Superficial peroneal neuromodulation of nonobstructive urinary retention induced by prolonged pudendal afferent activity in cats.

The purpose of this study is to determine whether superficial peroneal nerve stimulation (SPNS) can improve nonobstructive urinary retention (NOUR) induced by prolonged pudendal nerve stimulation (PNS). In this exploratory acute study using eight cats under anesthesia, PNS and SPNS were applied by nerve cuff electrodes. Skin surface electrodes were also used for SPNS. A double lumen catheter was inserted via the bladder dome for bladder infusion and pressure measurement and to allow voiding without a physical urethral outlet obstruction. The voided and postvoid residual (PVR) volumes were also recorded. NOUR induced by repetitive (4-13 times) application of 30-min PNS significantly (P < 0.05) reduced voiding efficiency by 49.5 ± 16.8% of control (78.3 ± 7.9%), with a large PVR volume at 208.2 ± 82.6% of control bladder capacity. SPNS (1 Hz, 0.2 ms) at 1.5-2 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) or intermittently (SPNSi) during cystometrograms to improve the PNS-induced NOUR. SPNSc and SPNSi applied by nerve cuff electrodes significantly (P < 0.05) increased voiding efficiency to 74.5 ± 18.9% and 67.0 ± 15.3%, respectively, and reduced PVR volume to 54.5 ± 39.0% and 88.3 ± 56.0%, respectively. SPNSc and SPNSi applied noninvasively by skin surface electrodes also improved NOUR similar to the stimulation applied by a cuff electrode. This study indicates that abnormal pudendal afferent activity could be a pathophysiological cause for the NOUR occurring in Fowler's syndrome and a noninvasive superficial peroneal neuromodulation therapy might be developed to treat NOUR in patients with Fowler's syndrome.

Mapping and neuromodulation of lower urinary tract function using spinal cord stimulation in female rats.

Spinal cord epidural stimulation (SCS) represents a form of neuromodulation for the management of spasticity and pain. This technology has recently emerged as a new approach for potentially augmenting locomotion and voiding function in humans and rodents after spinal cord injury. However, the effect of SCS on micturition has not been studied extensively. Here, SCS was first applied as a direct stimulus onto individual segmental levels of the lumbar spinal cord in rats to map evoked external urethral sphincter (EUS) electromyography activity and SCS-induced voiding contractions. SCS of L2-3 inhibited EUS tonic activity, and SCS on L3 (L3/SCS) inhibited EUS tonic activity and elicited EUS bursting. In contrast, SCS of L1 and L4-6 evoked EUS tonic contractions, which resembled the urethral guarding reflex during bladder storage. Next, the effects of a bilateral pelvic nerve crush (PNC) injury on urodynamic function were examined at 14 days post-operatively. The PNC injury resulted in decreased voiding efficiency and maximum intravesical pressure, whereas the post-voiding residual volume was increased, suggestive of an underactive bladder. Finally, L3/SCS was performed to induce a voiding contraction and enable voiding in rats with a PNC injury. Voiding efficiency was significantly increased, and the residual volume was decreased by L3/SCS in rats after the PNC injury. We conclude that L3/SCS may be used to induce micturition reflexes in a partially filled bladder, reduce urethral resistance, and augment bladder emptying after PNC injury.

Sacral neuromodulation blocks pudendal inhibition of reflex bladder activity in cats: insight into the efficacy of sacral neuromodulation in Fowler's syndrome.

This study tested the hypothesis that sacral neuromodulation, i.e., electrical stimulation of afferent axons in sacral spinal root, can block pudendal afferent inhibition of the micturition reflex. In α-chloralose-anesthetized cats, pudendal nerve stimulation (PNS) at 3-5 Hz was used to inhibit bladder reflex activity while the sacral S1 or S2 dorsal root was stimulated at 15-30 Hz to mimic sacral neuromodulation and to block the bladder inhibition induced by PNS. The intensity threshold (T) for PNS or S1/S2 dorsal root stimulation (DRS) to induce muscle twitch of anal sphincter or toe was determined. PNS at 1.5-2T intensity inhibited the micturition reflex by significantly ( P < 0.01) increasing bladder capacity to 150-170% of control capacity. S1 DRS alone at 1-1.5T intensity did not inhibit bladder activity but completely blocked PNS inhibition and restored bladder capacity to control level. At higher intensity (1.5-2T), S1 DRS alone inhibited the micturition reflex and significantly increased bladder capacity to 135.8 ± 6.6% of control capacity. However, the same higher intensity S1 DRS applied simultaneously with PNS, suppressed PNS inhibition and significantly ( P < 0.01) reduced bladder capacity to 126.8 ± 9.7% of control capacity. S2 DRS at both low (1T) and high (1.5-2T) intensity failed to significantly reduce PNS inhibition. PNS and S1 DRS did not change the amplitude and duration of micturition reflex contractions, but S2 DRS at 1.5-2T intensity doubled the duration of the contractions and increased bladder capacity. These results are important for understanding the mechanisms underlying sacral neuromodulation of nonobstructive urinary retention in Fowler's syndrome.

