Capsaicin-Sensitive Sensory Nerves Indirectly Modulate Motor Function of the Urinary Bladder

Abstract

PurposeThe urinary bladder (UB) is innervated by both sensory and autonomic nerves. Recent studies have shown that sensory neuropeptides induced contractions in the detrusor muscle. Therefore, in a mouse model, we investigated the presence of interactions between the submucosal sensory nerves and the autonomic nerves that regulate the motor function of the detrusor muscle.MethodsUB samples from male C57BL/6 mice were isolated, cut into strips, and mounted in an organ bath. Dose-response curves to norepinephrine and phenylephrine were studied in UB strips with and without mucosa, and the effects of preincubation with a receptor antagonist and various drugs on relaxation were also studied using tissue bath myography.ResultsPhenylephrine-induced relaxation of the UB strips showed concentration-related effects. This relaxation appeared in both mucosa-intact and mucosa-denuded UB strips, and was significantly inhibited by lidocaine, silodosin, and guanethidine (an adrenergic neuronal blocker). Meanwhile, phenylephrine-induced relaxation was inhibited by pretreatment with propranolol and calcitonin gene-related peptide (CGRP)–depletory capsaicin in UB strips with and without mucosa.ConclusionsThe present study suggests that phenylephrine activates the α-1A adrenergic receptor (AR) of the sensory nerve, and then activates capsaicin-sensitive sensory nerves to release an unknown substance that facilitates the release of norepinephrine from adrenergic nerves. Subsequently, norepinephrine stimulates β-ARs in the detrusor muscle in mice, leading to neurogenic relaxation of the UB. Further animal and human studies are required to prove this concept and to validate its clinical usefulness.

The Influence of an Adrenergic Antagonist Guanethidine on the Distribution Pattern and Chemical Coding of Caudal Mesenteric Ganglion Perikarya and Their Axons Supplying the Porcine Bladder

“…Recent studies have shown similar results in the lower urinary tract. The inhibitory effect of GUA on the noradrenergic innervation was observed in the bladder detrusor in mice [ 36 ] and rats [ 51 ], and in the urinary bladder neck in pigs [ 38 ]. It is believed that decrease in the density of noradrenergic fibers in target tissues caused by the action of GUA is related to its direct sympathomimetic effect leading to the release of NA from stores in the effector organs [ 52 ], which is followed by inhibition of the re-uptake and re-synthesis of NA, leading to its depletion in the noradrenergic varicosities [ 25 ].…”

“…It has been shown that in most species, including humans, α 1 -adrenoceptor stimulation produces weak detrusor contraction, whereas a stronger contraction is observed in the trigone, bladder base and/or in the bladder neck [ 63 ]. On the other hand, it has been observed that activation of α 1 adrenergic receptors in the urothelium in rats [ 64 ], and the treatment of sensory submucosal nerve fibers in mice [ 36 ] with phenylephrine leads to the release of some unknown neurotransmitters from both sources, which in turn facilitate detrusor relaxation, probably by augmentation of noradrenaline release from the sympathetic nerves. Subsequently, noradrenaline stimulates β-adrenoceptors on the detrusor muscle, leading to relaxation of the urinary bladder [ 36 ].…”

“…On the other hand, it has been observed that activation of α 1 adrenergic receptors in the urothelium in rats [ 64 ], and the treatment of sensory submucosal nerve fibers in mice [ 36 ] with phenylephrine leads to the release of some unknown neurotransmitters from both sources, which in turn facilitate detrusor relaxation, probably by augmentation of noradrenaline release from the sympathetic nerves. Subsequently, noradrenaline stimulates β-adrenoceptors on the detrusor muscle, leading to relaxation of the urinary bladder [ 36 ]. Another mechanism, observed in the bladder neck, relies on prejunctional activation of α 2 adrenoceptors by NA and leads to nitric oxide (NO) release causing smooth muscle relaxation [ 65 ].…”

“…In the case of the urinary bladder, GUA was mainly used to block the effects of sympathetic innervation in functional tests concerning the influence of various biologically active substances and drugs on the contractile activity of this organ. These studies were carried out in humans [ 30 ] and in various animal species such as rabbits, cats, guinea pigs, sheep, rats, mice [ 31 , 32 , 33 , 34 , 35 , 36 ] and pigs [ 37 , 38 , 39 ]. However, based on the available literature, there are no relevant data on the influence of GUA on the neuroarchitecture of sympathetic pathways supplying the urinary bladder.…”

The Afferent Sensory Pathway: The Unsung Hero of Neural Interactions Controlling Detrusor Contractions

“…This is mediated by capsaicin-sensitive prostate afferents. Chang et al [ 11 ] propose that in mice, phenylephrine activates the α-1A adrenergic receptor of a sensory nerve, and then activates a capsaicin-sensitive sensory nerve, causing it to release an unknown substance that facilitates the release of norepinephrine from adrenergic nerves. Subsequently, norepinephrine stimulates β-adrenergic receptors in the detrusor muscle, which leads to neurogenic relaxation of the bladder.…”