotrophins and purinergic systems. Finally, I discuss the results from recent RNAseq profiling of SGCs to reveal useful molecular markers for characterization, functional study, and therapeutic targets of SGCs. SIGNIFICANCE STATEMENT: Satellite glial cells (SGCs) are the largest glial subtypes in sensory ganglia and play a critical role in mediating sensory neuron crosstalk, an underlying mechanism in colon-bladder cross-sensitization. Identification of novel and unique molecular markers of SGCs can advance the discovery of therapeutic targets in treatment of chronic pain including visceral pain comorbidity., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Aim: After spinal cord injuries (SCIs), patients may develop either detrusor-sphincter dyssynergia (DSD) or urinary incontinence, depending on the level of the spinal injury. DSD and incontinence reflect the loss of coordinated neural control among the detrusor muscle, which increases bladder pressure to facilitate urination, and urethral sphincters and pelvic floor muscles, which control the bladder outlet to restrict or permit bladder emptying. Transcutaneous magnetic stimulation (TMS) applied to the spinal cord after SCI reduced DSD and incontinence. We defined, within a mathematical model, the minimum neuronal elements necessary to replicate neurogenic dysfunction of the bladder after a SCI and incorporated into this model the minimum additional neurophysiological features sufficient to replicate the improvements in bladder function associated with lumbar TMS of the spine in patients with SCI., Methods: We created a computational model of the neural circuit of micturition based on Hodgkin-Huxley equations that replicated normal bladder function. We added interneurons and increased network complexity to reproduce dysfunctional micturition after SCI, and we increased the density and complexity of interactions of both inhibitory and excitatory lumbar spinal interneurons responsive to TMS to provide a more diverse set of spinal responses to intrinsic and extrinsic activation of spinal interneurons that remains after SCI., Results: The model reproduced the re-emergence of a spinal voiding reflex after SCI. When we investigated the effect of monophasic and biphasic TMS at two frequencies applied at or below T10, the model replicated the improved coordination between detrusor and external urethral sphincter activity that has been observed clinically: low-frequency TMS (1 Hz) within the model normalized control of voiding after SCI, whereas high-frequency TMS (30 Hz) enhanced urine storage., Conclusion: Neuroplasticity and increased complexity of interactions among lumbar interneurons, beyond what is necessary to simulate normal bladder function, must be present in order to replicate the effects of SCI on control of micturition, and both neuronal and network modifications of lumbar interneurons are essential to understand the mechanisms whereby TMS reduced bladder dysfunction after SCI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fardadi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca 2+ channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca 2+ channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling. NEW & NOTEWORTHY This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness.

Professor LIU Zhishun 's clinical experience of electroacupuncture (EA) for pediatric neurogenic bladder of lower motor neuron type in children is summarized. Considering the unique physiological and pathological characteristics of children, with the strategy of combining "disease-symptom-location" in the selection of acupoints, professor LIU Zhishun proposes that the main disease location is the bladder and kidney, with the involvement of the conception vessel, governor vessel, kidney meridian of foot- shaoyin and the bladder meridian of foot- taiyang . The primary acupoint prescription-1 (bilateral Zhongliao [BL 33], Ciliao [BL 32] and Huiyang [BL 35]) and primary acupoint prescription-2 (Guanyuan [CV 4], Zhongji [CV 3] and bilateral Sanyinjiao [SP 6]) are selected to promote the yang of the governor vessel, stimulate the yin of the conception vessel, and invigorate the bladder's qi transformation. Before acupuncture, the four-step method is applied to precisely locate Ciliao (BL 32) and Zhongliao (BL 33). During acupuncture, the importance of achieving deqi is emphasized, with deep insertion in the sacral area to reach the disease location. Based on the tolerance characteristics of children, low-frequency EA and gentle moxibustion treatment are applied.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function. NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Objectives: This study investigated the relationship between Denonvilliers' fascia (DF) and the pelvic plexus branches in women and explored the possibility of using the DF as a positional marker in nerve-sparing radical hysterectomy (RH)., Methods: This study included eight female cadavers. The DF, its lateral border, and the pelvic autonomic nerves running lateral to the DF were dissected and examined. The pelvis was cut into two along the mid-sagittal line. The uterine artery, deep uterine veins, vesical veins, and nerve branches to the pelvic organs were carefully dissected., Results: The nerves ran sagitally, while the DF ran perpendicularly to them. The rectovaginal ligament was continuous with the DF, forming a single structure. The DF attached perpendicularly and seamlessly to the pelvic plexus. The pelvic plexus branches were classified into a ventral part branching to the bladder, uterus, and upper vagina and a dorsal part branching to the lower vagina and rectum as well as into four courses. Nerves were attached to the rectovaginal ligament and ran on its surface to the bladder ventral to the DF. The uterine branches split from the common trunk of these nerves. The most dorsal branch to the bladder primarily had a common trunk with the uterine branch, which is the most important and should be preserved in nerve-sparing Okabayashi RH., Conclusion: The DF can be used as a marker for nerve course, particularly in one of the bladder branches running directly superior to the DF, which can be preserved in nerve-sparing Okabayashi RH., Competing Interests: Declaration of competing interest KC received lecture honoraria from Ethicon (Tokyo, Japan), Terumo (Tokyo, Japan), and Chugai Pharmaceutical Co. (Tokyo, Japan). KI received lecture honoraria from AstraZeneca (Tokyo, Japan). RK received research funds from Yakult Pharmaceutical Industry Co. (Tokyo, Japan) and Chugai Pharmaceutical Co. (Tokyo, Japan) and lecture honoraria from Japan Vaccine Co. (Tokyo, Japan), MSD Japan (Tokyo, Japan), and Chugai Pharmaceutical Co. (Tokyo, Japan). SM, KY, and KA declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Office bladder chemodenervation, performed via cystoscopy with intradetrusor onabotulinumtoxinA (BOTOX) injections, is a common treatment for overactive bladder/urge urinary incontinence. Transcutaneous electric nerve stimulation (TENS) has shown to provide analgesia during office hysteroscopy. Adjuvant analgesia using TENS during bladder chemodenervation has not been studied., Objective: The primary outcome is a clinically significant (10-mm) difference in pain visual analog scale (VAS) measurements during injections for chemodenervation using active TENS compared with placebo TENS. We hypothesize that active TENS use will significantly change pain VAS scores. Secondary outcomes include 5-point pain Likert scale, satisfaction 10-point scale, and adverse events., Study Design: This was a double-blind randomized control trial of men and women with urinary urge incontinence undergoing office chemodenervation performed in an academic and private setting. Participants were randomized into 2 groups: chemodenervation with active TENS or placebo TENS. Power calculation determined 100 patients would be required detect a difference of 10 mm on pain VAS., Results: One hundred one (85 female and 16 male) participants were recruited. No differences were noted in the demographics. Participants in the active TENS group reported a difference of greater than 10 mm in pain VAS scores (48 ± 23 vs 31 ± 23, P = 0.01). Satisfaction index scores were high but no difference was noted between groups (8.6 vs 8.7, P = 0.68)., Conclusions: Most participants were eligible to use TENS units. Transcutaneous electric nerve stimulation is a safe and noninvasive adjuvant analgesia option for patients undergoing this procedure. Lower pain levels and high satisfaction rates suggest that this is an additional analgesic option during outpatient chemodenervation., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023 American Urogynecologic Society. All rights reserved.)

