Opioid Modulation of the Micturition Reflex at the Level of the Pontine Micturition Center

Noto, Hiromitsu; Roppolo, James R.; Groat, William C. de; Nishizawa, Osamu; Sugaya, Kimio; Tsuchida, Seigi

doi:10.1159/000282243

Cited by 29 publications

(34 citation statements)

References 11 publications

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“…The present results demonstrating an inhibitory function of supraspinal opioid receptors are consistent with results of studies in decerebrate cats and dogs showing that injections of fentanyl, a -opioid receptor agonist, into the PMC increases bladder capacity during saline CMGs, an effect reversed by injection of naloxone into the PMC (17). This experiment establishes the presence of opioid-inhibitory receptors in the PMC.…”

Section: Discussionsupporting

confidence: 92%

“…This selectivity suggests that neuromodulation targets the afferent limb of the micturition reflex or the supraspinal switching mechanism in the PAG-PMC circuitry but does not alter the efferent (motor) limb of the circuit. Local injections of neurotransmitters or their antagonists into the PMC of decerebrate cats can elicit similar selective changes in bladder capacity without altering the amplitude of reflex bladder contractions (12,17), providing further support for the proposal that the PAG-PMC circuitry is a likely site of action of TNS.…”

Section: Discussionmentioning

confidence: 62%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 62%

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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“…Naloxone administered intracerebroventricularly also reverses the effects of systemically administered morphine. Naloxone administered alone intracerebroventricularly or injected directly into the PMC facilitates the micturition reflex, indicating that micturition is tonically inhibited by a supraspinal opioid mechanism (264,478). Both μ and δ opioid receptors mediate inhibitory effects that are blocked by naloxone (264,398).…”

Section: Pontine Micturition Center and Supraspinal Pathwaysmentioning

confidence: 99%

Neural Control of the Lower Urinary Tract

1997

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This article summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract. The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. The neural control of micturition is organized as a hierarchical system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brain stem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brain stem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary micturition, leading to urinary incontinence. Neuroplasticity underlying these developmental and pathological changes in voiding function is discussed.

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“…The tonic enkephalinergic inhibition of the micturition reflex is believed to be mediated at several possible levels, including the peripheral bladder ganglia, sacral spinal cord, or brainstem (Noto et al, 1991). Studies using several types of MOR drugs have shown that the MOR modulation of bladder motility is exerted both at supraspinal and spinal sites in various species.…”

Section: A New Drug Candidate For Overactive Bladdermentioning

confidence: 99%

“…Opioids have been well known to exert an inhibitory effect on the micturition reflex at various CNS sites, including the pontine micturition center (Noto et al, 1991), sacral parasympathetic nucleus (de Groat et al, 1983), and urethral sphincter motor nucleus in the spinal cord (Thor et al, 1989). Thus, opioid receptors are believed to be potential molecular targets for drugs acting on the CNS for OAB treatment.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of TRK-130 (Naltalimide), a Novel Opioid Ligand, as a New Therapeutic Agent for Overactive Bladder

Fujimura

Izumimoto

Momen

et al. 2014

J Pharmacol Exp Ther

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We characterized 6R,14S)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]phthalimide; naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand-binding assays with cells expressing human m-opioid receptors (MORs), d-opioid receptors (DORs), or k-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (K i for MORs, DORs, and KORs 5 0.268, 121, and 8.97 nM, respectively). In a functional assay (cAMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC 50 (E max )

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Opioid Modulation of the Micturition Reflex at the Level of the Pontine Micturition Center

Cited by 29 publications

References 11 publications

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

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

Neural Control of the Lower Urinary Tract

Characteristics of TRK-130 (Naltalimide), a Novel Opioid Ligand, as a New Therapeutic Agent for Overactive Bladder

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