Multiple Reflex Pathways Contribute to Bladder Activation by Intraurethral Stimulation in Persons With Spinal Cord Injury.

OBJECTIVE: To measure the urodynamic effects of electrical co-stimulation of 2 individual sites in the proximal and distal urethra in persons with spinal cord injury (SCI). This work was motivated by preclinical findings that selective co-stimulation of the cranial urethral sensory nerve and the dorsal genital nerve, which innervate the proximal and distal portions of the urethra, respectively, increased reflex bladder activation and voiding efficiency. MATERIALS AND METHODS: Electrical co-stimulation of urethral afferents was conducted in persons with chronic SCI during urodynamics. The effects of different frequencies of intraurethral stimulation at multiple urethral locations on bladder pressure and pelvic floor electromyographic activity were measured. RESULTS: Electromyographic activity indicated that multiple reflex pathways were recruited through stimulation that contributed to bladder activation. The size of reflex bladder contractions evoked by stimulation was dependent on stimulation location or reflex activated and stimulation frequency. CONCLUSION: Pudendal nerve afferents are a promising target to restore lost bladder control, as stimulation with different frequencies may be used to treat urinary incontinence and increase continent volumes or to generate stimulation-evoked bladder contractions for on-demand voiding. This work identified that co-stimulation of multiple afferent reflex pathways can enhance activation of spinal circuits and may enable improved bladder emptying in SCI when stimulation of a single pathway is not sufficient.

Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder.

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2 PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.

Spinal stimulation of the upper lumbar spinal cord modulates urethral sphincter activity in rats after spinal cord injury.

After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6-8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD.

Sacral neuromodulation effects on periurethral sensation and urethral sphincter activity.

AIMS: To characterize the effect of sacral neuromodulation (SNM) on urethral neuromuscular function. METHODS: Following IRB approval, women with refractory overactive bladder (OAB) underwent standardized urethral testing prior to and after Stage 1 SNM implantation. Periurethral sensation was measured using current perception thresholds (CPT). Striated urethral sphincter activity was quantified using concentric needle electromyography (CNE) and Multi-Motor Unit Action Potential (MUP) analysis software. Nonparametric analyses were used to characterize pre/post changes with intervention. Baseline CPT and CNE findings were compared between SNM responders and non-responders. RESULTS: Twenty-seven women were enrolled in this pilot study with a mean age of 61 ± 13 years. Twenty of 26 women (76.9%) responded to SNM and went to Stage 2 permanent implantation. Four (14.8%) withdrew after Stage 1 implantation; three of the four withdrawals had not had therapeutic responses to SNM. CPT and CNE parameters did not significantly differ from baseline 2 weeks after SNM. Pre-SNM urethral sensation was not significantly different between responders and non-responders. However, responders had larger amplitude, longer duration and more turns and phases at baseline approaching significance, reflecting more successful urethral reinnervation, than non-responders. CONCLUSIONS: SNM does not alter urethral neuromuscular function 2 weeks post Stage 1 implantation.

Pudendal neuromodulation improves voiding efficiency in diabetic rats.