Introduction: Bladder storage dysfunction is associated with low quality of life in men and remains a challenging field in pharmacotherapy because of low persistence followed by patient-perceived lack of efficacy and adverse effects. The persistent desire for the development of novel pharmacotherapy is evident, leading to numerous research efforts based on its pathophysiology., Areas Covered: This review describes the pathophysiology, current pharmacotherapeutic strategies, and emerging novel drugs for male bladder storage dysfunction. The section on emerging pharmacotherapy provides an overview of current research, focusing on high-potential target molecules, particularly those being evaluated in ongoing clinical trials., Expert Opinion: As pharmacotherapies targeting alpha-adrenergic, beta-adrenergic, and muscarinic receptors - the current primary targets for treating male bladder storage dysfunction - have demonstrated insufficient efficacy and side effects, researchers are exploring various alternative molecular targets. Numerous targets have been identified as central to regulating bladder afferent nerve activity, and their pharmacological effects and potential have been evaluated in animal-based experiments. However, there is a limited number of clinical trials for these new pharmacotherapies, and they have not demonstrated clear superiority over current treatments. Further research is needed to develop new effective pharmacotherapies for bladder storage dysfunction in men.

Objectives: To determine and summarize the available data on urinary, sexual, and health-related quality-of-life (HRQOL) outcomes after traditional radical cystectomy (RC), reproductive organ-preserving RC (ROPRC) and nerve-sparing RC (NSRC) for bladder cancer (BCa) in female patients., Methods: The PubMed, SCOPUS and Web of Science databases were searched to identify studies reporting functional outcomes in female patients undergoing RC and urinary diversion for the treatment of BCa. The outcomes of interest were voiding function (for orthotopic neobladder [ONB]), sexual function and HRQOL. The following independent variables were derived and included in the meta-analysis: pooled rate of daytime and nighttime continence/incontinence, and intermittent self-catheterization (ISC) rates. Analyses were performed separately for traditional, organ- and/or nerve-sparing surgical approaches., Results: Fifty-three studies comprising 2740 female patients (1201 traditional RC and 1539 organ-/nerve-sparing RC, and 264 nerve-sparing-alone RC) were eligible for qualitative synthesis; 44 studies comprising 2418 female patients were included in the quantitative synthesis. In women with ONB diversion, the pooled rates of daytime continence after traditional RC, ROPRC and NSRC were 75.2%, 79.3% and 71.2%, respectively. The pooled rate of nighttime continence after traditional RC was 59.5%; this rate increased to 70.7% and 71.7% in women who underwent ROPRC and NSRC, respectively. The pooled rate of ISC after traditional RC with ONB diversion in female patients was 27.6% and decreased to 20.6% and 16.8% in patients undergoing ROPRC and NSRC, respectively. The use of different definitions and questionnaires in the assessment of postoperative sexual and HRQOL outcomes did not allow a systematic comparison., Conclusions: Female organ- and nerve-sparing surgical approaches during RC seem to result in improved voiding function. There is a significant need for well-designed studies exploring sexual and HRQOL outcomes to establish evidence-based management strategies to support a shared decision-making process tailored towards patient expectations and satisfaction. Understanding expected functional, sexual and quality-of-life outcomes is necessary to allow individualized pre- and postoperative counselling and care delivery in female patients planned to undergo RC., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.

