Bladder afferent signaling: recent findings

Abstract

Purpose: Much current research on lower urinary tract physiology focuses on afferent mechanisms. The main goals are to define and control the signaling pathways by which afferent information is generated and conveyed to the central nervous system. We summarize recent research on bladder afferent mechanisms.

Materials and methods: We systematically reviewed the literature by searching PubMed up to June 2009 with focus on the last 5 years.

Results: At least 2 signaling pathways can be identified, including the urothelial and the myogenic pathway. The urothelial pathway is a functional unit consisting of the urothelium, interstitial cells and afferent nerves in the lamina propria. Signaling occurs via muscle-mucosal mechanoreceptors, mucosal mechanoreceptors and chemoreceptors. The myogenic pathway is activated via in-series mechanoreceptors responding to distention and via spontaneous contractile activity in units of myocytes generating afferent noise.

Conclusions: To control dysfunctional micturition we must know more about all components involved in normal micturition control, including how afferent information is handled by the central nervous system.

Figure 1

Human LUT innervation. Coordination between bladder and outlet (bladder neck, urethra and urethral sphincters) is mediated by sympathetic (hypogastric), parasympathetic (pelvic) and somatic (pudendal) nerves. Primary cell bodies of Aδ and C-fiber afferents of pelvic and pudendal nerves are contained in lower lumbar and sacral DRG, and afferent innervation in hypogastric nerve arises in rostral lumbar DRG.

Figure 2

LUT afferent nerve classes and distribution. A, fiber classes in bladder wall and urethra. B, in pelvic nerve 4 types of mechanosensitive fibers were identified by stretch, stroke and probe. C, proportion of afferent fiber types recorded in pelvic nerve. D, low and high threshold receptive fields of pelvic nerve muscle fibers based on response to stretch. E, receptive fields of 4 pelvic nerve fiber classes. B to E, adapted from Xu and Gebhart.

Figure 3

Simultaneous recordings show pathological bladder spontaneous contractile activity and corresponding afferent firing. A, normal adult. B, normal adult expanded time base. C, T8-T9 level spinal cord transected (SCT) mouse bladder. D, SCT mouse bladder expanded time base. Arrows indicate action potential of different amplitudes recorded from 3 fibers that responded to spontaneous contraction. E, effect of 10 µM nifedipine on spontaneous contractions and afferent firing in SCT mouse bladder. Reprinted with permission from Elsevier.

Figure 4

Multiple pharmacological targets in bladder may be selected to modulate afferent activity, including receptors on urothelium, interstitial cells and afferent terminals. For example, stretch mediated release of transmitters from urothelium can be inhibited by desensitizing TRPV1 channels using capsaicin or RTX. Interstitial cell activity can be inhibited by blocking P2Y6 receptor activation, eg selective P2Y6 antagonist MRS2578 or c-kit, eg c-kit tyrosine kinase inhibitor Gleevec™. Afferent nerves can be modulated directly by targeting numerous receptors, such as those shown. Clinical studies also showed efficacy of compounds such as botulinum toxin A (BTX-A) on sensory symptoms indicating an action on afferent nerves.