Role of spinal GABA<sub>A</sub>receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats

Xiao, Zhiying; Reese, Jeremy; Schwen, Zeyad; Shen, Bing; Wang, Jicheng; Roppolo, James R.; Groat, William C. de; Tai, Changfeng

doi:10.1152/ajprenal.00679.2013

Cited by 34 publications

(52 citation statements)

References 31 publications

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“…This is consistent with previous studies where administration of GABA A antagonists excited the bladder (24,27), although a recent study reported that picrotoxin increased bladder capacity in cats (56).…”

Section: Effectiveness Of Stimulation-evoked Inhibitionsupporting

confidence: 93%

Section: Gabaergic Mechanisms Participate In Inhibition Of Both Nocicmentioning

confidence: 88%

“…Although previous reports suggested that separate pathways may govern inhibition of nociceptive and nonnociceptive bladder contractions (44,56), GABAergic mechanisms appear critical for inhibition of both types of contractions. A recent study of low-dose picrotoxin found that picrotoxin blocked inhibition of nociceptive, but not nonnociceptive, bladder contractions (56). This finding, when combined with our results, suggests that the nociceptive bladder state produced by infusion of AA may shift the response to picrotoxin to lower doses since blockade of pudendal afferent inhibition of nociceptive bladder contractions occurred at a lower dose than nonnociceptive bladder contractions.…”

Section: Gabaergic Mechanisms Participate In Inhibition Of Both Nocicmentioning

confidence: 88%

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A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

McGee

Danziger

Bamford

et al. 2014

American Journal of Physiology-Renal Physiology

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McGee MJ, Danziger ZC, Bamford JA, Grill WM. A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation. Am J Physiol Renal Physiol 307: F921-F930, 2014. First published August 20, 2014 doi:10.1152/ajprenal.00330.2014.-Electrical stimulation of pudendal afferents can inhibit bladder contractions and increase bladder capacity. Recent results suggest that stimulation-evoked bladder inhibition is mediated by a mechanism other than activation of sympathetic bladder efferents in the hypogastric nerve, generating ␣-adrenergic receptor-mediated inhibition at the vesical ganglia and/or ␤-adrenergic receptor-mediated direct inhibition of the detrusor muscle. We investigated several inhibitory neurotransmitters that may instead be necessary for stimulation-evoked inhibition and found that intravenous picrotoxin, a noncompetitive GABAA antagonist, significantly and reversibly blocked pudendal afferent stimulation-evoked inhibition of bladder contractions in a dose-dependent manner. Similarly, intravenous picrotoxin also blocked pudendal afferent stimulation-evoked inhibition of nociceptive bladder contractions evoked by acetic acid infusion. Furthermore, intrathecal administration of picrotoxin at the lumbosacral spinal cord also blocked bladder inhibition by pudendal afferent stimulation. On the other hand, glycinergic, adrenergic, or opioidergic mechanisms were not necessary for bladder inhibition evoked by pudendal afferent stimulation. These results identify a lumbosacral spinal GABAergic mechanism of bladder inhibition evoked by pudendal afferent stimulation. electrical stimulation; bladder inhibition; pudendal nerve; dorsal nerve of the penis; GABA; picrotoxin IMPROVED BLADDER CONTROL IS an unmet need in persons with urinary incontinence (1) and in persons with neurological disease or injury, such as spinal cord injury (9). Electrical stimulation is a promising approach to treat overactive bladder (OAB), which can produce urgency and incontinence and impair quality of life (8, 32). In particular, pudendal afferent stimulation inhibits distension-evoked bladder contractions and improves continence (51). We sought to identify the mechanism(s) of bladder inhibition by pudendal afferent stimulation.Pudendal nerve (PN) stimulation may be an alternative to sacral nerve stimulation to improve continence (33), and in patients who do not respond to sacral neuromodulation it may be a successful treatment option (29,34,41). Low-frequency (ϳ10 Hz) pudendal afferent stimulation inhibits bladder contractions, thereby promoting continence in preclinical animal studies (4, 46, 52). Inhibition of bladder contractions and increased bladder capacities elicited by low-frequency pudendal afferent stimulation can also be achieved after chronic spinal cord injury (43, 47). However, the mechanisms of action of PN stimulation-mediated bladder inhibition are unclear, and such knowledge may improve patient selection and enable improvements in therapy.Initial studies suggested that pudendal afferent stimu...

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Section: Effectiveness Of Stimulation-evoked Inhibitionsupporting

confidence: 93%

Section: Gabaergic Mechanisms Participate In Inhibition Of Both Nocicmentioning

confidence: 88%

Section: Gabaergic Mechanisms Participate In Inhibition Of Both Nocicmentioning

confidence: 88%

See 1 more Smart Citation

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

McGee

Danziger

Bamford

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Our previous studies in cat revealed that spinal GABA A receptors play an important role in pudendal neuromodulation of bladder overactivity (Xiao et al, 2014), whereas opioid and glycine receptors have no or a minor role (Mally et al, 2013;Rogers et al, 2016). In contrast, we showed that opioid receptors have an essential role in tibial neuromodulation of bladder overactivity in the cat .…”

Section: Introductionmentioning

confidence: 51%

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

Jiang

Fuller

Bandari

et al. 2016

J Pharmacol Exp Ther

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In a-chloralose-anesthetized cats, we examined the role of GABA A , glycine, and opioid receptors in sacral neuromodulationinduced 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 6 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 6 9.0% and 134.8 6 8.9% of saline control, respectively. Picrotoxin, a GABA A 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 A receptors play an important role in sacral neuromodulation of bladder overactivity, whereas glycine receptors only play a minor role to facilitate the GABA A inhibitory mechanism. The poststimulation inhibition unmasked by blocking spinal GABA A receptors was mediated by an opioid mechanism.

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“…On the other hand, inhibitory modulation of reflex bladder activity elicited by pudendal nerve stimulation (PNS) in the cat is markedly different than TNS and foot neuromodulation. PNS inhibition of bladder overactivity is resistant to naloxone (13), does not produce poststimulation inhibition (22), and is mediated in part by activation of GABAergic receptors in the spinal cord (31). PNS inhibition also has a different frequency-response curve, eliciting an increase in bladder capacity only at low frequencies (5-10 Hz) and not at higher frequencies (20 -40 Hz) (28).…”

Section: Discussionmentioning

confidence: 99%

Role of the brain stem in tibial inhibition of the micturition reflex in cats

Ferroni

Slater

Shen

et al. 2015

American Journal of Physiology-Renal Physiology

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This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in ␣-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (Ͼ2 h) poststimulation inhibition that significantly (P Ͻ 0.05) increased bladder capacity to 30 -60% above control; however, TNS did not produce this effect during AA irritation. TNS applied during CMGs at 5 Hz but not 30 Hz significantly (P Ͻ 0.01) increased bladder capacity to 127.3 Ϯ 6.1% of saline control or 187.6 Ϯ 5.0% of AA control. During AA irritation, naloxone (an opioid receptor antagonist) administered intravenously (1 mg/kg) or directly to the surface of the rostral brain stem (300 -900 g) eliminated acute TNS inhibition and significantly (P Ͻ 0.05) reduced bladder capacity to 62.8 Ϯ 22.6% (intravenously) or 47.6 Ϯ 25.5% (brain stem application). Results of this and previous studies indicate 1) forebrain circuitry rostral to the pons is not essential for TNS inhibition; and 2) opioid receptors in the brain stem have a critical role in TNS inhibition of overactive bladder reflexes but are not involved in inhibition of normal bladder reflexes. neuromodulation; brain stem; opioid; tibial; cat TIBIAL NEUROMODULATION, a Food and Drug Administration (FDA)-approved therapy for overactive bladder (OAB) symptoms, including urgency, frequency, and incontinence (7,19,20,29), is often used to treat patients whose symptoms are not completely controlled by drugs or who have unacceptable drug side effects (1,2,8,18). However, the mechanisms underlying tibial neuromodulation therapy are uncertain. Understanding the site of action and neurotransmitters involved in the inhibition of bladder reflexes by tibial nerve stimulation (TNS) is important for developing new OAB treatments by combining drug therapies with tibial neuromodulation to achieve a higher efficacy with fewer side effects (14,33).Previous studies in cats have demonstrated the inhibitory effect of TNS on bladder reflexes elicited during non-nociceptive saline distention as well as nociceptive acetic acid (AA) irritation (23,27). The failure of TNS to inhibit reflex bladder contractions during AA irritation in animals with acute spinal cord transection at the T9/T10 level (32) indicates that supraspinal neural circuits are necessary for TNS inhibition. However, it is unknown whether these supraspinal circuits are located in the forebrain or in the brain stem.A major clinical benefit of TNS is the long-lasting poststimulation inhibitory effect, which allows...

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

Cited by 34 publications

References 31 publications

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

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

Role of the brain stem in tibial inhibition of the micturition reflex in cats

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

Cited by 34 publications

References 31 publications

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

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

Role of the brain stem in tibial inhibition of the micturition reflex in cats

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

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