Purpose: The subtrigonal perivesical nerve plexus contains a large proportion of the bladder's innervation. A transurethral radiofrequency ablation approach has successfully denervated this region to alleviate overactive bladder symptoms, with some urothelial heat injury. We report a novel transvaginal RFA device (DENERA) and assess its feasibility and efficacy in denervating the perivesical nerve plexus of in vivo sheep., Methods: In 14 adult female in vivo sheep, pulsed radiofrequency energy was applied transvaginally for three cycles of 4 min, maintaining the tissue temperature at 45°C, with 30 s of rest between each cycle. The control group (n = 4) was sacrificed without ablation, and various groups were sacrificed 1 week (n = 3), 4 weeks (n = 4), and 12 weeks (n = 3) after ablation. The bladder subtrigones were harvested then analyzed with H&E, S100, and TH immunostaining to quantify their neural density and neural vacuolization., Results: The ablation procedure increased the neural vacuolization the most at 1 week and decreased the neural density the most at 4 weeks, with both variables displaying a significant change followed by a slight rebound towards baseline at 12 weeks. The H&E analysis showed that the needles penetrated deep into the subtrigonal detrusor muscle. The sheep recovered from the procedure with no complications or damage in the bladder wall or urothelium., Conclusions: This study shows that one DENERA treatment can cause subtrigonal denervation with some rebound afterwards and no complications. DENERA may become a promising OAB treatment option that can ablate the perivesical plexus without harming the urothelium., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background and Objective: Tibial nerve stimulation (TNS) has long been used to effectively treat lower urinary tract dysfunction (LUTD). Although numerous studies have concentrated on TNS, its mechanism of action remains elusive. This review aimed to concentrate on the mechanism of action of TNS against LUTD., Materials and Methods: A literature search was performed in PubMed on October 31, 2022. In this study, we introduced the application of TNS for LUTD, summarized different methods used in exploring the mechanism of TNS, and discussed the next direction to investigate the mechanism of TNS., Results and Conclusions: In this review, 97 studies, including clinical studies, animal experiments, and reviews, were used. TNS is an effective treatment for LUTD. The study of its mechanisms primarily concentrated on the central nervous system, tibial nerve pathway, receptors, and TNS frequency. More advanced equipment will be used in human experiments to investigate the central mechanism, and diverse animal experiments will be performed to explore the peripheral mechanism and parameters of TNS in the future., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Adrenoceptors importantly contribute to the physiological regulation of lower urinary tract (LUT) function and have become a target of several clinically successful treatments for major LUT diseases. In the bladder dome, β-adrenoceptor subtypes are found in multiple cell types and mediate relaxation of detrusor smooth muscle, perhaps partly indirectly by acting on afferent nerves and cells of the mucosa. β 3 -adrenoceptor agonists such as mirabegron and vibegron are used to treat overactive bladder syndrome. In the bladder trigone and urethra, α 1 -adrenoceptors cause contraction and thereby physiologically contribute to bladder outlet resistance. α 1 -adrenoceptors in the prostate also cause contraction and pathophysiologically elevate bladder outlet resistance leading to voiding dysfunction in benign prostatic hyperplasia. α 1 -adrenoceptor antagonist such as tamsulosin is widely used as a first-line option to treat LUT symptoms in men, but it remains unclear to which extent and how smooth muscle relaxation contributes to symptom relief., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The stimulation paradigm for sacral neuromodulation has remained largely unchanged since its inception. We sought to determine, in rats, whether stimulation-induced increases in bladder capacity correlated with the proportion of sensory pudendal (PudS) neurons at each stimulated location (L6, S1). If supported, this finding could guide the choice of stimulation side (left/right) and level (S2, S3, S4) in humans. Unexpectedly, we observed that acute stimulation at clinically relevant (low) amplitudes [1-1.5 × motor threshold (T m )], did not increase bladder capacity, regardless of stimulus location (L6 or S1). More importantly for the ability to test our hypothesis, there was little anatomic variation, and S1 infrequently contributed nerve fibers to the PudS nerve. During mapping studies we noticed that large increases in PudS nerve activation occurred at amplitudes exceeding 2T m . Thus, additional cystometric studies were conducted, this time with stimulation of the L6-S1 trunk, to examine further the relationship between stimulation amplitude and cystometric parameters. Stimulation at 1T m to 6T m evoked increases in bladder capacity and decreases in voiding efficiency that mirrored those produced by PudS nerve stimulation. Many animal studies involving electrical stimulation of nerves of the lower urinary tract use stimulation amplitudes that exceed those used clinically (∼1T m ). Our results confirm that high amplitudes generate immediate changes in cystometric parameters; however, the relationship to low-amplitude chronic stimulation in humans remains unclear. Additional studies are needed to understand changes that occur with chronic stimulation, how these changes relate to therapeutic outcomes, and the contribution of specific nerve fibers to these changes. NEW & NOTEWORTHY Acute low-amplitude electrical stimulation of sacral nerve (sacral neuromodulation) did not increase bladder capacity in anesthetized CD, obese-prone, or obese-resistant rats. Increasing stimulation amplitude correlated with increases in bladder capacity and pudendal sensory nerve recruitment. It is unclear how the high-amplitude acute stimulation that is commonly used in animal experiments to generate immediate effects compares mechanistically to the chronic low-amplitude stimulation used clinically.

Urothelium and Lamina Propria (LP) are considered an integrate sensory system which is able to control the detrusor activity. Complete supra‐sacral spinal cord lesions cause Neurogenic Detrusor Overactivity (NDO) whose main symptoms are urgency and incontinence. NDO therapy at first consists in anti‐muscarinic drugs; secondly, in intra‐vesical injection of botulinum toxin. However, with time, all the patients become insensitive to the drugs and decide for cystoplastic surgery. With the aim to get deeper in both NDO and drug's efficacy lack pathogenesis, we investigated the innervation, muscular and connective changes in NDO bladders after surgery by using morphological and quantitative methodologies. Bladder innervation showed a significant global loss associated with an increase in the nerve endings located in the upper LP where a neurogenic inflammation was also present. Smooth muscle cells (SMC) anomalies and fibrosis were found in the detrusor. The increased innervation in the ULP is suggestive for a sprouting and could condition NDO evolution and drug efficacy length. Denervation might cause the SMC anomalies responsible for the detrusor altered contractile activity and intra‐cellular traffic and favour the appearance of fibrosis. Inflammation might accelerate these damages. From the clinical point of view, an early anti‐inflammatory treatment could positively influence the disease fate. [ABSTRACT FROM AUTHOR]

