The concept of peripheral modulation of bladder sensation

Abstract

It is recognized that, as the bladder fills, there is a corresponding increase in sensation. This awareness of the volume in the bladder is then used in a complex decision making process to determine if there is a need to void. It is also part of everyday experience that, when the bladder is full and sensations strong, these sensations can be suppressed and the desire to void postponed. The obvious explanation for such altered perceptions is that they occur centrally. However, this may not be the only mechanism. There are data to suggest that descending neural influences and local factors might regulate the sensitivity of the systems within the bladder wall generating afferent activity. Specifically, evidence is accumulating to suggest that the motor-sensory system within the bladder wall is influenced in this way. The motor-sensory system, first described over 100 years ago, appears to be a key component in the afferent outflow, the afferent "noise," generated within the bladder wall. However, the presence and possible importance of this complex system in the generation of bladder sensation has been overlooked in recent years. As the bladder fills the motor activity increases, driven by cholinergic inputs and modulated, possibly, by sympathetic inputs. In this way information on bladder volume can be transmitted to the CNS. It can be argued that the ability to alter the sensitivity of the mechanisms generating the motor component of this motor-sensory system represents a possible indirect way to influence afferent activity and so the perception of bladder volume centrally. Furthermore, it is emerging that the apparent modulation of sensation by drugs to alleviate the symptoms of overactive bladder (OAB), the anti-cholinergics and the new generation of drugs the β 3 sympathomimetics, may be the result of their ability to modulate the motor component of the motor sensory system. The possibility of controlling sensation, physiologically and pharmacologically, by influencing afferent firing at its point of origin is a "new" concept in bladder physiology. It is one that deserves careful consideration as it might have wider implications for our understanding of bladder pathology and in the development of new therapeutic drugs. In this overview, evidence for the concept peripheral modulation of bladder afferent outflow is explored.

Keywords: afferent nerves; bladder; modulation; pharmacology; sensation.

Figure 1.

The components of afferent noise in the guinea pig. (A) Illustrates the broad elements of the afferent systems associated with the bladder: components of afferent noise. Four are identified: pain, mechano-sensory, urothelial and motor-sensory. Each sends afferent information to the CNS but only the motor-sensory system has the potential for an output from the CNS and inputs from peripheral afferent fibers. (B) Illustrates in more detail some of the component parts of the systems making up afferent noise. The afferent out flow to the CNS can again be seen for each system: 1, pain; 2, mechano-sensitive (stretch); 3, urothelial; 4, motor-sensory. For the motor-sensory system, part of the complex regulatory systems involved in the regulation of motor activity may be occurring via the intra-mural ganglia and local neural circuits within the bladder wall. Reprinted from reference with permission.

Figure 2.

Motor activity and the generation of afferent firing. (A) Illustrates one of the original records of non-voiding motor activity recorded in the cat from where it was first proposed that this activity was associated with afferent firing and the control of micturition. (B) Illustrates confirmation of this concept showing the motor activity in the cat (upper record) with associated bursts of afferent nerve activity (lower record) (reprinted from reference with permission). (C) Shows a cystometric record from a conscious rat during bladder filling. Voids can be seen at the beginning and end of the recording. During the filling phase small non-voiding contractions appear, progressively increasing in amplitude and frequency as the bladder fills. The progressive increase in motor activity implies that the intensity of afferent activity is also increasing during filling (reprinted from reference with permission).

Figure 3. The effects of the β₃ specific agonist mirabegron on motor sensory noise in the conscious partially obstructed rat (modifed from reference ¹⁰). (A) Illustrates an original record showing 4 filling and voiding cycles during cystometry in a conscious rat. The micturition contractions are easily seen. The first 2 cycles are under control conditions and the motor component of the motor-sensory system, the non-voiding activity, is apparent. This is more clearly seen in section (B) where the non-voiding activity has been isolated by filtering. The β₃ specific agonist (YM-178, mirabegron) was then added and the effects on the following filling and voiding cycles noted. The drug clearly affects the non-voiding activity but has little effect on the amplitude of the voiding contraction. (Reprinted from reference with permission). (B) Shows a cartoon proposing how on-voiding activity and micturition activity is generated in the rat. The accepted parasympathetic motor system is there to initiate the large voiding contraction. In addition the system generating and modulating the motor component of the motor-sensory noise behaves as though it had a “pacemaker” controlled by cholinergic (excitatory) and adrenergic (inhibitory) inputs. Afferent fibers (green) respond to the local contractions and stretches sending information related to bladder volume to the CNS.

Figure 4. Images of afferent nerves and intra-mural ganglia in the guinea pig bladder. The sections were stained for choline-acetyltransferase (ChAT) (red) detecting the enzyme responsible for synthesising acetylcholine. The sections were also stained with an antibody to calcitonin gene related peptide (CGRP) (green). Almost certainly these CGRP fibers are afferent fibers. (A and B) Show images of sub-urothelial cholinergic (A) and peptidergic (CGRP) (B) nerves indicating two distinct populations of afferent fiber. (C and D) Show cholinergic terminals (C, red) within the intra-mural-ganglia as are CGRP terminals (C and D, green). These observations suggest the possibility of integration of different inputs into these neurons. Panel E shows a cartoon illustrating the possible interactions of afferent collaterals, both peptidergic (CGRP) and cholinergic with the intra-mural ganglia. An output to the muscle is postulated that is in addition to the conventional parasympathetic system involved in the initiation of the voiding contraction (reprinted from reference with permission).