Pudendal Nerve Stimulation Inhibition Research Articles

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

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 cmH2O). 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 cmH2O 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.

PD55-04 TIBIAL AND PUDENDAL NEUROMODULATION OF SPINAL NEURON ACTIVITY INDUCED BY BLADDER DISTENTION

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology II1 Apr 2018PD55-04 TIBIAL AND PUDENDAL NEUROMODULATION OF SPINAL NEURON ACTIVITY INDUCED BY BLADDER DISTENTION Todd Yecies, Shun Li, Yan Zhang, Daniel Cai, Bing Shen, Jicheng Wang, James Roppolo, William De Groat, and Changfeng Tai Todd YeciesTodd Yecies More articles by this author , Shun LiShun Li More articles by this author , Yan ZhangYan Zhang More articles by this author , Daniel CaiDaniel Cai More articles by this author , Bing ShenBing Shen More articles by this author , Jicheng WangJicheng Wang More articles by this author , James RoppoloJames Roppolo More articles by this author , William De GroatWilliam De Groat More articles by this author , and Changfeng TaiChangfeng Tai More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2624AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Neuromodulation is an FDA-approved treatment for overactive bladder (OAB), however the mechanisms underlying neuromodulation are not completely understood. Prior studies have suggested that perigenital stimulation (PGS), pudendal nerve stimulation (PNS) and tibial nerve stimulation (TNS) can alter afferent sensory signaling from the bladder, however the sites of action (spinal or supraspinal) for bladder neuromodulation are not clear. We present a novel approach to identify individual bladder related neurons (BRNs) and assess the effect of PGS, PNS, and TNS on BRN activity. METHODS The S2 level of the spinal cord was exposed in α-chloralose anesthetized cats. Bladder pressure was modulated using a urethral catheter attached to an adjustable height reservoir. Using a tungsten micro-electrode lowered into the S2 spinal cord, individual neurons with firing patterns that changed with bladder pressure were identified. The effect of PGS, PNS (5Hz, 0.2 ms) at 2 times the threshold to induce anal twitch (2T), and TNS (5Hz, 0.2 ms) at 2 and 4 times the threshold to induce toe movement (2 and 4T) on BRN activity were studied. Naloxone, an opioid receptor antagonist, was administered intravenously (1.0mg/kg) to a subset of cats to determine the role of opiate signaling in PNS and TNS inhibition of BRN signaling. RESULTS A total of 19 BRNs were identified in 12 cats. Of these, 18 were positively stimulated by increased bladder pressure, while 1 was inhibited by rises in bladder pressure. BRNs demonstrated increased activity with increased bladder pressure (p<0.01). Both PNS and TNS at 2T significantly inhibited BRN activity at bladder pressures of 10, 20, 30, and 40 cm H2O (p<0.05). Perigenital stimulation inhibited BRN activity at all tested bladder pressures (p=0.037). TNS at 4T for a 30 minute period provided a brief post-stimulation inhibitory effect at 20-40cm H2O (p<0.01) which dissipated within a 5 minute recovery window. Administration of IV naloxone increased background neuron activity (p=0.04) but had no effect on PNS and TNS-mediated inhibition of BRN activity. CONCLUSIONS Individual BRNs could be reliably identified within the feline S2 spinal cord. Perigenital stimulation, TNS and PNS significantly inhibited BRN activity at different bladder pressures. TNS and PNS inhibition was not effected by naloxone, suggesting non-opiate mediated inhibition. Through this novel technique of measuring BRN activity, the effect of pharmacologic or neuromodulatory interventions to manage OAB can be more precisely delineated to reveal the potential sites of action. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1057 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Todd Yecies More articles by this author Shun Li More articles by this author Yan Zhang More articles by this author Daniel Cai More articles by this author Bing Shen More articles by this author Jicheng Wang More articles by this author James Roppolo More articles by this author William De Groat More articles by this author Changfeng Tai More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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.

Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition.

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

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

Role of glycine in nociceptive and non-nociceptive bladder reflexes and pudendal afferent inhibition of these reflexes in cats.

