Urothelial mucosal signaling and the overactive bladder-ICI-RS 2013

Abstract

There is abundant evidence that the lower urinary tract (LUT) mucosal layer is involved both in mechanosensory functions that regulate bladder contractile activity and in urethral sensation. Changes to the mucosa can be associated with a number of bladder pathologies. For example, alterations of the urothelium and underlying lamina propria at both the molecular and structural levels have been reported in both patients and animals associated with disorders such as bladder pain syndrome and diabetic cystopathy. In contrast to the urinary bladder, much less is known about the urothelium/lamina propria of the bladder neck/proximal urethra. There are important gender differences in the outflow region both anatomically and with respect to innervation, hormonal sensitivity, and location of the external urethral sphincter. There is reasonable evidence to support the view that the mucosal signaling pathway in the proximal urethra is important for normal voiding, but it has also been speculated that the proximal urethra can initiate bladder overactivity. When dysfunctional, the proximal urethra may be an interesting target, for example, botulinum toxin injections aiming at eliminating both urgency and incontinence due to detrusor overactivity.

Receptors, channels, and signalling in the urothelial sensory system in the bladder

“…Many different receptors and ion channels have been identified in the urothelium and many are implicated in mechanoceptive or nociceptive sensations 2,12,13,24–26 . These receptors and ion channels include purinergic (such as P2X 1–7 and P2Y 1 , P2Y 2 , and P2Y 4 ) 2,27 (TABLE 1), adrenergic (α and β) 2 , cholinergic (muscarinic; M 1 –M 5 and nicotinic α 2 –α 10 , β 2 and β 4 ) 2 , protease-activated receptors 28 , acid sensing ion channels (ASIC) (such as ASIC2a and ASIC3) 29 , neurotrophin receptors (p75 NTR and tropomyosin receptor kinases A and B) 30–33 , CRF receptors 1 and 2 (REF.…”

Effects of nicotinic receptor agonists on bladder afferent nerve activity in an in vitro bladder–pelvic nerve preparation

“…Epibatidine and nicotine could also influence afferent activity indirectly by modulating the release of neurotransmitters in the bladder because NNRs are expressed at various sites in the bladder-pelvic nerve preparation including efferent nerve terminals, urothelial cells and autonomic ganglion cells located in the extrinsic nerves innervating the bladder (Birder and Andersson, 2013; Birder et al, 2014; de Groat and Yoshimura, 2009; de Groat et al, 2015; Hisayama et al, 1988; Shinkai et al, 1991; Somogyi and de Groat, 1992). Indirect effects on afferent excitability due to stimulation of efferent pathways and release of acetylcholine or ATP were examined because in the majority of experiments bath application of epibatidine elicited bladder contractions.…”

Mucosal signaling in the bladder

“…However, it is the c-fibers that likely mediate mucosal signaling, especially in bladder disease. They are abundant in the suburothelium at the bladder neck and trigone, and the plexus becomes less prominent moving toward the dome (Birder et al, 2014;Andersson, 2002). c-Fibers respond to stretch at a higher threshold than Aδ fibers, and respond more readily to sensory input such as chemical irritants or cold exposure (Andersson, 2002).…”