Several studies have indicated that reactive oxygen species (ROS) can lead to detrusor overactivity (DO), but the underlying mechanisms are not known. Hydrogen dioxide (H 2 O 2 ) is used commonly to investigate the effects of ROS. In present study, we investigated the effects of H 2 O 2 on phasic spontaneous bladder contractions (SBCs) of isolated human-bladder strips (iHBSs) and the underlying mechanisms. Samples of bladder tissue were obtained from 26 patients undergoing cystectomy owing to bladder cancer. SBCs of iHBSs were recorded in organ-bath experiments. H 2 O 2 (1μM-10mM) concentration-dependently increased the SBCs of iHBSs. These enhancing effects could be mimicked by an agonist of transient receptor potential (TRP)A1 channels (allyl isothiocyanate) and blocked with an antagonist of TRPA1 channels (HC030031; 10 μM). H 2 O 2 induced enhancing effects also could be attenuated by desensitizing sensory afferents with capsaicin (10 μM), blocking nerve firing with TTX (1 μM), blocking neurokinin effects with NK2 receptor antagonist (SR48968, 10 μM), and blocking PGE2 synthesis with indomethacin (10 μM), respectively. Our study: (i) suggests activation of TRPA1 channels on bladder sensory afferents, and then release of substance P or PGE2 from sensory nerve terminals, contribute to the H 2 O 2 -induced enhancing effects on SBCs of iHBSs; (ii) provides insights for the mechanisms underlying ROS leading to DO; (iii) indicates that targeting TRPA1 channels might be the promising strategy against overactive bladder in conditions associated with excessive production of ROS., Competing Interests: Declaration of competing interest None of the contributing authors have any conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bladder dysfunction has been linked to the progression of renal failure in children with neurogenic bladder (NB) dysfunction. The purpose of this study was to determine whether bladder injuries in fetal rats with myelomeningocele (MMC) may be treated with folic acid., Methods: Pregnant Sprague-Dawley rats were randomly divided into three groups. On the 10th day of gestation, pregnant rats were intragastrically injected with all-trans retinoic acid (ATRA) (60 mg/kg) to induce MMC fetal rats. The same amount of olive oil was put into the control group to create normal fetal rats. The rats in the rescue group were given folic acid (40 mg/kg) by gavage 0.5 and 12 hr after ATRA therapy. Bladders were obtained via cesarean section on embryonic day E20.5 and examined for MMC. The histology of the fetuses was examined using hematoxylin and eosin staining, and immunohistochemistry (IHC) was utilized to determine the expression of α-smooth muscle actin (α-SMA) and neuron-specific nuclear-binding protein (NeuN). Furthermore, the levels of neuromuscular development-related and apoptotic proteins were determined by western blotting., Results: The incidence of MMC in the model group was 60.6% (20/33) while it was much lower in the rescue group (21.4%). In comparison to the model group, the weight and crown-rump length of the fetal rats in the rescue group were significantly improved. IHC revealed that there was no significant difference in the expression of α-SMA and NeuN between the control and ATRA groups, while the expression levels decreased significantly in the MMC group. Western blot analysis showed that there was no significant difference between the model and ATRA groups, but the expression of the α-SMA protein and the β3-tubulin was much lower in the MMC group than in the control group. After the administration of folic acid, the α-SMA and β3-tubulin proteins considerably increased in the folic acid-rescued MMC group and folic acid-rescued ATRA group. Meanwhile, in the control group, the expression of cleaved caspase-3 in the bladder tissue was significantly higher, and the expression of poly (ADP-ribose) polymerase (PARP) protein was significantly lower compared to the control group. Folic acid therapy reduced cleaved caspase-3 expression while increasing PARP expression in comparison to the MMC group., Conclusions: NB in MMC fetal rats is associated with the reduction of bladder nerve and smooth muscle-related protein synthesis. However, folic acid therapy can help improve these functional deficiencies. Folic acid also exhibits strong anti-apoptotic properties against NB in MMC fetal rats., (© 2023 Wiley Periodicals LLC.)

Objective: Neurogenic bladder (NGB) is a serious complication after spinal cord injury (SCI), a destructive neurological disease. This study focused on exploring the efficacy of the magnetic stimulation of sacral nerve roots combined with Tui-na in treating NGB after SCI., Methods: One hundred patients with NGB after SCI were studied, and intermittent clean catheterization was performed with a water intake program, and patients were grouped into four groups by the random number table method: general treatment group, Tui-na group, magnetic stimulation group, and combined treatment group. A series of relevant factors (voiding diary, urodynamics, and quality of life scores) and clinical efficacy of patients in the four groups before and after treatment were observed., Results: The magnetic stimulation of sacral nerve roots alone, Tui-na alone, and the combination of both were all effective in improving bladder function and quality of life in patients with NGB after SCI, including improvements in voiding frequency, single urine output, maximum urine output, residual urine output, bladder volume and quality of life scores in patients with NGB after SCI. The efficacy of the magnetic stimulation of sacral nerve roots combined with Tui-na was better than that of the magnetic stimulation of sacral nerve roots alone and the Tui-na alone., Conclusion: This research demonstrates that the magnetic stimulation of sacral nerve roots combined with Tui-na treatment could effectively improve the urinary system and the quality of life of patients with NGB after SCI, which is worthy of clinical promotion and application., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication that is recalcitrant to glucose control. Using the Akita mouse model (type 1) bred to be NLR family pyrin domain containing 3 (NLRP3) +/+ or NLRP3 -/- , we have previously found that females (mild hyperglycemia) progress from an overactive to underactive bladder phenotype and that this progression was dependent on NLRP3-induced inflammation. Here, we examined DBD in the male Akita mouse (severe hyperglycemia) and found by urodynamics only a compensated underactive-like phenotype (increased void volume and decreased frequency but unchanged efficiency). Surprisingly, this phenotype was still present in the NLRP3 -/- strain and so was not dependent on NLRP3 inflammasome-induced inflammation. To examine the cause of the compensated underactive-like phenotype, we assessed overall nerve bundle density and afferent nerve bundles (Aδ-fibers). Both were decreased in density during diabetes, but denervation was absent in the diabetic NLRP3 -/- strain so it was deemed unlikely to cause the underactive-like symptoms. Changes in bladder smooth muscle contractility to cell depolarization and receptor activation were also not responsible as KCl (depolarizing agent), carbachol (muscarinic agonist), and α,β-methylene-ATP (purinergic agonist) elicited equivalent contractions in denuded bladder strips in all groups. However, electrical field stimulation revealed a diabetes-induced decrease in contractility that was not blocked in the NLRP3 -/- strain, suggesting that the bladder compensated underactive-like phenotype in the male Akita mouse is likely through a decrease in efferent neurotransmitter release. NEW & NOTEWORTHY In this study, we show that diabetic bladder dysfunction (the most common diabetic complication) manifests through different mechanisms that may be related to severity of hyperglycemia and/or sex. Male Akita mice, which have severe hyperglycemia, develop bladder underactivity as a result of a decrease in efferent neurotransmitter release that is independent of inflammation. This contrasts with females, who have milder hyperglycemia, where diabetic bladder dysfunction progresses from overactivity to underactivity in an inflammation-dependent manner.

