Publications by authors named "Changfeng Tai"

101 Publications

Superficial Peroneal Neuromodulation of Persistent Bladder Underactivity Induced by Prolonged Pudendal Afferent Nerve Stimulation in Cats.

Am J Physiol Regul Integr Comp Physiol 2021 Mar 10. Epub 2021 Mar 10.

University of Pittsburgh.

The purpose of this study is to determine if superficial peroneal nerve stimulation (SPNS) can reverse persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PNS). In 16 α-chloralose anesthetized cats, PNS and SPNS were applied by nerve cuff electrodes. Skin surface electrodes were also used for SPNS. Bladder underactivity consisting of a significant increase in bladder capacity to 157.8±10.9% of control and a significant reduction in bladder contraction amplitude to 56.0±5.0% of control was induced by repetitive (4-16 times) application of 30-min PNS. SPNS (1 Hz, 0.2 ms) at 1.5 to 2 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) or intermittently (SPNSi) during a cystometrogram (CMG) to determine if the stimulation can reverse the PNS-induced bladder underactivity. SPNSc or SPNSi applied by nerve cuff electrodes during the prolonged PNS inhibition significantly reduced bladder capacity to 124.4±10.7% and 132.4±14.2% of control, respectively, and increased contraction amplitude to 85.3±6.2% and 75.8±4.7%, respectively. Transcutaneous SPNSc and SPNSi also significantly reduced bladder capacity and increased contraction amplitude. Additional PNS applied during the bladder underactivity further increased bladder capacity, while SPNSc applied simultaneously with the PNS reversed the increase in bladder capacity. This study indicates that a non-invasive superficial peroneal neuromodulation therapy might be developed to treat bladder underactivity caused by abnormal pudendal nerve somatic afferent activation that is hypothesized to occur in patients with Fowler's syndrome.
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http://dx.doi.org/10.1152/ajpregu.00346.2020DOI Listing
March 2021

Restoring both continence and micturition after chronic spinal cord injury by pudendal neuromodulation.

Exp Neurol 2021 Feb 24;340:113658. Epub 2021 Feb 24.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Neurogenic bladder management after spinal cord injury (SCI) is very challenging. Daily urethral catheterization is most commonly used to empty the bladder, which causes frequent infections of the lower urinary tract. This study reports a novel idea to restore both continence and micturition after SCI by an implantable pudendal nerve stimulator (PNS). The PNS was surgically implanted in four cats with complete SCI at T9-T10 spinal level and tested weekly for 13-14 weeks under awake conditions. These chronic SCI cats consistently exhibited large residual bladder volumes (average 40-50 ml) due to their inability to void efficiently, while urine leakage also occurred frequently. The PNS which consisted of stimulating the pudendal nerve at 20-30 Hz to trigger a spinal reflex bladder contraction and at the same time blocking the pudendal nerves bilaterally with 10 kHz stimulation to relax the external urethral sphincter and reduce the urethral outlet resistance successfully induced highly efficient (average 80-100%), low pressure (<50 cmHO) voiding. The PNS at 5 Hz also promoted urine storage by inhibiting reflex bladder activity and increasing bladder capacity. At the end of 14-week chronic testing, low pressure efficient voiding induced by PNS was further confirmed under anesthesia by directly measuring voiding pressure using a bladder catheter inserted through the bladder dome. This study demonstrated the efficacy and safety of the PNS in awake chronic SCI cats, suggesting that a novel neuroprosthesis can be developed for humans to restore bladder function after SCI by stimulating and/or blocking the pudendal nerves.
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http://dx.doi.org/10.1016/j.expneurol.2021.113658DOI Listing
February 2021

Model Analysis of Post-Stimulation Effect on Axonal Conduction and Block.

IEEE Trans Biomed Eng 2021 Feb 5;PP. Epub 2021 Feb 5.

Objective: To reveal the possible contribution of changes in membrane ion concentration gradients and ion pump activity to axonal conduction/block induced by long-duration electrical stimulation.

Methods: A new model for conduction and block of unmyelinated axons based on the classical Hodgkin-Huxley (HH) equations is developed to include changes in Na+ and K+ concentrations and ion pumps. The effects of long-duration stimulation on axonal conduction/block is analyzed by computer simulation using this new model.

Results: The new model successfully simulates initiation, propagation, and block of action potentials induced by short-duration (multiple milliseconds) stimulations that do not significantly change the ion concentrations in the classical HH model. In addition, the activity-dependent effects such as action potential attenuation and broadening observed in animal studies are also successfully simulated by the new model. Finally, the model successfully simulates axonal block occurring after terminating a long-duration (multiple seconds) direct current (DC) stimulation as observed in recent animal studies and reveals 3 different mechanisms for the post-DC block of axonal conduction.

Conclusion: Ion concentrations and pumps play an important role in post-stimulation effects and activity-dependent effects on axonal conduction/block. The duration of stimulation is a determinant factor because it influences the total charges applied to the axon, which in turn determines the ion concentrations inside and outside the axon.

Significance: Despite recent clinical success of many neurostimulation therapies, the effects of long-duration stimulation on axonal conduction/block are poorly understood. This new model could significantly impact our understanding of the mechanisms underlying different neurostimulation therapies.
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http://dx.doi.org/10.1109/TBME.2021.3057522DOI Listing
February 2021

Bladder underactivity induced by prolonged pudendal afferent activity in cats.