AIMS: Diabetic cystopathy is typically manifested as bladder voiding dysfunction, and numerous patients are refractory to standard therapy. In this study, we determined whether electrical stimulation (ES) of the sensory branch of the pudendal nerve could engage an augmenting reflex and thereby improve bladder emptying in a diabetic animal model with cystopathy. METHODS: The efficiency of bladder emptying with ES of the sensory branch of the pudendal nerve at different stimulation intensities was measured in rats at 8 or 18 weeks after the induction of diabetes with streptozotocin. RESULTS: The voiding efficiency (VE) was reduced from 74 ± 4% to 30 ± 8% in rats with diabetes for 8 weeks and from 73 ± 6% to 20 ± 6% in rats with diabetes for 18 weeks. ES at lower intensities (0.025-0.05 mA) applied to the pudendal sensory nerve did not affect the VE in rats with diabetes for 18 weeks but increased the VE in rats with diabetes for 8 weeks. Subsequently, when the stimulation intensity was elevated to 0.1-0.3 mA, the VEs in rats with diabetes for both 8 and 18 weeks increased to 40-50%. CONCLUSIONS: The results of the present study are consistent with the essential role for pudendal sensory feedback in efficient bladder emptying, and electrical activation of the sensory branch of the pudendal nerve was efficient restoring the voiding function in diabetic animals with cystopathy. This could provide an approach to improve bladder emptying in diabetic patients with voiding dysfunction.

Sacral nerve stimulation for neuromodulation of the lower urinary tract.

Sacral neuromodulation (SNM) has become a standard treatment option for patients suffering from urinary urge incontinence, urgency-frequency, and/or nonobstructive urinary retention refractory to conservative and pharmacologic treatment. Since its initial development, the manufacturer of InterStim therapy (Medtronic, Inc., Minneapolis, MN, USA), has introduced technical modifications, while surgeons and researchers have adapted and published various innovations and alterations of the implantation technique. In this article, we feature our SNM technique including patient selection, comprehensive dialogue/evaluation, procedure details, and appropriate follow up. Although there is often great variability in patients with lower urinary tract dysfunction, we maintain that great success can be achieved with a systematic and methodical approach to SNM.

High frequency sacral root nerve block allows bladder voiding.

AIMS: Dyssynergic reflexive external urethral sphincter (EUS) activity following spinal cord injury can prevent bladder voiding, resulting in significant medical complications. Irreversible sphincterotomies or neurotomies can prevent EUS activation and allow bladder voiding, but may cause incontinence or loss of sacral reflexes. We investigated whether kilohertz frequency (KF) electrical conduction block of the sacral roots could prevent EUS activation and allow bladder voiding. METHODS: The S2 sacral nerve roots were stimulated bilaterally to generate bladder pressure in six cats. One S1 nerve root was stimulated proximally (20 Hz biphasic pulse trains) to evoke EUS pressure, simulating worst-case dyssynergic EUS reflexes. KF waveforms (12.5 kHz biphasic square wave) applied to an electrode implanted distally on the S1 nerve root blocked nerve conduction, preventing the increase in EUS pressure and allowing voiding. RESULTS: Applying KF waveforms increased bladder voiding in single, limited-duration trials from 3 ± 6% to 59 ± 12%. Voiding could be increased to 82 ± 9% of the initial bladder volume by repeating or increasing the duration of the trials. CONCLUSIONS: Sacral nerve block can prevent EUS activation and allow complete bladder voiding, potentially eliminating the need for a neurotomy. Eliminating neurotomy requirements could increase patient acceptance of bladder voiding neuroprostheses, increasing patient quality of life and reducing the cost of patient care.

[Botulinum toxin versus sacral neuromodulation for idiopathic detrusor overactivity]. / Botulinomtoxin vs. sakrale Neuromodulation bei idiopathischer Detrusorüberaktivität.

Idiopathic detrusor overactivity (motory urge) negatively affects the live of patients. Conservative treatment is not always effective and has multiple side effects. Sacral neuromodulation is a second line therapy for the treatment of idiopatic detrusor overactivity. Over the last decade, botulinum toxin injections have been increasingly used as alternative although there are only few randomized studies. Goal of this review is to compare efficiacy, safety and cost effectiveness of both methods.

[Neuro-urological dysfunction of the lower urinary tract in CNS diseases: pathophysiology, epidemiology, and treatment options]. / Neurourologische Funktionsstörungen des unteren Harntraktes bei Erkrankungen des ZNS : Pathophysiologie, Epidemiologie und Therapieoptionen.