Objective: To compare the ability of the obturator nerve block (ONB) and increased plasma ignition distance practice (IPDP) techniques to inhibit obturator nerve reflex (ONR) occurring with bipolar transurethral resection of the bladder., Methods: Sixty patients who had a tumor placed at the lateral sidewall or had a tumor in another part of the bladder along with the lateral wall were randomly enrolled. Cystoscopic and ultrasonographic examinations and a computerized tomography scanning of the urinary bladder were used to determine the ONB side. Group 1 consisted of patients who had the ONB procedure. Group 2 consisted of patients who had IPIDP. The severity of the ONR was classified as severe, mild, and very mild. The study's primary endpoint was ONR occurrences and successful completion of the surgery. The secondary endpoints were bleeding and bladder perforation., Results: There was a significant difference in the occurrence of ONR between the two groups (P = 0.0011). However, there was no significant difference between the two groups in the ability to resect the tumor and complete the surgery (P = .764). There was no correlation between the ONR and the tumor size (P = 0.478)., Conclusion: Our study concluded that both ONB and IPIDP have comparable results, especially in resecting tumors and completing the operation. IPIDP has some advantages over ONB, such as shorter operative time, lower total costs, and less trained personnel requirements., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. Despite this, the full array of ion channels that regulate bladder afferent responses to mechanical stimuli have yet to be determined. Here, we investigated the role of low-voltage-activated T-type calcium (Ca V 3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V 3.2, but not Ca V 3.1 or Ca V 3.3, in individual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V 3.2 with TTA-A2 and ABT-639, selective blockers of T-type calcium channels, dose-dependently attenuated ex-vivo bladder afferent responses to distension in the absence of changes to muscle compliance. Further evaluation revealed that Ca V 3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objective: To determine the efficacy of novel wearable transcutaneous tibial nerve stimulation (TTNS) device on bladder reflex in cats compared to implantable tibial nerve stimulation (ITNS)., Materials and Methods: Two self-adhesive electrodes of the TTNS device were placed at the left leg, and ITNS was applied to stimulate the tibial nerve of the right leg, respectively. The intensity threshold (T) was defined as inducing observable toe movement. Multiple cystometrograms (CMGs) with normal saline (NS) infusion were performed to determine the inhibitory effects of TTNS and ITNS on the micturition reflex., Results: TTNS at 4 times T (4 T), 6 times T (6 T), and the maximum output current intensity 24 mA significantly increased the bladder capacity (BC) compared to the control level (8.70 ± 2.46 ml) (all p < 0.05); however, there was no statistical significance among the three intensities. At the same time, ITNS at 2 times T (2 T), 4 T, 6 T, and the current intension 24 mA could significantly increase the BC compared to the control level (all p < 0.05). Likewise, no significant difference was observed among the four intensities (p > 0.05). The T values of TTNS were higher than those of ITNS (p = 0.02). The inhibitory effects of TTNS and ITNS revealed no significant difference at their respective 2 T, 4 T, 6 T, and 24 mA. Neither TTNS nor ITNS changed the contraction duration and amplitude (all p > 0.05)., Conclusions: TTNS was effective in increasing BC. The non-invasive neuromodulation technique could achieve a similar effect as ITNS., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Xiao and colleagues in China reported successful restoration of bladder control in patients with spinal cord injury (SCI) by establishing a somatic-autonomic reflex pathway through lumbar-to-sacral ventral root nerve rerouting. We evaluated long-term results in eight patients who underwent this procedure at a German university clinic between 2005 and 2007. The primary outcome was the occurrence of voiding upon stimulation of the skin, with normalization of bladder pressure when filling, as assessed with videourodynamics at each visit. Videourodynamic variables, urinary tract infections, and bladder/stool events recorded in a patient diary were stored in a prospective database and reviewed retrospectively. Intraoperative testing indicated successful nerve rerouting in all eight patients. Duration of follow-up was 71 mo (range: 56–86). No patient reached the primary goal of voluntary voiding with normalization of detrusor pressure at any point during follow-up. No improvements in videourodynamic or diary variables regarding bladder function were observed. In view of the lack of short (12–18 mo) and long-term (71 mo) success in our patients and others, the risks of any surgical procedure using general anesthesia, and potential for unmet expectations to wreak havoc on patient emotional well-being, we cannot recommend this procedure for patients with SCI. Patient summary Although the hope was to improve long-term outcomes of spinal cord injury patients, intraspinal nerve rerouting did not improve or normalize bladder function. In view of the lack of success, we cannot recommend this procedure until proven in clinical studies. [ABSTRACT FROM AUTHOR]

Postganglionic neurons of the autonomic nervous system lie outside of the central nervous system and innervate specific target effectors such as organs or glands. The major pelvic ganglion (MPG) is one such ganglion that plays a significant role in controlling bladder function in rodents. However, because of technical and physical constraints in recording electrophysiological signals from these neurons in vivo, the functional neural activity in MPG is mostly unknown. Transgenic animal models expressing genetically encoded calcium indicators now provide opportunities to monitor the activity of populations of neurons in vivo to overcome these challenges related to traditional electrophysiological methods. However, like many peripheral neurons, the MPG is not conducive to conventional fluorescent microscopy techniques, as it is located in the pelvic cavity, thus limiting robust optical access by benchtop microscopes. Here, we present an endoscopic approach based on a custom miniscope system (UCLA V3) that allows for effective in vivo monitoring of neural activity in the MPG for the first time. We show that our imaging approach can monitor activity of hundreds of MPG neurons simultaneously during the filling and emptying of the bladder in a urethane-anesthetized transgenic mouse line expressing GCaMP6s in cholinergic MPG neurons. By using custom analysis scripts, we isolated the activity of hundreds of individual neurons and show that populations of neurons have distinct phasic activation patterns during sequential bladder filling and voiding events. Our imaging approach can be adapted to record activity from autonomic neurons across different organs and systems in both healthy and disease models. NEW & NOTEWORTHY The functional activity and information processing within autonomic ganglia is mostly unknown because of technical and physical constraints in recording electrophysiological signals from these neurons in vivo. Here, we use a micro-endoscopic approach to measure in vivo functional activity patterns from a population of autonomic neurons controlling bladder function for the first time. This approach can be adapted to record activity from autonomic neurons across different organs and systems in both healthy and disease models.

