Involvement of Opioid Receptors in Inhibition of Bladder Overactivity Induced by Foot Stimulation in Cats

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The purpose of this study was to determine whether duloxetine [a serotonin (5-HT)-norepinephrine reuptake inhibitor] combined with transcutaneous foot stimulation or WAY-100635 (a 5-HT1A antagonist) can enhance inhibition of bladder overactivity in cats. Cystometrograms were performed on eight cats under α-chloralose anesthesia by infusing saline and then 0.25% acetic acid (AA) to induce bladder overactivity. To inhibit bladder overactivity, foot stimulation (5 Hz) was applied via transcutaneous pad electrodes to the right hindfoot at two and four times the threshold intensity for inducing a toe twitch. Duloxetine (0.003-3 mg/kg) was administered intravenously to determine the effect of combination treatment. After the 3 mg/kg dose of duloxetine, WAY-100635 (0.5 mg/kg) was given intravenously. AA irritation significantly (P < 0.0001) reduced bladder capacity to 42.7 ± 7.4% of the saline control capacity. Foot stimulation alone at both two and four times the threshold intensity significantly (P < 0.0001) inhibited bladder overactivity and increased bladder capacity to 66.7 ± 6.3% and 85.7 ± 6.5% of the saline control, respectively. Duloxetine alone dose dependently inhibited bladder overactivity and completely restored bladder capacity to the saline control (109 ± 15.5%) at 3 mg/kg. Although duloxetine combined with foot stimulation did not further enhance inhibition, WAY-100635 (0.5 mg/kg) given after 3 mg/kg duloxetine further increased (P = 0.008) bladder capacity to 162.2 ± 22.5% of the saline control. Although duloxetine and foot stimulation independently inhibited bladder overactivity, combined treatment did not enhance inhibition. Duloxetine combined with WAY-100635, however, synergistically enhanced bladder inhibition, indicating a potential novel treatment for overactive bladder if duloxetine is combined with a 5-HT1A receptor antagonist drug.

Section: Discussionmentioning

confidence: 97%

Inhibition of bladder overactivity by duloxetine in combination with foot stimulation or WAY-100635 treatment in cats

Schwen

Matsuta

Shen

et al. 2013

Self Cite

“…This putative reduction in opioid inhibition by AA might also contribute to the bladder overactivity in CNS intact cats. Information about TNS inhibition of reflex bladder activity may also provide insights into the mechanisms of action of other types of neuromodulation such as foot stimulation because the latter and TNS exhibit similar properties, including naloxone sensitivity (15,24,25) and prolonged poststimulation inhibition (4,27). Inhibition by TNS or foot stimulation also has similar frequency characteristics during AA CMGs, producing an increase in bladder capacity over a wide range of frequencies (5-30 Hz) (23,26).…”

Section: Discussionmentioning

confidence: 99%

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

Ferroni

Slater

Shen

et al. 2015

Self Cite

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...

“…Studies in the cat have shown that neuromodulation-induced inhibition of bladder contractions may involve endogenous opioids (5,16,27). Additional studies are required to determine whether the contribution of the opioid pathway differs depending on the specific nerve target (e.g., SN) or stimulation parameters and which receptor subtypes are involved.…”

Section: Su X Nickles a Nelson Dementioning

confidence: 99%

“…Peripherally, activation of opioid receptors triggers recurrent inhibition from bladder parasympathetic preganglionic neurones to prevent prolonged bladder contractions (17). It is not known whether endogenous opioid peptides are released during either normal or pathologic micturition or whether endogenous opioids can produce a net inhibitory action on a pathologic micturition reflex.Studies in the cat have shown that neuromodulation-induced inhibition of bladder contractions may involve endogenous opioids (5,16,27). Additional studies are required to determine whether the contribution of the opioid pathway differs depending on the specific nerve target (e.g., SN) or stimulation parameters and which receptor subtypes are involved.…”

mentioning

confidence: 99%

Role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve stimulation

Nickles

Nelson

2013

The role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve (SN) stimulation was studied in anesthetized female rats, using the rat model of isovolumetric bladder contraction. SN stimulation at a fixed frequency of 10 Hz attenuated bladder contraction frequency; the magnitude of the inhibition was directly proportional to the current intensity. Neither the κ-opioid antagonist nor-binaltorphimine (2 mg/kg iv) nor the δ-opioid antagonist naltrindole (5 mg/kg iv) attenuated the bladder inhibitory response to SN stimulation. In contrast, the μ-opioid receptor antagonist naloxone (NLX; 0.03 mg/kg iv) blocked the inhibitory responses evoked by SN stimulation at therapeutic current intensities at ≤1 × motor threshold current (Tmot). An action at spinal and supraspinal centers was further confirmed by the ability of intrathecal or intracerebroventricular administration of NLX methiodide to attenuate the bladder inhibitory effects of 1 × Tmot SN stimulation. The magnitude of SN-mediated neuromodulation using therapeutically relevant stimulation intensity (Tmot) is equivalent to 0.16 mg/kg of systemically administered morphine, which produces 50% inhibition of bladder contraction frequency. These results suggest that the inhibitory effects of lower intensity SN stimulation may be mediated through the release of endogenous μ-opioid peptides. Additionally, these data suggest that neuromodulation may offer a mode of treating the symptoms of overactive bladder with efficacy equal to the opioid drugs but without their liability for abuse and dependence.