The lower urinary tract (LUT) is regulated by a complex neural network that is subject to supraspinal control. Neurological disorders, especially of the central nervous system (CNS), can rapidly lead to disruption of this control. Multiple sclerosis, Parkinson's disease, multiple system atrophy, and stroke are neurological disorders which quite frequently cause dysfunction of the LUT. With respect to the pathophysiology of bladder dysfunction in CNS diseases there are various hypotheses regarding the individual disorders: disturbances of neural communication between the frontal cortex and pontine micturition center, between the pontine micturition center and the lumbosacral parts of the spinal cord, and between the basal ganglia, thalamus, and anterior cingulate gyrus appear to play a pivotal role in the development of bladder dysfunction. The symptoms and urodynamic presentation of LUT dysfunction can vary considerably depending on the disease and disease progression and can change in the course of the disease. The incidence and prevalence of LUT dysfunctions rise with increasing progression of the underlying neurological disease.Various conservative, minimally invasive, and open surgical procedures are available to prevent harmful sequelae and to improve the quality of life of these patients. As yet, however, few data exist on most of the treatment options in cases of the above-mentioned CNS diseases. Intermittent self-catheterization and antimuscarinic medications are among the most important conservative treatment options. Injection of botulinum neurotoxin type A into the detrusor muscle and increasingly sacral or pudendal neuromodulation are among the most important minimally invasive treatment options. Surgical methods include reconstructive continent or incontinent urinary diversion.When planning therapy the patient's current needs and neurological limitations as well as possible disease progression must be taken into consideration. It is often advisable to consult with and enlist the cooperation of the attending neurologist when planning treatment.

Reinnervation of urethral and anal sphincters with femoral motor nerve to pudendal nerve transfer.

AIMS: Lower motor neuron damage to sacral roots or nerves can result in incontinence and a flaccid urinary bladder. We showed bladder reinnervation after transfer of coccygeal to sacral ventral roots, and genitofemoral nerves (L1, 2 origin) to pelvic nerves. This study assesses the feasibility of urethral and anal sphincter reinnervation using transfer of motor branches of the femoral nerve (L2-4 origin) to pudendal nerves (S1, 2 origin) that innervate the urethral and anal sphincters in a canine model. METHODS: Sacral ventral roots were selected by their ability to stimulate bladder, urethral sphincter, and anal sphincter contraction and transected. Bilaterally, branches of the femoral nerve, specifically, nervus saphenous pars muscularis [Evans HE. Miller's anatomy of the dog. Philadelphia: W.B. Saunders; 1993], were transferred and end-to-end anastomosed to transected pudendal nerve branches in the perineum, then enclosed in unipolar nerve cuff electrodes with leads to implanted RF micro-stimulators. RESULTS: Nerve stimulation induced increased anal and urethral sphincter pressures in five of six transferred nerves. Retrograde neurotracing from the bladder, urethral sphincter, and anal sphincter using fluorogold, fast blue, and fluororuby, demonstrated urethral and anal sphincter labeled neurons in L2-4 cord segments (but not S1-3) in nerve transfer canines, consistent with reinnervation by the transferred femoral nerve motor branches. Controls had labeled neurons only in S1-3 segments. Postmortem DiI and DiO labeling confirmed axonal regrowth across the nerve repair site. CONCLUSIONS: These results show spinal cord reinnervation of urethral and anal sphincter targets after sacral ventral root transection and femoral nerve transfer (NT) to the denervated pudendal nerve. These surgical procedures may allow patients to regain continence.

Urethral sphincter EMG-controlled dorsal penile/clitoral nerve stimulation to treat neurogenic detrusor overactivity.

The goal of this study was to investigate whether real-time external urethral sphincter (EUS) EMG-controlled dorsal genital nerve (DGN) stimulation can suppress undesired detrusor bladder contractions in patients with both neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD). Detrusor pressure (Pdet) and EUS EMG were recorded in 12 neurogenic patients who underwent two filling cystometries. The first one was without stimulation and was intended to confirm the NDO and DSD and to set the EMG detection threshold. The second one was with real-time EMG-controlled stimulation of DGNs. Two detection methods were analyzed to detect bladder contractions. The first method was a Kurtosis-scaled root mean square (RMS) detector and was used on-line. The second was a simple RMS detector and was used off-line. Of 12 patients included, 10 patients showed both NDO and DSD. In nine of these ten patients relevant EMG concomitant to detrusor activity was detected and stimulation could suppress at least one detrusor contraction. The second filling compared to the first one showed an increase of 84% in bladder capacity (p = 0.002) and a decrease of 106% in Pdet (p = 0.002). Nine false-positive detections occurred during the ten fillings with electrical stimulation. The mean increases of both time and Pdet between stimulation and bladder contraction onsets for method 1 were 1.8 s and 4 cmH(2)O and for method 2 were 0.9 s and 2 cmH(2)O, respectively. This study shows that EUS EMG can be used in real time to detect the onset of a bladder contraction. In combination with DGN stimulation has been shown to be feasible to suppress undesired bladder contractions and in turn to increase bladder capacity in subjects with both NDO and DSD.