Background: Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory pathways, it is likely that those syndromes involve a cross-sensitization of the bladder and the colon. The precise pathophysiology remains poorly understood., Aim: To develop a model of chronic bladder-colon cross-sensitization and to investigate the mech-anisms involved., Methods: Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia. Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions. Myeloperoxidase, used as a marker of colorectal inflammation, was measured in the colon, and colorectal permeability was measured using chambers. c-Fos protein expression, used as a marker of neuronal activation, was assessed in the spinal cord (L6-S1 level) using immunohistochemistry. Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord. The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot., Results: Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline ( P < 0.0001). This effect started 1 h post-injection and lasted up to 7 d post-injection. No increased permeability or inflammation was shown in the bladder or colon 7 d post-injection. Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord ( P < 0.0001). In green fluorescent protein on the fractalkine receptor-positive mice, intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord ( P < 0.0001). NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection ( P = 0.007 and 0.023 respectively). Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline, a microglia inhibitor, by intracerebroventricular injection of CP-99994 dihydrochloride, a NK1 antagonist, and by intracerebroventricular injection of SB203580, a MAPK-p38 inhibitor., Conclusion: We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice. Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension, mediated by neuroglial interactions, MAPK-p38 phosphorylation and the NK1 receptor., Competing Interests: Conflict-of-interest statement: None of the authors have any conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Traumatic spinal cord injury (SCI) results in the time-dependent development of urinary impairment due to neurogenic detrusor overactivity (NDO) and detrusor-sphincter-dyssynergia (DSD). This is known to be accompanied by massive changes in the bladder wall. It is presently less clear if the urethra wall also undergoes remodelling. To investigate this issue, female rats were submitted to complete spinal transection at the T8/T9 level and left to recover for 1 week and 4 weeks. To confirm the presence of SCI-induced NDO, bladder function was assessed by cystometry under urethane anesthesia before euthanasia. Spinal intact animals were used as controls. Urethras were collected and processed for further analysis. Following thoracic SCI, time-dependent changes in the urethra wall were observed. Histological assessment revealed marked urethral epithelium reorganization in response to SCI, as evidenced by an increase in epithelial thickness. At the muscular layer, SCI resulted in strong atrophy of the smooth muscle present in the urethral sphincter. Innervation was also affected, as evidenced by a pronounced decrease in the expression of markers of general innervation, particularly those present in sensory and sympathetic nerve fibres. The present data show an evident impact of SCI on the urethra, with significant histological rearrangement, accompanied by sensory and sympathetic denervation. It is likely that these changes will affect urethral function and contribute to SCI-induced urinary dysfunction, and they deserve further investigation.

Objective. Epidural spinal cord stimulation (SCS) is a potential intervention to improve limb and autonomic functions, with lumbar stimulation improving locomotion and thoracic stimulation regulating blood pressure. Here, we asked whether sacral SCS could be used to target the lower urinary tract (LUT) and used a high-density epidural electrode array to test whether individual electrodes could selectively recruit LUT nerves. Approach . We placed a high-density epidural SCS array on the dorsal surface of the sacral spinal cord and cauda equina of anesthetized cats and recorded the stimulation-evoked activity from nerve cuffs on the pelvic, pudendal and sciatic nerves. Main results . Here we show that sacral SCS evokes responses in nerves innervating the bladder and urethra and that these nerves can be activated selectively. Sacral SCS always recruited the pelvic and pudendal nerves and selectively recruited both of these nerves in all but one animal. Individual branches of the pudendal nerve were always recruited as well. Electrodes that selectively recruited specific peripheral nerves were spatially clustered on the arrays, suggesting anatomically organized sensory pathways. Significance. This selective recruitment demonstrates a mechanism to directly modulate bladder and urethral function through known reflex pathways, which could be used to restore bladder and urethral function after injury or disease., (Creative Commons Attribution license.)

Storage and voiding functions in urinary bladder are well-known, yet fundamental physiological events coordinating these behaviors remain elusive. We sought to understand how voiding function is influenced by the rate at which the bladder fills. We hypothesized that faster filling rates would increase afferent sensory activity and increase micturition rate. In vivo, this would mean animals experiencing faster bladder filling would void more frequently with smaller void volumes. To test this hypothesis, we measured afferent nerve activity during different filling rates using an ex vivo mouse bladder preparation and assessed voiding frequency in normally behaving mice noninvasively (UroVoid). Bladder afferent nerve activity depended on the filling rate, with faster filling increasing afferent nerve activity at a given volume. Voiding behavior in vivo was measured in UroVoid cages. Male and female mice were given access to tap water or, to induce faster bladder filling rates, water containing 5% sucrose. Fluid intake increased dramatically in mice consuming 5% sucrose. As expected, micturition frequency was elevated in the sucrose group. However, even with the greatly increased rate of urine production, void volumes were unchanged in both genders. Although faster filling rates generated higher afferent nerve rates ex vivo, this did not translate into more frequent, smaller-volume voids in vivo. This suggests afferent nerve activity is only one factor contributing to the switch from bladder filling to micturition. Together with afferent nerve activity, higher centers in the central nervous system and the state of arousal are likely critical to coordinating the micturition reflex.

Abstract: The transient receptor potential cation channel subfamily M member-3 (TRPM3) channel is a recently recognized noxious heat sensor that is involved in inflammatory thermal hyperalgesia. To examine its involvement in the development of hyperalgesia in interstitial cystitis/painful bladder syndrome (IC/PBS), rats with cyclophosphamide (CYP)-induced chronic cystitis were used as a model of IC/PBS. Mechanical and thermal hyperalgesia in lower abdominal region overlying the bladder in CYP rats were measured using von Frey filaments and radiant heat, respectively. Transient receptor potential cation channel subfamily M member-3 expression at the mRNA, protein, and functional levels in dorsal root ganglion neurons innervating the bladder was detected using RNA in situ hybridization (RNAscope), Western blotting, immunohistochemistry, and Ca 2+ imaging, respectively. Transient receptor potential cation channel subfamily M member-3 channels were expressed on most of the bladder primary afferent nerve terminals containing calcitonin gene-related peptide and their cell bodies in L6-S1 dorsal root ganglion. Activation of TRPM3 in the bladder wall by its specific agonist pregnenolone sulphate or CIM0216 induced spontaneous bladder pain, calcitonin gene-related peptide release, and neurogenic inflammation that was evidenced by edema, plasma extravasation, inflammatory cell accumulation, and mast cell infiltration. In CYP rats, pretreatment with the TRPM3 antagonist primidone (2 mg/kg, i.p.) significantly alleviated the mechanical and thermal hyperalgesia, bladder submucosal edema, mast cell infiltration, and bladder hyperactivity. Cyclophosphamide-induced cystitis was associated with TRPM3 upregulation at the mRNA, protein, and functional levels in bladder afferent neurons. Our results suggest that upregulation of TRPM3 channels is involved in the development of chronic pain in CYP-induced cystitis, and targeting TRPM3 may be a pharmacological strategy for treating bladder pain in IC/PBS., (Copyright © 2022 International Association for the Study of Pain.)