Am J Physiol Regul Integr Comp Physiol 2021 01 4;320(1):R80-R87. Epub 2020 Nov 4.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

The purpose of this study was to determine the effects of pudendal nerve stimulation (PNS) on reflex bladder activity and develop an animal model of underactive bladder (UAB). In six anesthetized cats, a bladder catheter was inserted via the urethra to infuse saline and measure pressure. A cuff electrode was implanted on the pudendal nerve. After determination of the threshold intensity (T) for PNS to induce an anal twitch, PNS (5 Hz, 0.2 ms, 2 T or 4 T) was applied during cystometrograms (CMGs). PNS (4-6 T) of 30-min duration was then applied repeatedly until bladder underactivity was produced. Following stimulation, control CMGs were performed over 1.5-2 h to determine the duration of bladder underactivity. When applied during CMGs, PNS (2 T and 4 T) significantly ( < 0.05) increased bladder capacity while PNS at 4 T also significantly ( < 0.05) reduced bladder contraction amplitude, duration, and area under contraction curve. Repeated application of 30-min PNS for a cumulative period of 3-8 h produced bladder underactivity exhibiting a significantly ( < 0.05) increased bladder capacity (173 ± 14% of control) and a significantly ( < 0.05) reduced contraction amplitude (50 ± 7% of control). The bladder underactivity lasted more than 1.5-2 h after termination of the prolonged PNS. These results provide basic science evidence supporting the proposal that abnormal afferent activity from external urethral/anal sphincter could produce central inhibition that underlies nonobstructive urinary retention (NOUR) in Fowler's syndrome. This cat model of UAB may be useful to investigate the mechanism by which sacral neuromodulation reverses NOUR in Fowler's syndrome.
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http://dx.doi.org/10.1152/ajpregu.00239.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847056PMC
January 2021

Poststimulation Block of Pudendal Nerve Conduction by High-Frequency (kHz) Biphasic Stimulation in Cats.

Neuromodulation 2020 Aug 5;23(6):747-753. Epub 2019 Nov 5.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: To determine the relationship between various parameters of high-frequency biphasic stimulation (HFBS) and the recovery period of post-HFBS block of the pudendal nerve in cats.

Materials And Methods: A tripolar cuff electrode was implanted on the pudendal nerve to deliver HFBS in ten cats. Two hook electrodes were placed central or distal to the cuff electrode to stimulate the pudendal nerve and induce contractions of external urethral sphincter (EUS). A catheter was inserted toward the distal urethra to slowly perfuse the urethra and record the back-up pressure generated by EUS contractions. After determining the block threshold (T), HFBS (6 or 10 kHz) of different durations (1, 5, 10, 20, 30 min) and intensities (1T or 2T) was used to produce the post-HFBS block.

Results: HFBS at 10 kHz and 1T intensity must be applied for at least 30 min to induce post-HFBS block. However, 10 kHz HFBS at a higher intensity (2T) elicited post-HFBS block after stimulation of only 10 min; and 10 kHz HFBS at 2T for 30 min induced a longer-lasting (1-3 h) post-HFBS block that fully recovered with time. HFBS of 5-min duration at 6 kHz produced a longer period (20.4 ± 2.1 min, p < 0.05, N = 5 cats) of post-HFBS block than HFBS at 10 kHz (9.5 ± 2.1 min).

Conclusion: HFBS of longer duration, higher intensity, and lower frequency can produce longer-lasting reversible post-HFBS block. This study is important for developing new methods to block nerve conduction by HFBS.
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http://dx.doi.org/10.1111/ner.13060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447838PMC
August 2020

Pudendal Nerve Block by Low-Frequency (≤1 kHz) Biphasic Electrical Stimulation.

Neuromodulation 2020 Aug 6. Epub 2020 Aug 6.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.

Objectives: To test the hypothesis that poststimulation block of nerve conduction can be achieved by low-frequency (≤1 kHz) biphasic stimulation (LFBS).

Materials And Methods: A tripolar cuff electrode was placed around the pudendal nerve in cats to deliver LFBS (1 kHz, 500 Hz, and 100 Hz). Two bipolar hook electrodes were placed central and distal to the cuff electrode to induce external urethral sphincter (EUS) contractions. A catheter was inserted into the urethra to record EUS contraction pressure. Pudendal nerve block by LFBS was confirmed by the failure of the central hook electrode stimulation to induce EUS contractions, while the distal hook electrode stimulation still induced contractions.

Results: Pudendal nerve conduction was completely blocked by LFBS at different frequencies (1 kHz, 500 Hz, and 100 Hz) after terminating LFBS. The post-LFBS block induced at the minimal stimulation intensity and duration was fully reversible within the same time period (10-15 min on average) for the three frequencies. However, the stimulation duration to induce block significantly (p < 0.05) increased from 23 ± 8 sec to 95 ± 14 sec when frequency increased from 100 Hz to 1 kHz.

Conclusion: This study discovered that LFBS (≤1 kHz), like high-frequency (≥5 kHz) biphasic stimulation (HFBS), can induce poststimulation block. The result provides support for the theory that biphasic stimulation waveforms block axonal conduction by changing intracellular and extracellular ion concentrations. The post-LFBS block provides the opportunity to develop new neuromodulation devices for clinical applications where initial nerve firing is acceptable.
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http://dx.doi.org/10.1111/ner.13241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921907PMC
August 2020

Superficial peroneal neuromodulation of nonobstructive urinary retention in cats.

Neurourol Urodyn 2020 08 16;39(6):1679-1686. Epub 2020 Jun 16.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Aims: To determine if superficial peroneal nerve stimulation (SPNS) can improve nonobstructive urinary retention (NOUR).

Methods: In α-chloralose anesthetized cats, NOUR was induced by repetitive application (4-16 times) of 30-minute tibial nerve stimulation (TNS: 5 Hz frequency, 0.2 ms pulse width) at 4 to 6 times threshold intensity (T) for inducing toe twitches. SPNS (1 Hz, 0.2 ms) at 2 to 4 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) during a cystometrogram (CMG) or during voiding (SPNSv) by a surgically implanted cuff electrode or by skin surface electrodes to determine if the stimulation reduced NOUR induced by prolonged TNS.

Results: During control CMGs, efficient (86.4% ± 5.5%) voiding occurred with a postvoid residual (PVR) volume equal to 14.9% ± 6.2% of control bladder capacity. NOUR elicited by prolonged TNS significantly (P < .05) increased bladder capacity to 168.6% ± 15.5% of control, reduced voiding efficiency to 30.4% ± 4.8%, and increased PVR to 109% ± 9.2% of control. Using the implanted cuff electrode, SPNSc and SPNSv significantly (P < .05) increased voiding efficiency to 66.7% ± 7.4% and 65.0% ± 5.9%, respectively, and reduced PVR to 52.2% ± 11.4% and 64.3% ± 11.6%, respectively. SPNSc but not SPNSv significantly (P < .05) reduced bladder capacity to 133.4% ± 15% of control. Transcutaneous SPNSv but not SPNSc also significantly (P < .05) reversed the TNS-induced NOUR responses.