Effects of periurethral neuromuscular electrical stimulation on the voiding frequency in rats.

INTRODUCTION AND HYPOTHESIS: This study aims to test the hypothesis that a urethra-to-bladder inhibitory pathway exists through which periurethral neuromuscular electrical stimulation (NMES) inhibits overactive bladder contractions in rats. METHODS: Bladder overactivity was induced in 22 female Sprague Dawley rats by injection of ketamine/xylazine/acepromizine (K/X/A). A bipolar electrode was placed surgically in the periurethral region to deliver NMES. Intravesical pressure, bladder inter-contraction interval (ICI) and voided volume (VV) were monitored while the bladder was continuously infused with saline. RESULTS: K/X/A induced more frequent bladder contractions (ICI = 48.6 +/- 20.1 s, before cutting the pubo-symphasis) compared to a 10-min ICI induced by urethane. NMES significantly increased ICI (63.1 +/- 31.3 s before vs. 97.2 +/- 42.9 s after NMES, p < 0.001) and VV (0.063 = 0.041 ml before vs. 0.088 = 0.044 ml after NMES, p < 0.02). CONCLUSIONS: Injection of K/X/A may potentially be used as a model of bladder overactivity. NMES inhibits bladder contractions in rats with bladder overactivity, which supports the existence of a urethra-to-bladder inhibitory pathway.

Stimulated smooth muscle neosphincter in male intrinsic sphincter deficiency: Proof of principle studies in a rabbit model.

AIMS: Intrinsic sphincter deficiency (ISD) causes significant disability and impairment of quality of life despite a range of treatment options. We investigated a novel method to improve sphincter function that does not appear to have been previously attempted, that is, transplantation to create a smooth muscle cuff, that subsequently becomes innervated, around the urethra. METHODS: Bladder pressure and passage of urine were measured in conscious, sedated rabbits of three groups: 6 control (unoperated) rabbits, 8 rabbits rendered incontinent by incision of their urethral wall, and 12 lesioned rabbits treated by transplantation of a circumferential strip of autologous dartos muscle whose innervation was later stimulated electrically. Effects of stimulation were tested up to 6 months after surgery. RESULTS: Lesions of the proximal urethra caused the bladder to leak at filling volumes that previously caused no leak. The volume added to cause first leak was less than half the volume added to cause a voiding reflex in unoperated rabbits. Transplantation of dartos to the lesioned bladder neck did not affect urodynamic parameters. However, electrical stimulation of the innervation of the transplant increased the bladder volume necessary to cause voiding and restored voiding pressures and filling volumes towards normal. These effects were maintained for 6 months and were not related to spontaneous healing. CONCLUSIONS: Free transplants of smooth muscle that become innervated offer promise as a treatment for ISD that is unlikely to cause urethral erosion and will not require a pump to restore continence.

Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B.

Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate cross-organ sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6-S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB 1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra.

Functional impact of the rhabdosphincter branch of the pelvic nerve on the membranous urethra in comparison to that of the pudendal nerve in male rabbits.