This study examined the role of glycinergic transmission in nociceptive and non-nociceptive bladder reflexes and in inhibition of these reflexes by pudendal nerve stimulation (PNS). Cystometrograms (CMGs) were performed in α-chloralose anesthetized cats by intravesical infusion of saline or 0.25% acetic acid (AA) to trigger, respectively, non-nociceptive or nociceptive bladder reflexes. PNS at 2 or 4 times threshold (T) intensity for inducing anal twitch was used to inhibit the bladder reflexes. Strychnine (a glycine receptor antagonist) was administered in cumulative doses (0.001-0.3 mg/kg, i.v.) at 60-120 min intervals. Strychnine at 0.001-0.3 mg/kg significantly (P < 0.05) increased bladder capacity and reduced contraction amplitude during saline CMGs but did not change these parameters during AA CMGs except at the 0.3 mg/kg dose which increased bladder capacity. Strychnine did not alter PNS inhibition during saline CMGs except at the highest dose at 2T intensity, but significantly (P < 0.05) suppressed PNS inhibition during AA CMGs after 0.001-0.003 mg/kg doses at 2T and 4T intensities. During AA CMGs strychnine (0.3 mg/kg) also unmasked a post-PNS excitatory effect that significantly reduced bladder capacity after termination of PNS. Glycinergic inhibitory neurotransmission in the central nervous system plays an unexpected role to tonically enhance the magnitude and reduce the bladder volume threshold for triggering the non-nociceptive bladder reflex. This is attributable to inhibition by glycine of another inhibitory mechanism. Glycine also has a minor role in PNS inhibition of the nociceptive bladder reflex. Neurourol. Urodynam. 35:798-804, 2016. © 2015 Wiley Periodicals, Inc.

MP12-01 SPINAL METABOTROPIC GLUTAMATE RECEPTOR 5 INVOLVEMENT IN PUDENDAL INHIBITION OF NOCICEPTIVE BLADDER REFLEX IN CATS

INTRODUCTION AND OBJECTIVES: Spinal cord transection (SCT) results in disruption of the Ad-fiber mediated supraspinal voiding reflex with emergence of a C-fiber mediated spinal reflex. Pudendal nerve stimulation (PNS) can increase bladder capacity and reduce storage pressures in both acute and chronic spinal cord injury models. Metabotropic glutamate receptor 5 (mGluR5) is widely expressed in the CNS and has been shown to suppress excitatory transmission of the micturition reflex. This study investigates the role and location of mGluR5 in pudendal nerve inhibition of C-fiber mediated spinal bladder reflex using an acute SCT model. METHODS: Cystometrograms (CMGs) were performed on 12 cats under a-chloralose anesthesia. Saline control capacity was establish followed by acute SCT at T9/T10. CMGs were performed using 0.25% acetic acid (AA) to activate nociceptive C-fiber bladder afferents and induce spinal bladder reflexes. PNS was applied at 5 Hz at 2 and 4 times the threshold (T) for inducing anal twitch. Under isovolumetric conditions, MTEP (a selective mGluR5 antagonist) was given (3 mg/kg, i.v.) to determine its effect on PNS. Six of the cats were treated with propranolol (3 mg/kg, i.v.) prior to MTEP administration. Hexamethonium (10 mg/kg, i.v.) was given at the end of each experiment to block the spinal bladder reflex. RESULTS: Following T9/T10 SCT and AA irritation, CMGs showed a spinal bladder reflex resulting in low amplitude (<50 cmH2O), short duration (<30 s) contractions at a significantly lower bladder volume 78.69% 26.2% of saline control capacity. During AA irritation, MTEP resulted in a significant increase in control capacity from 71.77% 24.17% to 93.97 34.05% but did not significantly change maximal contraction amplitude. MTEP given after propranolol resulted in significantly reduced contraction amplitude from 18.57 5.2 to 6.62 3.0 cmH2O and significantly increased capacity from 56.91 25.8% to 78.53 31.94%. MTEP resulted in elimination of PNS inhibition at both 2T and 4T stimulation without changing the control capacity. Propranolol did not fully remove PNS inhibition, but MTEP after propranolol treatment completely eliminated the PNS inhibition. CONCLUSIONS: Our study reveals the presence of mGluR5 in the nociceptive C-fiber mediated spinal bladder reflex and substantiates the role of spinal mGluR5 in PNS inhibition of the nociceptive C-fiber mediated bladder reflex. Understanding of the location and neurotransmitters involved in PNS may help to create new therapies for overactive bladder.

Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (<50 cmH2O) and short duration (<20 s) at a smaller bladder capacity ∼80% of saline control capacity. PNS significantly (P < 0.01) increased bladder capacity from 85.5 ± 10.1 to 137.3 ± 14.1 or 148.2 ± 11.2% at 2T or 4T stimulation, respectively, where T is the threshold intensity for PNS to induce anal twitch. MTEP {3-[(2-methyl-4-thiazolyl)ethynyl]pyridine; 3 mg/kg iv, a selective mGluR5 antagonist} completely removed the PNS inhibition and significantly (P < 0.05) increased bladder capacity from 71.8 ± 9.9 to 94.0 ± 13.9% of saline control, but it did not change the bladder contraction amplitude. After propranolol (3 mg/kg iv, a β1/β2-adrenergic receptor antagonist) treatment, PNS inhibition remained but MTEP significantly (P < 0.05) reduced the bladder contraction amplitude from 18.6 ± 2.1 to 6.6 ± 1.2 cmH2O and eliminated PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the bladder contraction amplitude from 20.9 ± 3.2 to 8.1 ± 1.5 cmH2O on average demonstrating that spinal reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex.

Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats.

This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose-anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch, respectively. During a cystrometrogram (CMG), PNS at 2T and 4T significantly (P < 0.05) increased bladder capacity from 58.0 ± 4.7% to 85.8 ± 10.3% and 96.5 ± 10.7%, respectively, of saline control capacity, while TNS failed to inhibit spinal reflex bladder contractions. After administering propranolol (3 mg/kg iv, a β₁/β₂-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (P < 0.05) reduced to 64.5 ± 9.5% and 64.7 ± 7.3%, respectively, of the saline control capacity. However, the residual PNS inhibition (about 10% increase in capacity) was still statistically significant (P < 0.05). Propranolol treatment also significantly (P = 0.0019) increased the amplitude of bladder contractions but did not change the control bladder capacity. Naloxone (1 mg/kg iv, an opioid receptor antagonist) had no effect on either spinal reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the amplitude of the reflex bladder contractions. This study indicates an important role of β₁/β₂-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity.

Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats.

The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P < 0.01) reduced the amplitude of the reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions.

Effects of Duloxetine and WAY100635 on Pudendal Inhibition of Bladder Overactivity in Cats

This study was aimed at determining the effect of duloxetine (a serotonin-norepinephrine reuptake inhibitor) on pudendal inhibition of bladder overactivity. Cystometrograms were performed on 15 cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, pudendal nerve stimulation (PNS) at 5 Hz was applied to the right pudendal nerve at two and four times the threshold (T) intensity for inducing anal twitch. Duloxetine (0.03-3 mg/kg) was administered intravenously to determine the effect on PNS inhibition. AA irritation significantly (P < 0.01) reduced bladder capacity to 27.9 ± 4.6% of saline control capacity. PNS alone at both 2T and 4T significantly (P < 0.01) inhibited bladder overactivity and increased bladder capacity to 83.6 ± 7.6% and 87.5 ± 7.7% of saline control, respectively. Duloxetine at low doses (0.03-0.3 mg/kg) caused a significant reduction in PNS inhibition without changing bladder capacity. However, at high doses (1-3 mg/kg) duloxetine significantly increased bladder capacity but still failed to enhance PNS inhibition. WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; a 5-HT1A receptor antagonist, 0.5-1 mg/kg i.v.) reversed the suppressive effect of duloxetine on PNS inhibition and significantly (P < 0.05) increased the inhibitory effect of duloxetine on bladder overactivity but did not enhance the effect of PNS. These results indicate that activation of 5-HT1A autoreceptors on the serotonergic neurons in the raphe nucleus may suppress duloxetine and PNS inhibition, suggesting that the coadministration of a 5-HT1A antagonist drug might be useful in enhancing the efficacy of duloxetine alone and/or the additive effect of PNS-duloxetine combination for the treatment of overactive bladder symptoms.

Role of spinal GABAAreceptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats

Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and nonnociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA; 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce nonnociceptive bladder activity. To modulate the bladder reflex, pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly (P < 0.01) reduced bladder capacity to 34.3 ± 7.1% of the saline control capacity, while PNS at 2T and 4T significantly (P < 0.01) increased AA bladder capacity to 84.0 ± 7.8 and 93.2 ± 15.0%, respectively, of the saline control. Picrotoxin (0.4 mg it) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (iv) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly (P < 0.05) reduced 2T PNS inhibition at low doses (0.01-0.1 mg/kg). During saline cystometry, PNS significantly (P < 0.01) increased bladder capacity to 147.0 ± 7.6% at 2T and 172.7 ± 8.9% at 4T of control capacity, and picrotoxin (0.4 mg it or 0.03-0.3 mg/kg iv) also significantly (P < 0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and nonnociceptive reflex bladder activities and in PNS inhibition of these activities.