Conclusions: This study shows that SPNS is effective in reversing NOUR induced by prolonged TNS. Transcutaneous SPNS provides the opportunity to develop a noninvasive neuromodulation therapy for NOUR to treat more patients than current sacral neuromodulation therapy.
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http://dx.doi.org/10.1002/nau.24438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927909PMC
August 2020

Thermal block of mammalian unmyelinated C fibers by local cooling to 15-25°C after a brief heating at 45°C.

J Neurophysiol 2020 06 6;123(6):2173-2179. Epub 2020 May 6.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

The purpose of this study was to examine the changes in cold block of unmyelinated C fibers in the tibial nerve by preconditioning with heating and to develop a safe method for thermal block of C-fiber conduction. In seven cats under α-chloralose anesthesia, C-fiber-evoked potentials elicited by electrical stimulation were recorded on the tibial nerve during block of axonal conduction induced by exposing a small segment (9 mm) of the nerve to cooling (from 35°C to ≤5°C) or heating (45°C). Before heating, partial, reproducible, and reversible cold block was first detected at a threshold cold block temperature of 15°C and complete cold block occurred at a temperature of ≤5°C. After the nerve was heated at 45°C for 5-35 min, the threshold cold block temperature significantly ( < 0.05) increased from 15°C to 25°C and the complete cold block temperature significantly ( < 0.05) increased from ≤5°C to 15°C on average. The increased cold block temperatures persisted for the duration of the experiments (30-100 min) while the amplitude of the C-fiber-evoked potential measured at 35°C recovered significantly ( < 0.05) to ~80% of control. This study discovered a novel thermal method to block mammalian C fibers at an elevated temperature (15-25°C), providing the opportunity to develop a thermal nerve block technology to suppress chronic pain of peripheral origin. The interaction between heating and cooling effects on C-fiber conduction indicates a possible interaction between different temperature-sensitive channels known to be present in the mammalian C fibers. Our study discovered that the temperature range for producing a partial to complete cold block of mammalian C-fiber axons can be increased from 5-15°C to 15-25°C on average after a preheating at 45°C. This discovery raises many basic scientific questions about the influence of temperature on nerve conduction and block. It also raises the possibility of developing a novel implantable nerve block device to treat many chronic diseases including chronic pain.
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http://dx.doi.org/10.1152/jn.00133.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311731PMC
June 2020

Response of hypogastric afferent fibers to bladder distention or irritation in cats.

Exp Neurol 2020 07 3;329:113301. Epub 2020 Apr 3.

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

The goal of this study in anesthetized cats was to identify silent hypogastric nerve (HGN) afferent fibers that do not respond to bladder distention but become responsive after chemical irritation of the bladder. The HGN was split into multiple filaments small enough for recording action potentials from single or multiple afferent fibers. The bladder was distended by infusion of either saline or 0.5% acetic acid (AA) through a urethral catheter while recording intravesical pressure. A total of 90 HGN filaments from 17 cats responded to bladder distention with saline or AA. Three types of HGN afferents were identified. The first type was non-nociceptive mechano-sensitive that responded to bladder distention at normal physiological pressures (10-40 cmHO). The second type was nociceptive mechano-sensitive that only responded to high-pressure (50-80 cmHO) bladder distention with saline but responded to low-pressure bladder distention after sensitization with AA. The third type was chemo-sensitive nociceptive that was silent even during high-pressure bladder distention but after sensitization with AA did respond to low-pressure bladder distention. These results indicate that HGN afferents as well as pelvic nerve afferents may play a role in bladder nociception. The HGN afferent fibers that are silent during bladder distention at normal physiological pressures but become responsive after chemical irritation are important for understanding the possible pathophysiological mechanism underlying bladder allodynia in painful bladder syndrome.
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http://dx.doi.org/10.1016/j.expneurol.2020.113301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237284PMC
July 2020

Additive Inhibition of Reflex Bladder Activity Induced by Bilateral Pudendal Neuromodulation in Cats.

Front Neurosci 2020 7;14:80. Epub 2020 Feb 7.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States.

Objective: To determine the inhibitory effect on bladder activity induced by bilateral pudendal neuromodulation.

Methods: In 10 cats under anesthesia, two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves for stimulation. A double lumen catheter was inserted into the bladder through the urethra to infuse saline and measure bladder pressure. During repeated cystometrograms (CMGs) pudendal nerve stimulation (PNS: 5 Hz, 0.2 ms, 5-15 min) was applied unilaterally or bilaterally at 1- or 2-times intensity threshold () for inducing anal sphincter twitching. PNS inhibition was indicated by the increase in bladder capacity measured by CMGs.

Results: Unilateral PNS at 1T did not significantly increase bladder capacity, but at 2T significantly ( < 0.05) increased bladder capacity by about 30%. Bilateral PNS at 1T also failed to increase bladder capacity, but at 2T significantly ( < 0.05) increased bladder capacity by about 60%, indicating an additive effect induced by the bilateral 2T PNS. Unilateral 1T PNS did not enhance the inhibitory effect induced by contra-lateral 2T PNS.

Conclusion: This study in anesthetized cats reveals that an additive inhibition of reflex bladder activity can be induced by bilateral pudendal neuromodulation, indicating that bilateral PNS might achieve better therapeutic efficacy in treating overactive bladder (OAB) than unilateral PNS.
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http://dx.doi.org/10.3389/fnins.2020.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020809PMC
February 2020

Prolonged nonobstructive urinary retention induced by tibial nerve stimulation in cats.