INTRODUCTION: The innervation of the membranous urethra (MU) is still under debate. We analysed the functional effects of electrostimulation of the rhabdosphincter branch of the pelvic nerve (RBP) on the MU in a standardized male rabbit model, paying attention both to the efferent and the possible afferent effects of stimulation. MATERIAL AND METHODS: Six male rabbits (chinchilla bastards) were included in this study. Pudendal nerve branches as well as pelvic nerve branches were exposed bilaterally in all animals. Randomized electrostimulation trials of both the pudendal nerve fibres and the RBP were carried out using a biphasic signal (0.3 mA, 200 mus). The stimulation frequency ranged from 10 to 40 Hz in a randomized pattern. Changes in MU pressure were measured urodynamically. The pressure changes occurring as a result of stimulation were compared in both nerve structures. At the end of the stimulation trial, the RBP and the pudendal nerve were dissected at different positions before repeating the stimulation and the MU pressure recording. RESULTS: The mean MU baseline pressure without stimulation was 24 cm H(2)O (range 21-27) in all animals. During unilateral pudendal stimulation, the mean pressure response rose by highly significant values (p < 0.005) compared to baseline. The pressure response was frequency dependent. Stimulation of the RBP resulted in a small but significant change of the MU pressure in the lower frequency range (10 and 20 Hz) (p > 0.05). On performing stimulation at higher frequencies, there was no significant difference from baseline. The pressure response of the MU during stimulation of the intact RBP did not differ significantly from the response after dissection of the RBP. However, after dissecting the pudendal nerve, the MU pressure response to RBP stimulation was diminished. CONCLUSION: Our results confirm the primacy of the pudendal nerve in the innervation of the MU. Stimulation of the RBP, however, may produce an afferent signal which is transmitted to the pudendal nerve, thus resulting in a pressure increase of the MU and contributing towards continence. We showed the importance of the RBP to maintain full urinary continence in rabbits. Our results suggest that substantially higher continence rates can be achieved through a nerve-sparing procedure in radical prostatectomy. Nerve-sparing radical prostatectomy incidentally also protects the RBP from injury.

Colon mustard oil instillation induced cross-organ reflex sensitization on the pelvic-urethra reflex activity in rats.

We investigated the participation of cyclin-dependent kinase-5 (Cdk5)-mediated N-methyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation in cross-organ reflex sensitization caused by colon irritation. The external urethral sphincter electromyogram (EUSE) reflex activity evoked by the pelvic afferent nerve test stimulation (TS, 1 stimulation/30s) and protein expression in the spinal cord and dorsal root ganglion tissue (T13-L2 and L6-S2 ipsilateral to the stimulation) in response to colon mustard oil (MO) instillation were tested in anesthetized rats. When compared with a baseline reflex activity with a single action potential evoked by the TS before the administration of test agents, MO instillation into the descending colon sensitized the evoked activity characterized by elongated firing in the reflex activity in association with increased protein levels of Cdk5, PSD95, and phosphorylated NR2B (pNR2B) but not of total NR2B (tNR2B) in the spinal cord tissue. Both cross-organ reflex sensitization and increments in protein expression were reversed by intra-colonic pretreatments with ruthenium red (a non-selective transient receptor potential vanilloid, TRPV, antagonist), capsaizepine (a TRPV1-selective antagonist), lidocaine (a nerve conduction blocker) as well as by the intra-thecal pretreatment with APV (a NRMDR antagonist) Co-101244 (a NR2B-selective antagonist) and roscovitine (a Cdk5 antagonist). Moreover, compared with the control group, both the increase in pNR2B and the cross-organ reflex sensitization were attenuated in the si-RNA of NR2B rats. All these results suggested that Cdk-dependent NMDAR NR2B subunit phosphorylation mediates the development of cross-organ pelvic-urethra reflex sensitization caused by acute colon irritation which could possibly underlie the high concurrence of pelvic pain syndrome with irritable bowel syndrome.

Lead placement and associated nerve distribution of an implantable periurethral electrostimulator.

The aim of this study was to determine gross and neuroanatomic features of a novel periurethral neuromuscular electrostimulator. Periurethral leads were placed in eight female cadavers. In two cases, leads were imaged after placement to enhance anatomic understanding. Pelvic viscera were removed en bloc for analysis of lead placement in the six remaining cadavers. Excised tissue was sectioned and immunostained to identify general, afferent, sympathetic, and nitric oxide synthase efferent nerve fibers. The electrodes were found within/lateral (n = 4), within/posterolateral (n = 9), and anterolateral (n = 1) to the external urethral sphincter (distance 0.25 +/- 0.5, 2.9 +/- 3.3, and 1.0 +/- 0.0 mm, respectively). The electrode to the urethra and vagina distance averaged 7.6 +/- 3.4 and 8.8 +/- 4.3 mm, respectively. Variable density staining for all nerve types was found around the electrode. A periurethral electrode interfaces the external urethral sphincter, and the adjacent distribution of nerve fibers supports proposed neuromuscular therapeutic mechanisms.