Objective: Bladder dysfunction after nerve injury has a variable presentation, and extent of injury determines whether the bladder is spastic or atonic. The authors have proposed a series of 3 nerve transfers for functional innervation of the detrusor muscle and external urethral sphincter, along with sensory innervation to the genital dermatome. These transfers are applicable to only cases with low spinal segment injuries (sacral nerve root function is lost) and largely preserved lumbar function. Transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor contraction by thigh adduction. External urethra innervation (motor and sensory) may be accomplished by transfer of the vastus medialis nerve to the pudendal nerve. The sensory component of the pudendal nerve to the genitalia may be further enhanced by transfer of the saphenous nerve (sensory) to the pudendal nerve. The main limitations of coapting the nerve donors to their intrapelvic targets are the bifurcation or arborization points of the parent nerve. To ensure that the donor nerves had sufficient length and diameter, the authors sought to measure these parameters., Methods: Twenty-six pelvic and anterior thigh regions were dissected in 13 female cadavers. After the graft and donor sites were clearly exposed and the branches identified, the donor nerves were cut at suitable distal sites and then moved into the pelvis for tensionless anastomosis. Diameters were measured with calipers., Results: The obturator nerve was bifurcated a mean ± SD (range) of 5.5 ± 1.7 (2.0-9.0) cm proximal to the entrance of the obturator foramen. In every cadaver, the authors were able to bring the posterior division of the obturator nerve to the vesical branch of the pelvic nerve (located internal to the ischial spine) in a tensionless manner with an excess obturator nerve length of 2.0 ± 1.2 (0.0-5.0) cm. The distance between the femoral nerve arborization and the anterior superior iliac spine was 9.3 ± 1.8 (6.5-15.0) cm, and the distance from the femoral arborization to the ischial spine was 12.9 ± 1.4 (10.0-16.0) cm. Diameters were similar between donor and recipient nerves., Conclusions: The chosen donor nerves were long enough and of sufficient caliber for the proposed nerve transfers and tensionless anastomosis.

The inferior hypogastric plexus (IHP) lies in the extraperitoneal pelvis, and supplies branches to pelvic and perineal viscera. In men, the rectoprostatic fascia (Denonvillier's fascia) forms a distinct double fascial layer between the seminal glands and the rectum. The hypogastric nerve projections to the prostate and seminal glands run anterior to this. An analagous fascial layer in women between the vagina and cervix posteriorly and the urinary bladder anteriorly has recently been described. The purpose of this study was to examine the anatomy of the vesicovaginal fascia (VVF) and to determine its relationship to the anterior branches of the IHP. This dissection study examined the fascial layers between the posterior urinary bladder and anterior vagina/cervix (VVF) in 15 female embalmed cadavers and three fresh specimens. Anterior branches of the IHP were identified and followed distally. The relationship between these nerve projections and the VVF was examined. In 16 dissection, the VVF was identified as a complete fascial plane extending beneath the vesicouterine pouch to the neck of the bladder inferiorly and to the endopelvic fascia laterally. Anterior projections from the hypogastric nerves and IHP maintained an extraperitoneal course passing anteriorly to the VVF towards the urinary bladder The VVF is a distinct fascial structure and projections of the hypogastric nerves pass anterior to this. This may have implications for nerve sparing hysterectomy., (© 2022 The Authors. Clinical Anatomy published by Wiley Periodicals LLC on behalf of American Association for Clinical Anatomists and the British Association for Clinical Anatomists.)

Capsaicin acts on sensory nerves via vanilloid receptors. TRPV1 has been extensively studied with respect to functional lower urinary tract (LUT) conditions in rodents and humans. We aimed to (1) provide background information on capsaicin and TRPV1 and its mechanisms of action and basis for clinical use, (2) review the use of acute intravesical capsaicin instillation (AICI) in rodents to mimic various LUT disorders in which capsaicin sensitive C-fibers are involved and (3) discuss future innovative treatments. A comprehensive search of the major literature databases until June 2022 was conducted. Both capsaicin-sensitive and resistant unmyelinated bladder afferent C-fibers are involved in non-neurogenic overactive bladder/detrusor overactivity (OAB/DO). AICI is a suitable model to study afferent hyperactivity mimicking human OAB. Capsaicin-sensitive C-fibers are also involved in neurogenic DO (NDO) and potential targets for NDO treatment. AICI has been successfully tested for NDO treatment in humans. Capsaicin-sensitive bladder afferents are targets for NDO treatment. TRPV1-immunoreactive nerve fibers are involved in the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS). The AICI experimental model appears relevant for the preclinical study of treatments targeting bladder afferents for refractory IC/BPS. The activity of capsaicin-sensitive bladder afferents is increased in experimental bladder outlet obstruction (BOO). The AICI model may also be relevant for bladder disorders resulting from C-fiber hyperexcitabilities related to BOO. In conclusion, there is a rationale for the selective blockade of TRPV1 channels for various bladder disorders. The AICI model is clinically relevant for the investigation of pathophysiological conditions in which bladder C-fiber afferents are overexcited and for assessing innovative treatments for bladder disorders based on their pathophysiology.

