Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

The contribution of metabotropic glutamate receptors (mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under α-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly ( P < 0.0001) reduced bladder capacity to 26.6 ± 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 ± 8.3% at 2T ( P < 0.01) and 80.8 ± 9.2% at 4T ( P = 0.0001) of saline control capacity. LY341495 (0.1–5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00368.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. R42-R49 ◽

Cited By ~ 13

Author(s):

Marc J. Rogers ◽

Zhiying Xiao ◽

Bing Shen ◽

Jicheng Wang ◽

Zeyad Schwen ◽

...

Keyword(s):

Receptor Antagonist ◽

Nerve Stimulation ◽

Adrenergic Receptor ◽

Bladder Capacity ◽

Spinal Reflex ◽

Saline Control ◽

Tibial Nerve Stimulation ◽

Bladder Activity ◽

Propranolol Treatment

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.

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Prolonged nonobstructive urinary retention induced by tibial nerve stimulation in cats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00277.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. R428-R434

Author(s):

Shun Li ◽

Jeffery Browning ◽

Katherine Theisen ◽

Todd Yecies ◽

Bing Shen ◽

...

Keyword(s):

Urinary Retention ◽

Nerve Stimulation ◽

Basic Science ◽

Science Studies ◽

Tibial Nerve ◽

Medical Condition ◽

Outlet Obstruction ◽

Bladder Capacity ◽

Residual Volume ◽

Tibial Nerve Stimulation

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 ( P < 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 ( P < 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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Prolonged poststimulation inhibition of bladder activity induced by tibial nerve stimulation in cats

AJP Renal Physiology ◽

10.1152/ajprenal.00526.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. F385-F392 ◽

Cited By ~ 53

Author(s):

Changfeng Tai ◽

Bing Shen ◽

Mang Chen ◽

Jicheng Wang ◽

James R. Roppolo ◽

...

Keyword(s):

Spinal Cord ◽

Short Duration ◽

Nerve Stimulation ◽

Clinical Observation ◽

Tibial Nerve ◽

Bladder Capacity ◽

Inhibitory Effect ◽

Tibial Nerve Stimulation ◽

Bladder Symptoms ◽

Bladder Activity

Inhibition of bladder activity by tibial nerve stimulation was investigated in α-chloralose-anesthetized cats with an intact spinal cord. Short-duration (3–5 min) tibial nerve stimulation at both low (5 Hz) and high (30 Hz) frequencies applied repeatedly during rhythmic isovolumetric bladder contractions was effective in inhibiting reflex bladder activity. Both frequencies of stimulation were also effective in inducing inhibition that persisted after the termination of the stimulation. The poststimulation inhibitory effect induced by the short-duration stimulation significantly increased bladder capacity to 181.6 ± 24.36% of the control capacity measured before applying the stimulation. Thirty-minute continuous stimulation induced prolonged poststimulation inhibition of bladder activity, which lasted for more than 2 h and significantly increased bladder capacity to 161.1 ± 2.9% of the control capacity. During the poststimulation periods, 5-Hz stimulation applied during the cystometrogram elicited a further increase (∼30% on average) in bladder capacity, but 30-Hz stimulation was ineffective. These results in cats support the clinical observation that tibial nerve neuromodulation induces a long-lasting poststimulation inhibitory effect that is useful in treating overactive bladder symptoms.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00623.2014 ◽

2015 ◽

Vol 308 (8) ◽

pp. F832-F838 ◽

Cited By ~ 5

Author(s):

Jeremy N. Reese ◽

Marc J. Rogers ◽

Zhiying Xiao ◽

Bing Shen ◽

Jicheng Wang ◽

...

Keyword(s):

Metabotropic Glutamate Receptor ◽

Bladder Capacity ◽

Spinal Reflex ◽

Saline Control ◽

Metabotropic Glutamate Receptor 5 ◽

Contraction Amplitude ◽

Metabotropic Glutamate ◽

Bladder Contraction ◽

C Fiber

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.

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Recruitment of unmyelinated C-fibers mediates the bladder-inhibitory effects of tibial nerve stimulation in a continuous-fill anesthetized rat model

AJP Renal Physiology ◽

10.1152/ajprenal.00502.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. F163-F171 ◽

Cited By ~ 2

Author(s):

Jason P. Paquette ◽

Paul B. Yoo

Keyword(s):

Overactive Bladder ◽

Nerve Stimulation ◽

Tibial Nerve ◽

Bladder Capacity ◽

Bladder Function ◽

Fiber Types ◽

Percutaneous Tibial Nerve Stimulation ◽

Inhibitory Effects ◽

C Fibers ◽

Tibial Nerve Stimulation

Although percutaneous tibial nerve stimulation is considered a clinically effective therapy for treating overactive bladder, the mechanism by which overactive bladder symptoms are suppressed remains unclear. The goal of the present study was to better understand the role of specific neural inputs (i.e., fiber types) on the bladder-inhibitory effects of tibial nerve stimulation (TNS). In 24 urethane-anesthetized rats, a continuous suprapubic saline infusion model was used to achieve repeated filling and emptying of the bladder. A total of 4 TNS trials (pulse frequency: 5 Hz) were applied in randomized order, where each trial used different amplitude settings: 1) no stimulation (control), 2) Aβ-fiber activation, 3) Aδ-fiber activation, and 4) C-fiber activation. Each stimulation trial was 30 min in duration, with an intertrial washout period of 60−90 min. Our findings showed that TNS evoked statistically significant changes in bladder function (e.g., bladder capacity, residual volume, voiding efficiency, and basal pressure) only at stimulation amplitudes that electrically recruited unmyelinated C-fibers. In a subset of experiments, TNS also resulted in transient episodes of overflow incontinence. It is noted that changes in bladder function occurred only during the poststimulation period. The bladder-inhibitory effects of TNS in a continuous bladder filling model suggests that electrical recruitment of unmyelinated C-fibers has important functional significance. The implications of these findings in percutaneous tibial nerve stimulation therapy should be further investigated.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00422.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. F247-F253 ◽

Cited By ~ 4

Author(s):

Shun Li ◽

Xing Li ◽

Katherine Theisen ◽

Jeffery Browning ◽

Bing Shen ◽

...

Keyword(s):

Nerve Stimulation ◽

Tibial Nerve ◽

Control Level ◽

Bladder Capacity ◽

Saphenous Nerve ◽

Bladder Pressure ◽

Contraction Amplitude ◽

Hindlimb Muscles ◽

Tibial Nerve Stimulation ◽

Bladder Underactivity

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 cmH2O) 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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