Am J Physiol Regul Integr Comp Physiol 2020 02 8;318(2):R428-R434. Epub 2020 Jan 8.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Nonobstructive urinary retention (NOUR) is a medical condition without an effective drug treatment, but few basic science studies have focused on this condition. In α-chloralose-anesthetized cats, the bladder was cannulated via the dome and infused with saline to induce voiding that could occur without urethral outlet obstruction. A nerve cuff electrode was implanted for tibial nerve stimulation (TNS). The threshold (T) intensity for TNS to induce toe twitch was determined initially. Repeated (6 times) application of 30-min TNS (5 Hz, 0.2 ms, 4-6T) significantly ( < 0.05) increased bladder capacity to 180% of control and reduced the duration of the micturition contraction to 30% of control with a small decrease in contraction amplitude (80% of control), which resulted in urinary retention with a low-voiding efficiency of 30% and a large amount of residual volume equivalent to 130% of control bladder capacity. This NOUR condition persisted for >2 h after the end of repeated TNS. However, lower frequency TNS (1 Hz, 0.2 ms, 4T) applied during voiding partially reversed the NOUR by significantly ( < 0.05) increasing voiding efficiency to 60% and reducing residual volume to 70% of control bladder capacity without changing bladder capacity. These results revealed that tibial nerve afferent input can activate either an excitatory or an inhibitory central nervous system mechanism depending on afferent firing frequencies (1 vs. 5 Hz). This study established the first NOUR animal model that will be useful for basic science research aimed at developing new treatments for NOUR.
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http://dx.doi.org/10.1152/ajpregu.00277.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052595PMC
February 2020

Low pressure voiding induced by a novel implantable pudendal nerve stimulator.

Neurourol Urodyn 2019 06 4;38(5):1241-1249. Epub 2019 Apr 4.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Aim: To validate the functionality of an implantable pudendal nerve stimulator under development for Food and Drug Administration approval to restore bladder function after spinal cord injury.

Methods: In nine cats under anesthesia, two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves and one bipolar cuff electrode was implanted on the right pudendal nerve central to the tripolar cuff electrode. The pudendal nerve stimulator was implanted subcutaneously on the left lower back along the lumbosacral spine and connected to the cuff electrodes. In five cats, a double lumen catheter was inserted into the bladder through the urethra to infuse saline and measure bladder pressure and another catheter was inserted into the distal urethra to perfuse and measure the back pressure caused by urethral contraction. In four cats, a bladder catheter was inserted into the bladder dome and the urethra was left open so that voiding could occur without urethral outlet obstruction.

Results: The implantable pudendal nerve stimulator was controlled wirelessly and successfully provided the required stimulation waveforms to different cuff electrodes. Pudendal nerve stimulation (PNS) at 5 Hz increased bladder capacity to about 200% of control capacity. PNS at 20 to 30 Hz induced large (80-100 cmH O) bladder contractions under isovolumetric conditions. When combined with ipsilateral or bilateral pudendal nerve block induced by 6 to 10 kHz stimulation, PNS at 20 to 30 Hz elicited low pressure (<40 cmH O) efficient (70%) voiding.

Conclusions: The implantable stimulator generated the required stimulation waveforms and successfully induced low pressure efficient voiding in anesthetized cats.
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http://dx.doi.org/10.1002/nau.23994DOI Listing
June 2019

Sympathetic afferents in the hypogastric nerve facilitate nociceptive bladder activity in cats.

Am J Physiol Renal Physiol 2019 04 23;316(4):F703-F711. Epub 2019 Jan 23.

Department of Urology, University of Pittsburgh , Pittsburgh, Pennsylvania.

This study in α-chloralose-anesthetized cats revealed a role of hypogastric nerve afferent axons in nociceptive bladder activity induced by bladder irritation using 0.25% acetic acid (AA). In cats with intact hypogastric and pelvic nerves, AA irritation significantly ( P < 0.05) reduced bladder capacity to 45.0 ± 5.7% of the control capacity measured during a saline cystometrogram (CMG). In cats with the hypogastric nerves transected bilaterally, AA irritation also significantly ( P < 0.05) reduced bladder capacity, but the change was significantly smaller (capacity reduced to 71.5 ± 10.6% of saline control, P < 0.05) than that in cats with an intact hypogastric nerve. However, application of hypogastric nerve stimulation (HGNS: 20 Hz, 0.2 ms pulse width) to the central end of the transected nerves at an intensity (16 V) strong enough to activate C-fiber afferent axons facilitated the effect of AA irritation and further ( P < 0.05) reduced bladder capacity to 48.4 ± 7.4% of the saline control. This facilitation by HGNS was effective only at selected frequencies (1, 20, and 30 Hz) when the stimulation intensity was above the threshold for activating C-fibers. Tramadol (an analgesic agent) at 3 mg/kg iv completely blocked the nociceptive bladder activity and eliminated the facilitation by HGNS. HGNS did not alter non-nociceptive bladder activity induced by saline distention of the bladder. These results indicate that sympathetic afferents in the hypogastric nerve play an important role in the facilitation of the nociceptive bladder activity induced by bladder irritation that activates the silent C-fibers in the pelvic nerve.
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http://dx.doi.org/10.1152/ajprenal.00522.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483026PMC
April 2019

Spinal interneuronal mechanisms underlying pudendal and tibial neuromodulation of bladder function in cats.

Exp Neurol 2018 10 7;308:100-110. Epub 2018 Jul 7.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

This study examined the mechanisms underlying pudendal and tibial neuromodulation of bladder function at the single neuron level in the spinal cord. A microelectrode was inserted into the S2 spinal cord of anesthetized cats to record single neuron activity induced by bladder distention over a range of constant intravesical pressures (10-40 cmHO). Pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) was applied at 5 Hz frequency and 0.2 ms pulse width and at multiples of the threshold (T) intensities for inducing anal or toe twitches. A total of 14 spinal neurons from 11 cats were investigated. Both PNS and TNS at 2 T intensity significantly (p < .05) reduced by 40-50% the frequency of firing induced by bladder distention at 20-40 cmHO in the same spinal neurons. This reduction was not changed by blocking opioid receptors with naloxone (1 mg/kg, i.v.). Activation of pudendal afferents by repeatedly stroking (3-5 times per second) the genital skin using a cotton swab also inhibited the neuron activity induced by bladder distention. Prolonged (30 min) TNS at 4 T intensity produced a short lasting (10-18 min) post-stimulation inhibition that reduced by 40-50% bladder-related neuron activity at different bladder pressures. These results indicate that PNS and TNS inhibition of reflex bladder activity may be mediated in part by convergence of inhibitory inputs onto the same population of bladder-related interneurons in laminae V-VII of the S2 spinal cord and that an opioid receptor mechanism is not involved in the inhibition.
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http://dx.doi.org/10.1016/j.expneurol.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118120PMC
October 2018

Frequency Dependent Tibial Neuromodulation of Bladder Underactivity and Overactivity in Cats.