Combined retrograde tracing and double-labelling immunofluorescence were used to investigate the distribution and chemical coding of neurons in testicular (TG) and aorticoerenal (ARG) ganglia supplying the urinary bladder trigone (UBT) in juvenile male pigs (n=4, 12 kg. of body weight). Retrograde fluorescent tracer Fast Blue (FB) was injected into the wall of the bladder trigone under pentobarbital anesthesia. After three weeks all the pigs were deeply anesthetized and transcardially perfused with 4% buffered paraformaldehyde. TG and ARG, were collected and processed for double-labelling immunofluorescence. The expression of tyrosine hydroxylase (TH) or dopamine beta-hydroxylase (DBH), neuropeptide Y (NPY), somatostatin (SOM), galanin (GAL), nitric oxide synthase (NOS) and vesicular acetylcholine transporter (VAChT) were investigated. The cryostat sections were examined with a Zeiss LSM 710 confocal microscope equipped with adequate filter blocks. The TG and ARG were found to contain many FB-positive neurons projecting to the UBT (UBT-PN). The UBT-PN were distributed in both TG and ARG. The majority of them were found in the right ganglia, mostly in TG. Immunohistochemistry disclosed that the vast majority of UBT-PN were noradrenergic (TH- and/or DBH-positive). Many noradrenergic neurons contained also immunoreactivity to NPY, SOM or GAL. Most of the UBT-PN were supplied with VAChT-, or NOS- IR (immunoreactive) varicose nerve fibres. This study has revealed a relatively large population of differently coded prevertebral neurons projecting to the porcine urinary bladder. As judged from their neurochemical organization these nerve cells constitute an important element of the complex neuro-endocrine system involved in the regulation of the porcine urogenital organ function., (Copyright© by the Polish Academy of Sciences.)

Study Objective: To examine whether objective bladder function after robot-assisted radical hysterectomy (RRH) for early-stage cervical cancer is correlated with subjective patient-reported outcomes and quality of life during the first year after RRH., Design: Prospective observational study., Setting: Karolinska University Hospital, Sweden., Patients: Women with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA2-IB1) between July 2017 and May 2019 were assessed for eligibility., Interventions: RRH., Measurements and Main Results: Subjective bladder function was evaluated with the Female Lower Urinary Tract Symptoms and Urinary Incontinence Quality of Life modules of the International Consultation on Incontinence Questionnaire. Objective urinary function was characterized with urodynamic tests, and the nerves ablated at RRH were quantified by using immunohistochemical staining of biopsies from the resected paracervix, vesicouterine, and sacrouterine ligaments. Twenty-seven women were included for analysis at baseline, 2 weeks, 3 months, and 12 months after surgery. RRH caused hypotonia of the urinary bladder (p <.05). Patient-reported outcomes of voiding and filling dysfunction were most significant 2 weeks after surgery (p <.05) but for most of the women, bladder function recovered within 3 months. No correlations were found with either subjective or objective urinary function and the number of ablated nerves., Conclusion: For most women, objective and subjective urinary bladder dysfunction recovered within 3 months after RRH. The absence of correlation between functional outcomes and ablated autonomous nerves suggests that other underlying causes play a significant role. Early detection of bladder overextension after RRH is paramount, and the role of postoperative bladder catheterization needs further investigation., (Copyright © 2022 AAGL. Published by Elsevier Inc. All rights reserved.)

This study examined the effect of sacral neuromodulation on persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PudNS). In 10 α-chloralose-anesthetized cats, repetitive application of 30-min PudNS induced bladder underactivity evident as an increase in bladder capacity during a cystometrogram (CMG). S1 or S2 dorsal root stimulation (15 or 30 Hz) at 1 or 1.5 times threshold intensity (T) for inducing reflex hindlimb movement (S1) or anal sphincter twitch (S2) was applied during a CMG to determine if the stimulation can reverse the bladder underactivity. Persistent (>3 h) bladder underactivity consisting of a significant increase in bladder capacity to 163.1 ± 11.3% of control was induced after repetitive (1-10 times) application of 30-min PudNS. S2 but not S1 dorsal root stimulation at 15 Hz and 1 T intensity reversed the PudNS-induced bladder underactivity by significantly reducing the large bladder capacity to 124.3 ± 12.9% of control. Other stimulation parameters were not effective. After the induction of persistent underactivity, recordings of reflex bladder activity under isovolumetric conditions revealed that S2 dorsal root stimulation consistently induced the largest bladder contraction at 15 Hz and 1 T when compared with other frequencies (5-40 Hz) or intensities (0.25-1.5 T). This study provides basic science evidence consistent with the hypothesis that abnormal pudendal afferent activity contributes to the bladder underactivity in Fowler's syndrome and that sacral neuromodulation treats this disorder by reversing the bladder inhibition induced by pudendal nerve afferent activity.

Following spinal cord injury (SCI), loss of spinal and supraspinal control results in desynchronisation of detrusor vesicae (parasympathicus) and external urethral sphincter (sympathicus) activity. Despite recovery of lower urinary tract function being a high priority in patients with SCI, effective treatment options are unavailable largely because mechanisms are poorly understood. Purpose and methods: We used a clinically relevant model of thoracic SCI compression injury in adult female Wistar rats and confirmed that lesion volumes following severe injuries were significantly greater compared to moderate injuries (p < 0.05). Between 1-9 weeks, we assessed recovery of bladder function as well as return of locomotor function using the Basso, Beattie and Bresnahan (BBB) score. Bladder morphometrics and overall intramural innervation patterns, as assessed with ß-III tubulin immunohistochemistry, were also examined. Results: Despite variability, bladder function was significantly worse following severe compared to moderate compression injury (p < 0.05); furthermore, the degree of bladder and locomotor dysfunction were significantly correlated (r = 0.59; p < 0.05). In addition, at 9 weeks after SCI we saw significantly greater increases in bladder dry weight (p < 0.05) and wall thickness following severe compared to moderate injury as well as increases in intramural axon density (moderate: 3× normal values; severe 5×; both p < 0.05) that also correlated with injury severity (r = 0.89). Conclusion: The moderate and severe compression models show consistent and correlated deficits in bladder and locomotor function, as well as in gross anatomical and histopathological changes. Increased intramural innervation may contribute to neurogenic detrusor overactivity and suggests the use of therapeutic agents which block visceromotoric efferents. [ABSTRACT FROM AUTHOR]

Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H 1 and H 2 receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 µM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H 1 receptor antagonist fexofenadine (5 µM) and the G q/11 inhibitor YM254890 (1 µM). Neither the muscarinic receptor antagonist atropine (1 µM), the Na + channel blocker tetrodotoxin (1 µM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 µM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-β-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 µM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 µM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function. NEW & NOTEWORTHY Histamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility.