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

Abstract

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...

Sacral neuromodulation of nociceptive bladder overactivity in cats

“…), indicating that nociceptive afferent input from the bladder can either block the post‐stimulation inhibition or activate a reflex mechanism that is resistant to post‐stimulation inhibition. Similar post‐stimulation inhibition was also observed for tibial neuromodulation in cats . The clinical implications of these results could be that those patients responding to tibial neuromodulation might have OAB caused by the overactivity in the supraspinal micturition pathway because clinical tibial neuromodulation utilizes a post‐stimulation effect.…”

“…Sacral neuromodulation could activate afferent fibers from both tibial and pudendal nerves that travel in the sacral dorsal roots. Our previous study in cats has shown that post‐stimulation inhibition can be induced by tibial nerve stimulation only during saline infusion (non‐nociceptive condition) but not during AA irritation (nociceptive condition), while pudendal nerve stimulation cannot induce a post‐stimulation effect under either bladder condition . These comparative results indicate that the afferent nerve fibers from the tibial nerve that travel in sacral dorsal roots might be responsible for the post‐stimulation inhibition elicited by sacral dorsal root stimulation under non‐nociceptive bladder condition .…”

“…Similar poststimulation inhibition was also observed for tibial neuromodulation in cats. 9 The clinical implications of these results could be that those patients responding to tibial neuromodulation might have OAB caused by the overactivity in the supraspinal micturition pathway because clinical tibial neuromodulation utilizes a post-stimulation effect. Meanwhile, those patients not responding to tibial neuromodulation might be better treated by pudendal or sacral neuromodulation that stimulates the nerve continuously and does not depend on a post-stimulation effect.…”

“…Meanwhile, those patients not responding to tibial neuromodulation might be better treated by pudendal or sacral neuromodulation that stimulates the nerve continuously and does not depend on a post‐stimulation effect. It is worth noting that in acute animal studies the post‐stimulation inhibition which lasted more than 2 h may not be comparable to the clinical post‐stimulation inhibition produced by chronic tibial neuromodulation that lasts for several weeks. Chronic animal studies are needed in order to determine the full duration of post‐stimulation inhibition observed in recent animal studies …”

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

“…Similar to tibial neuromodulation (Ferroni et al, 2015), sacral neuromodulation only produced poststimulation inhibition of reflex bladder activity during saline cystometry , but not during AA cystometry that induces bladder overactivity (Fig. 1).…”