Involvement of 5-HT3receptors in pudendal inhibition of bladder overactivity in cats

In the present study, the role of 5-HT3 receptors in pudendal neuromodulation of bladder activity and its interaction with opioid receptors were investigated in anesthetized cats. The bladder was distended with either saline to induce normal bladder activity or with 0.25% acetic acid (AA) to induce bladder overactivity. Pudendal afferent nerves were activated by 5-Hz stimulation at multiples of the threshold (T) intensity for the induction of anal twitching. AA irritation significantly reduced bladder capacity to 16.5 ± 3.3% of saline control capacity, whereas pudendal nerve stimulation (PNS) at 1.5-2 and 3-4 T restored the capacity to 82.0 ± 12% (P = 0.0001) and 98.6 ± 15% (P < 0.0001), respectively. Cumulative doses (1-3 mg/kg iv) of ondansetron, a 5-HT3 receptor antagonist, eliminated low-intensity (1.5-2 T) PNS inhibition and reduced high-intensity (3-4 T) PNS inhibition of bladder overactivity. During saline distention, PNS at 1.5-2 and 3-4 T significantly increased bladder capacity to 173.2 ± 26.4% (P = 0.036) and 193.2 ± 22.5% (P = 0.008), respectively, of saline control capacity, but ondansetron (0.003-3 mg/kg iv) did not alter PNS inhibition. Ondansetron (0.1-3 mg/kg) also significantly (P < 0.05) increased control bladder capacity (50-200%) during either AA irritation or saline distention. In both conditions, the effects of low- and high-intensity PNS were not significantly different. After ondansetron (3 mg/kg) treatment, naloxone (1 mg/kg iv) significantly (P < 0.05) decreased control bladder capacity (40-70%) during either AA irritation or saline distention but failed to affect PNS inhibition. This study revealed that activation of 5-HT3 receptors has a role in PNS inhibition of bladder overactivity. It also indicated that 5-HT3 receptor antagonists might be useful for the treatment of overactive bladder symptoms.

Effect of methysergide on pudendal inhibition of micturition reflex in cats

The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P<0.0001) reduced bladder capacity to 27.0±7.4% of saline control capacity. Pudendal nerve stimulation (PNS) at multiples of the threshold (T) intensity for inducing anal sphincter twitching restored bladder capacity to 60.1±8.0% at 1–2T (P<0.0001) and 92.2±14.1% at 3–4T (P=0.001) of the saline control capacity. Methysergide (0.03–1mg/kg, i.v.) suppressed low intensity (1–2T) PNS inhibition but not high intensity (3–4T) inhibition, and also significantly (P<0.05) increased control bladder capacity at the dosage of 0.3–1mg/kg. During saline infusion without AA irritation, PNS significantly increased bladder capacity to 150.8±9.9% at 1–2T (P<0.01) and 180.4±16.6% at 3–4T (P<0.01) of the saline control capacity. Methysergide (0.1–1mg/kg) significantly (P<0.05) increased saline control bladder capacity and suppressed PNS inhibition at the dosage of 0.03–1mg/kg. After methysergide treatment (1mg/kg), naloxone significantly (P<0.05) reduced control bladder capacity during AA infusion but had no effect during saline infusion. Naloxone also had no influence on PNS inhibition. These results suggest that 5-HT2 receptors play a role in PNS inhibition of reflex bladder activity and interact with opioid mechanisms in micturition reflex pathway. Understanding neurotransmitter mechanisms underlying pudendal neuromodulation is important for the development of new treatments for bladder disorders.