Neuromodulation 2018 Oct 27;21(7):700-706. Epub 2018 Jun 27.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: This study is aimed at determining if tibial nerve stimulation (TNS) can modulate both bladder underactivity and overactivity.

Methods: In α-chloralose anesthetized cats, tripolar cuff electrodes were implanted on both tibial nerves and TNS threshold (T) for inducing toe twitching was determined for each nerve. Normal bladder activity was elicited by slow intravesical infusion of saline; while bladder overactivity was induced by infusion of 0.25% acetic acid to irritate the bladder. Bladder underactivity was induced during saline infusion by repeated application (2-6 times) of 30-min TNS (5 Hz, 4-8T, 0.2 msec) to the left tibial nerve, while TNS (1 Hz, 4T, 0.2 msec) was applied to the right tibial nerve to reverse the bladder underactivity.

Results: Prolonged 5-Hz TNS induced bladder underactivity by significantly increasing bladder capacity to 173.8% ± 10.4% of control and reducing the contraction amplitude to 40.1% ± 15.3% of control, while 1 Hz TNS normalized the contraction amplitude and significantly reduced the bladder capacity to 130%-140% of control. TNS at 1 Hz in normal bladders did not change contraction amplitude and only slightly changed the capacity, but in both normal and underactive bladders significantly increased contraction duration. The effects of 1 Hz TNS did not persist following stimulation. Under isovolumetric conditions when the bladder was underactive, TNS (0.5-3 Hz; 1-4T) induced large amplitude and sustained bladder contractions. In overactive bladders, TNS during cystometry inhibited bladder overactivity at 5 Hz but not at 1 Hz.

Conclusions: This study indicates that TNS at different frequencies might be used to treat bladder underactivity and overactivity.
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http://dx.doi.org/10.1111/ner.12792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175618PMC
October 2018

Bladder underactivity after prolonged stimulation of somatic afferent axons in the tibial nerve in cats.

Neurourol Urodyn 2018 09 10;37(7):2121-2127. Epub 2018 Apr 10.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Aims: To establish an animal model of bladder underactivity induced by prolonged and intense stimulation of somatic afferent axons in the tibial nerve.

Methods: In seven cats under α-chloralose anesthesia, tibial nerve stimulation (TNS) of 30-min duration was repeatedly (3-8 times) applied at 4-6 times threshold (T) intensity for inducing a toe twitch to produce bladder underactivity determined by cystometry. Naloxone (1 mg/kg, i.v.) was administered to examine the role of opioid receptors in TNS-induced bladder underactivity.

Results: After prolonged (1.5-4 h) and intense (4-6T) TNS, a complete suppression of the micturition reflex occurred in six cats and an increase in bladder capacity to about 150% of control and a decrease in the micturition contraction amplitude to 50% of control occurred in one cat. The bladder underactivity was maintained for at least 1-1.5 h. Naloxone reversed the bladder underactivity, but an additional 30-min TNS removed the naloxone effect.

Conclusions: The results indicate that prolonged and intense activation of somatic afferent axons in the tibial nerve can suppress the central reflex mechanisms controlling micturition. This animal model may be useful for examining the pathophysiology of neurogenic bladder underactivity and for development of new treatments for underactive bladder symptoms.
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http://dx.doi.org/10.1002/nau.23577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146051PMC
September 2018

Saphenous nerve stimulation normalizes bladder underactivity induced by tibial nerve stimulation in cats.

Am J Physiol Renal Physiol 2018 08 25;315(2):F247-F253. Epub 2017 Oct 25.

Department of Urology, University of Pittsburgh , Pittsburgh, Pennsylvania.

This study in α-chloralose-anesthetized cats aimed at investigating the bladder responses to saphenous nerve stimulation (SNS). A urethral catheter was used to infuse the bladder with saline and to record changes in bladder pressure. With the bladder fully distended, SNS at 1-Hz frequency and an intensity slightly below the threshold (T) for inducing an observable motor response of the hindlimb muscles induced large amplitude (40-150 cmHO) bladder contractions. Application of SNS (1 Hz, 2-4T) during cystometrograms (CMGs), when the bladder was slowly (1-3 ml/min) infused with saline, significantly ( P < 0.05) increased the duration of the micturition contraction to >200% of the control without changing bladder capacity or contraction amplitude. Repeated application (1-8 times) of intense (4-8T intensity) 30-min tibial nerve stimulation (TNS) produced prolonged post-TNS inhibition that significantly ( P < 0.01) increased bladder capacity to 135.9 ± 7.6% and decreased the contraction amplitude to 44.1 ± 16.5% of the pre-TNS control level. During the period of post-TNS inhibition, SNS (1 Hz, 2-4T) applied during CMGs completely restored the bladder capacity and the contraction amplitude to the pre-TNS control level and almost doubled the duration of the micturition contraction. These results indicate that SNS at 1 Hz can facilitate the normal micturition reflex and normalize the reflex when it is suppressed during post-TNS inhibition. This study provides an opportunity to develop a novel neuromodulation therapy for underactive bladder using SNS.
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http://dx.doi.org/10.1152/ajprenal.00422.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139522PMC
August 2018

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

Am J Physiol Regul Integr Comp Physiol 2018 01 20;314(1):R34-R42. Epub 2017 Sep 20.

Department of Urology, University of Pittsburgh , Pittsburgh, Pennsylvania.

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.
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http://dx.doi.org/10.1152/ajpregu.00285.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866366PMC
January 2018

An excitatory reflex from the superficial peroneal nerve to the bladder in cats.

Am J Physiol Renal Physiol 2017 Nov 30;313(5):F1161-F1168. Epub 2017 Aug 30.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania;

This study in α-chloralose-anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger reflex bladder activity. With the bladder distended at a volume ~90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large-amplitude (40-150 cmHO) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline significantly ( < 0.01) reduced bladder capacity to ~80% of the control capacity and significantly ( < 0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS)-induced changes in bladder function, PNS was delivered following TNS. TNS of 30-min duration produced long-lasting poststimulation inhibition and significantly ( < 0.01) increased bladder capacity to 140.5 ± 7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly ( < 0.05) increased the duration of reflex bladder contractions to ~200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and nonobstructive urinary retention.
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http://dx.doi.org/10.1152/ajprenal.00265.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792160PMC
November 2017

Transcutaneous electrical stimulation of somatic afferent nerves in the foot relieved symptoms related to postoperative bladder spasms.

BMC Urol 2017 Jul 13;17(1):58. Epub 2017 Jul 13.

Department of Urology, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, China.

Background: Bladder spasm is a common side effect of urological surgery. Main treatment modalities include opioids or anticholinergic medication; however, bladder spasms still occur even after these interventions. Recent studies indicate that transcutaneous stimulation of the foot can result in 50% increase in bladder capacity in healthy adults, and inhibit bladder detrusor overactivity in spinal cord injured patients. In this study, we examined the effects of transcutaneous electrical stimulation of the foot on bladder spasms related symptoms.

Methods: Sixty-six male patients who underwent prostate or bladder surgeries due to benign prostatic hyperplasia or bladder diseases were randomly divided into two groups: the control group (n = 36) and the treatment group (n = 30). The control group received the routine postoperative care. The treatment group received daily transcutaneous electrical stimulation of the foot during 3 days after surgery; each time lasted for 60 min. All patients were evaluated by the Visual Analogue Scale for pain sensation, frequency of bladder spasm episodes, and a total score of bladder spasms symptoms.

Results: In the control group, the patients with bladder surgery had a higher Visual Analogue Scale score than patients with prostate surgery (P = 0.024). In both treatment and control groups, the Visual Analogue Scale score, spasm frequency, and total score of bladder spasm symptoms decreased from day 1 to day 3 (P <0.001). The Visual Analogue Scale score at day 2, total score of bladder spasm symptoms at day 2 and day 3 were significantly lower in the treatment group than in the control group (P <0.05).

Conclusion: These results provided preliminary evidence suggesting beneficial effects of stimulating somatic afferent nerves in the foot on postoperative bladder spasms.

Trial Registration: The study was registered with Chinese Clinical Trial Registry on June 13 2016 ( http://www.chictr.org.cn/ ) (Identifier: ChiCTR-INR-16008635).
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http://dx.doi.org/10.1186/s12894-017-0248-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513144PMC
July 2017

Using the Native Afferent Nervous System to Sense Bladder Fullness: State of the Art.

Curr Bladder Dysfunct Rep 2016 Dec 11;11(4):346-349. Epub 2016 Oct 11.

Department of Urology, University of Pittsburgh, 700 Kaufmann Building, 3471 Fifth Ave., Pittsburgh, PA 15213, USA.

The regulation of micturition involves complex neurophysiologic pathways, and its understanding has grown immensely over the past decade. Alternative approaches and applied technologies in the treatment of bladder dysfunction have minimized the complications that result from neurogenic bladder. The use of natural bladder mechanoreceptors and electroneneurographic (ENG) signal recordings from afferent nerves to chronically monitor bladder volume is a promising concept, but the technology to accomplish this has proven to be a great biomedical engineering challenge. The focus of this paper will be to describe the current state of ENG signal recording as a method to detect bladder fullness.
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http://dx.doi.org/10.1007/s11884-016-0391-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421995PMC
December 2016

Glutamatergic Mechanisms Involved in Bladder Overactivity and Pudendal Neuromodulation in Cats.

J Pharmacol Exp Ther 2017 07 20;362(1):53-58. Epub 2017 Apr 20.

Department of Urology (J.U., M.Y., X.J., C.J., B.S., J.W., C.T.), Department of Pharmacology and Chemical Biology (J.R.R., W.C.D., C.T.), and Department of Bioengineering (C.T.),University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Urology, Qilu Hospital, Shandong University, Jinan, P.R. China (X.J.)

The involvement of ionotropic glutamate receptors in bladder overactivity and pudendal neuromodulation was determined in -chloralose anesthetized cats by intravenously administering MK801 (a NMDA receptor antagonist) or CP465022 (an AMPA receptor antagonist). Infusion of 0.5% acetic acid (AA) into the bladder produced bladder overactivity. In the first group of 5 cats, bladder capacity was significantly ( < 0.05) reduced to 55.3±10.0% of saline control by AA irritation. Pudendal nerve stimulation (PNS) significantly ( < 0.05) increased bladder capacity to 106.8 ± 15.0% and 106.7 ± 13.3% of saline control at 2T and 4T intensity, respectively. T is threshold intensity for inducing anal twitching. MK801 at 0.3 mg/kg prevented the increase in capacity by 2T or 4T PNS. In the second group of 5 cats, bladder capacity was significantly ( < 0.05) reduced to 49.0 ± 7.5% of saline control by AA irritation. It was then significantly ( < 0.05) increased to 80.8±13.5% and 79.0±14.0% of saline control by 2T and 4T PNS, respectively. CP465022 at 0.03-1 mg/kg prevented the increase in capacity by 2T PNS and at 0.3-1 mg/kg prevented the increase in capacity by 4T PNS. In both groups, MK801 at 0.3 mg/kg and CP465022 at 1 mg/kg significantly ( < 0.05) increased the prestimulation bladder capacity (about 80% and 20%, respectively) and reduced the amplitude of bladder contractions (about 30 and 20 cmHO, respectively). These results indicate that NMDA and AMPA glutamate receptors are important for PNS to inhibit bladder overactivity and that tonic activation of these receptors also contributes to the bladder overactivity induced by AA irritation.
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http://dx.doi.org/10.1124/jpet.117.240895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454588PMC
July 2017

Sex difference in the contribution of GABA receptors to tibial neuromodulation of bladder overactivity in cats.

Am J Physiol Regul Integr Comp Physiol 2017 03 14;312(3):R292-R300. Epub 2016 Dec 14.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania;

This study investigated the role of γ-aminobutyric acid subtype B (GABA) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly ( < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly ( < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABA receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABA receptors in tibial neuromodulation of bladder overactivity in cats and that GABA receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity.
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http://dx.doi.org/10.1152/ajpregu.00401.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402006PMC
March 2017

Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats.

Am J Physiol Renal Physiol 2017 03 7;312(3):F482-F488. Epub 2016 Dec 7.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania; and

The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly ( < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly ( < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly ( < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01-1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.
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http://dx.doi.org/10.1152/ajprenal.00586.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374309PMC
March 2017

Transcutaneous Electrical Nerve Stimulation of the Foot: Results of a Novel At-home, Noninvasive Treatment for Nocturnal Enuresis in Children.

Urology 2017 Mar 25;101:80-84. Epub 2016 Oct 25.

Division of Pediatric Urology, Children's Hospital of Pittsburgh, Pittsburgh, PA.

Objective: To evaluate the effect of a novel at-home approach to electrical foot stimulation of peripheral tibial nerve branches on the frequency of nocturnal enuresis episodes in children.

Materials And Methods: Children aged 5 to 18 having 2 or more bedwetting episodes per week for at least 3 consecutive months were eligible. The study was a total of 6 weeks. Participants completed a baseline nighttime voiding diary during the first 2 weeks. This was followed by 2 weeks of foot stimulation for 60 minutes each night. During the stimulation period, and the following 2 weeks poststimulation, participants completed the nighttime voiding diary.

Results: Twenty-two patients with a mean age of 11.4 years (range 7-16) completed the study. Overall, there was a significant reduction in mean total wet nights from 9.0 ± 4.0 to 6.8 ± 4.8 during the stimulation period (P < .01) and a sustained significant reduction to 7.2 ± 5.0 wet nights during the poststimulation period (P = .02). Sixteen patients (72.7%) showed improvement of at least 1 less wet night during stimulation, demonstrating a significant improvement from a mean of 7.9 ± 3.7 to 4.8 ± 3.5 wet nights during the 2-week stimulation (P < .01) and maintained an improved mean of 5.1 ± 4.0 wet nights during the poststimulation period (P < .01). There were no adverse events experienced by any child.

Conclusion: Transcutaneous foot stimulation is a well-tolerated, noninvasive, at-home treatment that may reduce the number of wet nights in children with nocturnal enuresis.
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http://dx.doi.org/10.1016/j.urology.2016.10.023DOI Listing
March 2017

Lumbosacral spinal segmental contributions to tibial and pudendal neuromodulation of bladder overactivity in cats.

Neurourol Urodyn 2017 Aug 24;36(6):1496-1502. Epub 2016 Oct 24.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Aims: To determine the spinal segmental afferent contributions to tibial and pudendal inhibition of bladder overactivity.

Methods: Intravesical infusion of 0.5% acetic acid was used to irritate the bladder and induce bladder overactivity in anesthetized cats. Tibial or pudendal nerve stimulation was used to suppress the bladder overactivity and increase bladder capacity during cystometry. L5-S3 dorsal roots ipsilateral to the stimulation were exposed by a laminectomy and transected sequentially during the experiments to determine the role of individual dorsal roots in tibial or pudendal neuromodulation.

Results: Transection of L5 dorsal root had no effect. Transection of L6 dorsal root in four cats produced an average 18% reduction in tibial inhibition, which is not a significant change when averaged in the group of 10 cats. Transection of L7 dorsal root completely removed the tibial inhibition without changing reflex bladder activity or pudendal inhibition. Transection of S1 dorsal root reduced the pudendal inhibition, after which transection of S2 dorsal root completely removed the pudendal inhibition. Transection of S3 dorsal root had no effect. The control bladder capacity was increased only by transection of S2 dorsal root.

Conclusions: This study in cats revealed that tibial and pudendal neuromodulation of reflex bladder overactivity depends on activation of primary afferent pathways that project into different spinal segments. This difference may be related to the recent observation in cats that the two types of neuromodulation have different mechanisms of action.
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http://dx.doi.org/10.1002/nau.23159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507750PMC
August 2017

Influence of urothelial or suburothelial cholinergic receptors on bladder reflexes in chronic spinal cord injured cats.

Exp Neurol 2016 Nov 14;285(Pt B):147-158. Epub 2016 Jul 14.

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address:

The effects of intravesical administration of a muscarinic receptor agonist (oxotremorine-M, OXO-M) and antagonist (atropine methyl nitrate, AMN) and of a nicotinic receptor agonist (nicotine) and antagonist (hexamethonium, C) on reflex bladder activity were investigated in conscious female chronic spinal cord injured (SCI) cats using cystometry. OXO-M (50μM) decreased bladder capacity (BC) for triggering micturition contractions, increased maximal micturition pressure (MMP), increased frequency and area under the curve of pre-micturition contractions (PMC-AUC). Nicotine (250μM) decreased BC, increased MMP, but did not alter PMC-AUC. The effects of OXO-M on BC and PMC-AUC were suppressed by intravesical administration of AMN (50-100μM), and the effects of nicotine were blocked by hexamethonium (1mM). Antagonists infused intravesically alone did not alter reflex bladder activity. However, AMN (0.2mg/kg, subcutaneously) decreased PMC-AUC. 8-OH-DPAT (0.5mg/kg, s.c.), a 5-HT receptor agonist, suppressed the OXO-M-induced decrease in BC but not the enhancement of PMC-AUC. These results indicate that activation of cholinergic receptors located near the lumenal surface of the bladder modulates two types of reflex bladder activity (i.e., micturition and pre-micturition contractions). The effects may be mediated by activation of receptors on suburothelial afferent nerves or receptors on urothelial cells which release transmitters that can in turn alter afferent excitability. The selective action of nicotine on BC, while OXO-M affects both BC and PMC-AUC, suggests that micturition reflexes and PMCs are activated by different populations of afferent nerves. The selective suppression of the OXO-M effect on BC by 8-OH-DPAT without altering the effect on PMCs supports this hypothesis. The failure of intravesical administration of either AMN or hexamethonium alone to alter bladder activity indicates that cholinergic receptors located near the lumenal surface do not tonically regulate bladder reflex mechanisms in the SCI cat.
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http://dx.doi.org/10.1016/j.expneurol.2016.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122961PMC
November 2016

Neurotransmitter Mechanisms Underlying Sacral Neuromodulation of Bladder Overactivity in Cats.

Neuromodulation 2017 Jan 12;20(1):81-87. Epub 2016 Oct 12.

Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: To determine the role of opioid, β-adrenergic, and metabotropic glutamate 5 receptors in sacral neuromodulation of bladder overactivity.

Material And Methods: In α-chloralose anesthetized cats, intravesical infusion of 0.5% acetic acid (AA) irritated the bladder and induced bladder overactivity. Electric stimulation (5 Hz, 0.2 ms, 0.16-0.7V) of S1 or S2 sacral dorsal roots inhibited the bladder overactivity. Naloxone, propranolol, or MTEP were given intravenously (i.v.) to determine different neurotransmitter mechanisms.

Results: AA significantly (p < 0.05) reduced bladder capacity to 7.7 ± 3.3 mL from 12.0 ± 5.0 mL measured during saline infusion. S1 or S2 stimulation at motor threshold intensity significantly (p < 0.05) increased bladder capacity to 179.4 ± 20.0% or 219.1 ± 23.0% of AA control, respectively. Naloxone (1 mg/kg) significantly (p < 0.001) reduced the control capacity to 38.3 ± 7.3% and the bladder capacity measured during S1 stimulation to 106.2 ± 20.8% of AA control, but did not significantly change the bladder capacity measured during S2 stimulation. Propranolol (3 mg/kg) significantly (p < 0.01) reduced bladder capacity from 251.8 ± 32.2% to 210.9 ± 33.3% during S2 stimulation, but had no effect during S1 stimulation. A similar propranolol effect also was observed in naloxone-pretreated cats. In propranolol-pretreated cats during S1 or S2 stimulation, MTEP (3 mg/kg) significantly (p < 0.05) reduced bladder capacity and naloxone (1 mg/kg) following MTEP treatment further reduced bladder capacity. However, a significant inhibition could still be induced by S1 or S2 stimulation after all three drugs were administered.

Conclusions: Neurotransmitter mechanisms in addition to those activating opioid, β-adrenergic, and metabotropic glutamate 5 receptors also are involved in sacral neuromodulation.
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http://dx.doi.org/10.1111/ner.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507112PMC
January 2017

Contribution of GABAA, Glycine, and Opioid Receptors to Sacral Neuromodulation of Bladder Overactivity in Cats.

J Pharmacol Exp Ther 2016 Dec 11;359(3):436-441. Epub 2016 Oct 11.

Department of Urology, Qilu Hospital, Shandong University, Jinan, P.R. China (X.J., Z.Z.); Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania (X.J., T.W.F., J.B., U.B., Z.Z., B.S., J.W., C.T.); and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (J.R.R., W.C.d.G., C.T.)

In α-chloralose-anesthetized cats, we examined the role of GABA, glycine, and opioid receptors in sacral neuromodulation-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.5% acetic acid (AA). AA irritation significantly (P < 0.01) reduced bladder capacity to 59.5 ± 4.8% of saline control. S1 or S2 dorsal root stimulation at threshold intensity for inducing reflex twitching of the anal sphincter or toe significantly (P < 0.01) increased bladder capacity to 105.3 ± 9.0% and 134.8 ± 8.9% of saline control, respectively. Picrotoxin, a GABA receptor antagonist administered i.v., blocked S1 inhibition at 0.3 mg/kg and blocked S2 inhibition at 1.0 mg/kg. Picrotoxin (0.4 mg, i.t.) did not alter the inhibition induced during S1 or S2 stimulation, but unmasked a significant (P < 0.05) poststimulation inhibition that persisted after termination of stimulation. Naloxone, an opioid receptor antagonist (0.3 mg, i.t.), significantly (P < 0.05) reduced prestimulation bladder capacity and removed the poststimulation inhibition. Strychnine, a glycine receptor antagonist (0.03-0.3 mg/kg, i.v.), significantly (P < 0.05) increased prestimulation bladder capacity but did not reduce sacral S1 or S2 inhibition. After strychnine (0.3 mg/kg, i.v.), picrotoxin (0.3 mg/kg, i.v.) further (P < 0.05) increased prestimulation bladder capacity and completely blocked both S1 and S2 inhibition. These results indicate that supraspinal GABA receptors play an important role in sacral neuromodulation of bladder overactivity, whereas glycine receptors only play a minor role to facilitate the GABA inhibitory mechanism. The poststimulation inhibition unmasked by blocking spinal GABA receptors was mediated by an opioid mechanism.
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http://dx.doi.org/10.1124/jpet.116.235846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118644PMC
December 2016

Sacral neuromodulation of nociceptive bladder overactivity in cats.

Neurourol Urodyn 2017 Jun 29;36(5):1270-1277. Epub 2016 Aug 29.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Aims: To investigate the effects of electrical stimulation of sacral dorsal/ventral roots on irritation-induced bladder overactivity, reveal possible different mechanisms under nociceptive bladder conditions, and establish a large animal model of sacral neuromodulation.

Methods: Intravesical infusion of 0.5% acetic acid (AA) was used to irritate the bladder and induce bladder overactivity in cats under α-chloralose anesthesia. Electrical stimulation (5, 15, or 30 Hz) was applied to individual S1-S3 dorsal or ventral roots at or below motor threshold intensity. Repeated cystometrograms (CMGs) were performed with/without the stimulation to determine the inhibition of bladder overactivity.

Results: AA irritation induced bladder overactivity and significantly (P < 0.05) reduced the bladder capacity to 62.6 ± 11.7% of control capacity measured during saline CMGs. At threshold intensity for inducing reflex twitching of the anal sphincter or toe, S1/S2 dorsal root stimulation at 5 Hz but not at 15 or 30 Hz inhibited bladder overactivity and significantly (P < 0.05) increased bladder capacity to 187.3 ± 41.6% and 155.5 ± 9.7% respectively, of AA control capacity. Stimulation of S3 dorsal root or S1-S3 ventral roots was not effective. Repeated stimulation of S1-S3 dorsal root did not induced a post-stimulation inhibition.

Conclusions: This study established a cat model of sacral neuromodualation of nociceptive bladder overactivity. The results revealed that the mechanisms underlying sacral neuromodulation are different for nociceptive and non-nociceptive bladder activity.
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http://dx.doi.org/10.1002/nau.23105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521272PMC
June 2017