Effect of methysergide on pudendal inhibition of micturition reflex in cats
Introduction
Overactive bladder (OAB) is a symptom complex of urinary urgency, frequency and incontinence that can be treated by pudendal nerve or sacral neuromodulation (Peters et al., 2005, Peters et al., 2010, van Kerrebroeck et al., 2007). Pudendal neuromodulation has been reported to be superior to sacral neuromodulation in patients with intractable OAB or painful bladder syndrome (PBS) (Peters, 2002, Peters et al., 2005). However, the mechanisms underlying neuromodulation therapies are currently still unknown. Understanding the mechanisms could potentially improve the efficacy of these therapies or develop new treatments for bladder disorders (Andersson, 2004, Andersson and Wein, 2004).
Our studies in cats (Tai et al., 2012, Zhang et al., 2012) have identified an involvement of opioid receptors in tibial nerve stimulation-induced inhibition of nociceptive bladder overactivity caused by intravesical acetic acid (AA) irritation. Activation of opioid receptors also plays a minor role in pudendal nerve stimulation (PNS)-induced inhibition of non-nociceptive reflex bladder activity in cats caused by saline distention of the bladder (Chen et al., 2010); but does not contribute to PNS inhibition of nociceptive bladder overactivity (Mally et al., 2013). Thus, neurotransmitters other than endogenous opioid peptides must mediate PNS inhibition of reflex bladder activity.
Previous studies in various species (cats, rats, guinea pigs) have raised the possibility that 5-hydroxytryptamine (5-HT) may function as an inhibitory or excitatory transmitter that modulates the micturition reflex pathway in the brain and spinal cord (Cheng and de Groat, 2010, de Groat, 2002, Mbaki et al., 2012, Ramage, 2006) and that it also has an important role in the regulation of nociceptive mechanisms in the central nervous system (Basbaum and Fields, 1984). Thus, we have conducted a pharmacological study to examine the contribution of 5-HT to the inhibition of nociceptive and non-nociceptive bladder reflexes induced by PNS. We have used methysergide, a non-selective 5-HT2 receptor antagonist, which in a rat model of somatic nociception was effective after intrathecal administration in significantly reducing the antihyperalgesic effect of transcutaneous electrical nerve stimulation or mechanical joint manipulation (Radhakrishnan et al., 2003, Skyba et al., 2003). These results indicated that descending serotonin (5-HT) inhibitory mechanisms might be involved in neuromodulation of somatic nociception in the spinal cord.
In addition, intrathecal administration of methysergide to cats enhanced the axonal firing in the lateral funiculus of T11–T12 spinal segments elicited by electrical stimulation of bladder afferent axons in the pelvic nerve (Espey et al., 1998). These observations suggested that methysergide-sensitive 5-HT receptors generate a tonic inhibitory modulation of the ascending limb of the spinobulbospinal micturition reflex pathway (Espey et al., 1998). This modulatory input arises in the brain stem raphe nuclei where electrical (McMahon and Spillane, 1982, Morrison and Spillane, 1986) or chemical stimulation (Chen et al., 1993) has been shown to inhibit bladder reflexes. Therefore, the present study was undertaken to determine if methysergide-sensitive 5-HT receptors might be involved in PNS inhibition of nociceptive or non-nociceptive bladder reflexes.
Intravesical infusion of diluted (0.25%) AA was used in this study to irritate the bladder, activate the nociceptive bladder C-fiber afferents, and induce bladder overactivity in α-chloralose anesthetized cats, while saline infusion was used to distend the bladder, activate the non-nociceptive bladder Aδ-fiber afferents, and induce normal reflex bladder activity (Fowler et al., 2008, Häbler et al., 1990). PNS was employed as the antinociceptive stimulus to model the clinical use of pudendal neuromodulation in treating OAB or painful bladder syndrome (PBS) (Peters, 2002, Peters et al., 2005). Methysergide and naloxone (an opioid receptor antagonist) were administered intravenously to determine the role of 5-HT and opioid receptor mechanisms in the neuromodulation. WAY100635 (a 5-HT1A receptor antagonist) was used to exclude the possibility that methysergide affects the bladder activity through activation of 5-HT1A receptors.
Section snippets
Materials and methods
The Animal Care and Use Committee at the University of Pittsburgh approved all protocols involving the use of animals in this study.
PNS inhibition of reflex bladder activity
Intravesical infusion of 0.25% AA irritated the bladder, activated nociceptive bladder C-fiber afferents, and significantly (P < 0.0001) reduced bladder capacity to 27.0 ± 7.4% of the saline control capacity (11.2 ± 2.2 ml, N = 8 cats) (Figs. 1A and B). PNS at 1–2T or 3–4T intensity suppressed AA-induced bladder overactivity and significantly increased bladder capacity to 60.6 ± 8.0% (P < 0.0001) or 92.2 ± 14.1% (P = 0.001) of saline control capacity, respectively (Figs. 1A and B). After termination of the PNS,
Discussion
This study revealed that intravenous administration of methysergide, a non-selective 5-HT2 receptor antagonist, significantly increased bladder capacity during both AA and saline infusion CMGs (Figs. 2A, 3A and 4), partially suppressed the PNS inhibition of AA irritation-induced bladder overactivity and completely suppressed PNS inhibition of saline distention-induced bladder activity (Fig. 2, Fig. 3, Fig. 4). WAY100635, a selective 5-HT1A receptor antagonist, did not influence bladder capacity
Acknowledgment
This study is supported by the National Institute of Health under Grants DK-068566, DK-090006 and DK-091253.
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