273 INVOLVEMENT OF 5-HT2 RECEPTOR IN PUDENDAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER ACTIVITY IN CATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology (I)1 Apr 2013273 INVOLVEMENT OF 5-HT2 RECEPTOR IN PUDENDAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER ACTIVITY IN CATS Yosuke Matsuta, Zeyad Schwen, Abhijith Mally, Bing Shen, Jicheng Wang, James Roppolo, William de Groat, and Changfeng Tai Yosuke MatsutaYosuke Matsuta Pittsburgh, PA More articles by this author , Zeyad SchwenZeyad Schwen Pittsburgh, PA More articles by this author , Abhijith MallyAbhijith Mally Pittsburgh, PA More articles by this author , Bing ShenBing Shen Pittsburgh, PA More articles by this author , Jicheng WangJicheng Wang Pittsburgh, PA More articles by this author , James RoppoloJames Roppolo Pittsburgh, PA More articles by this author , William de GroatWilliam de Groat Pittsburgh, PA More articles by this author , and Changfeng TaiChangfeng Tai Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1657AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Understanding the neurotransmitter mechanisms involved in pudendal nerve inhibition of bladder activity could lead to identify new pharmacological targets for overactive bladder (OAB). Currently little is known about the effect of 5-hydroxytryptamine (5-HT)2 receptor on micturition reflex. This study used methysergide, a 5-HT2 receptor antagonist, and naloxone, an opioid receptor antagonist, to examine the involvement of these receptors in the inhibition of micturition reflex induced by pudendal nerve stimulation (PNS). METHODS Experiments were conducted in 20 cats under α-chloralose anesthesia. A tripolar cuff electrode was applied around the right pudendal nerve and connected to a stimulator. Drugs were administered via the right cephalic vein. Pharmacological studies were performed in two experimental groups (i.e. AA and saline group). In both group, cumulative doses (0.01, 0.03, 0.1, 0.3, and 1 mg/kg) of methysergide and then naloxone (1 mg/kg) were given. RESULTS AA irritated the bladder, induced bladder overactivity and significantly (p < 0.0001) reduced bladder capacity (BC) to 27.0 ± 7.4 % of saline control capacity. PNS (5 Hz, 0.2 ms) at 1-2 and 3-4 times the threshold (T) intensity for inducing an observable twitching of anal sphincter suppressed AA-induced bladder overactivity and significantly increased BC to 60.1 ± 8.0 % at 1-2T (p < 0.0001) and 92.2 ± 14.1 % at 3-4T (p = 0.001) of the saline control capacity. Methysergide (0.03-1 mg/kg, i.v.) suppressed PNS inhibition of bladder overactivity at low intensity (1-2T) but not at high intensity (3-4T). During saline infusion PNS increased BC to 150.8 ± 9.9 % at 1-2T (p < 0.01) and 180.4 ± 16.6 % at 3-4T (p < 0.01) of the saline control capacity. Methysergide significantly increased BC at the doses of 0.1-1 mg/kg (p < 0.05) and suppressed pudendal inhibition. After 1 mg/kg dose of methysergide, naloxone significantly (p < 0.05) reduced BC in AA condition, however, PNS-induced inhibition at 3-4T was still observed. On the other hand, naloxone did not change BC and PNS-induced inhibition in saline condition. CONCLUSIONS These results suggest that 5-HT2 receptor antagonist plays an inhibitory role in both nociceptive and non-nociceptive bladder activity. 5-HT2 receptor interacts with opioid receptor in micturition reflex pathway. Our study indicates methysergide (a FDA-approved drug with few side effects) could be a new treatment for OAB. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e111 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yosuke Matsuta Pittsburgh, PA More articles by this author Zeyad Schwen Pittsburgh, PA More articles by this author Abhijith Mally Pittsburgh, PA More articles by this author Bing Shen Pittsburgh, PA More articles by this author Jicheng Wang Pittsburgh, PA More articles by this author James Roppolo Pittsburgh, PA More articles by this author William de Groat Pittsburgh, PA More articles by this author Changfeng Tai Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Involvement of metabotropic glutamate receptor 5 in pudendal inhibition of nociceptive bladder activity in cats

This study used MTEP, a metabotropic glutamate receptor 5 (mGluR5) antagonist, to examine the role of mGluR5 in the neural control of the urinary bladder and in the inhibition of the micturition reflex by pudendal nerve stimulation (PNS). Experiments were conducted in 11 female cats under α-chloralose anaesthesia when the bladder was infused with either saline or 0.25% acetic acid (AA). AA irritated the bladder, induced bladder overactivity and significantly (P < 0.001) reduced bladder capacity to 14.9 ± 10.3% of the saline control capacity. MTEP (0.1-50 mg kg(-1), i.v.) significantly (P < 0.05) increased bladder capacity during saline distension but not during AA irritation. However, MTEP induced a transient inhibition of isovolumetric bladder contractions under both conditions. PNS (5 Hz), which was tested at the threshold (T) intensity for inducing a complete inhibition of isovolumetric bladder contractions and at an intensity of 3-4T, suppressed AA-induced bladder overactivity and significantly increased bladder capacity to 68.0 ± 31.3% at 1T (P < 0.05) and 98.5 ± 55.3% at 3-4T (P < 0.01) of the saline control capacity. MTEP dose dependently (0.1-50 mg kg(-1), i.v.) suppressed PNS inhibition of bladder overactivity at low intensity (1T) but not at high intensity (3-4T). During saline infusion PNS significantly (P < 0.05) increased bladder capacity to 167.7 ± 27.1% at 1T and 196.0 ± 37.4% at 3-4T. These inhibitory effects were not observed after MTEP (0.1-50 mg kg(-1), i.v.) which also increased bladder capacity. These results indicate that glutamic acid has a transmitter function in bladder and somato-bladder reflex mechanisms and raise the possibility that mGluR5 may be a target for pharmacological treatment of lower urinary tract disorders.