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      The concept of peripheral modulation of bladder sensation

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      Organogenesis
      Landes Bioscience
      bladder, sensation, afferent nerves, modulation, pharmacology

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          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.

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          Most cited references70

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          Tension receptors in the stomach and the urinary bladder.

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            Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder.

            It has been proposed that extracellular ATP may be involved in visceral mechanosensory transduction by activating ligand-gated ion channels (P2X receptors). In this study, we have investigated the effects of the P2X(3) agonist alpha,beta-methylene ATP (alpha,beta-meATP) and antagonist 2',3'-O-trinitrophenyl-ATP (TNP-ATP) on pelvic afferents innervating the urinary bladder using an in vitro mouse bladder-pelvic nerve preparation. Intravesical application of alpha,beta-meATP (0.03-1 mM) increased multifibre discharges in a concentration-dependent manner. The agonist potentiated, whereas TNP-ATP (0.03 mM) attenuated, the multifibre responses to bladder distensions. Single-unit analysis revealed that both high threshold (HT) fibres (> 15 mmHg; known to be associated with nociception) and low threshold (LT) fibres (< 15 mmHg; probably associated with non-nociceptive events) could be induced to discharge by intravesical alpha,beta-meATP (1 mM, 0.1 ml). The response of the vast majority (21/22, 95.5 %) of HT fibres to bladder distensions was enhanced with a significantly reduced threshold and an increased peak response after exposure to the agonist. On the other hand, 59.7 % (46/77) of LT fibres showed a greater peak and a slightly reduced threshold for response to bladder distension in the presence of alpha,beta-meATP. An additional 11 'silent' fibres became mechanosensitive after exposure to alpha,beta-meATP. TNP-ATP (0.03 mM) did not affect the threshold of LT fibres, but it reduced the peak response of some (22/51, 43.1 %) LT fibres. Conversely, the antagonist resulted in a markedly elevated threshold and reduced peak activity in the majority (13/16, 81.3 %) of HT fibres. The results support the view that P2X(3) receptor-mediated mechanisms contribute to both nociceptive and non-nociceptive (physiological) mechanosensory transduction in the urinary bladder.
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              Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging.

              Numerous studies have detailed age-related changes in the structure and function of the bladder that may contribute to the high prevalence of overactive bladder (OAB) in the elderly population, but the relation of these changes to OAB symptoms remains unclear. Physiologic and neurochemical studies have been conducted in human detrusor strips obtained from people of different ages, focusing on potential changes in cholinergic and purinergic neurotransmission, as well as the release and actions of acetylcholine (ACh) from nonneuronal bladder cells. Results from physiologic and microdialysis experiments indicate that purinergic transmission increases with age, whereas cholinergic transmission decreases. These effects are most likely because of decreased release of ACh and increased release of adenosine triphosphate (ATP) from postganglionic parasympathetic axons innervating the bladder. Immunohistochemical experiments showed that choline acetyltransferase in the human detrusor is contained not only in parasympathetic axons, but also in cells of the urothelium. The release of nonneuronal ACh increases with age and detrusor stretch. The age-related increase in purinergic transmission in the detrusor and other data indicating that responses to ATP are increased in detrusor overactivity suggest that purinergic receptor antagonists may provide a useful complement to muscarinic receptor antagonists in the treatment of older patients with OAB. Nonneuronal ACh release may play a key role in the storage phase of the micturition reflex, and this may explain, at least in part, the effectiveness of antimuscarinic agents for the treatment of OAB.
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                Author and article information

                Journal
                Organogenesis
                Organogenesis
                ORG
                Organogenesis
                Landes Bioscience
                1547-6278
                1555-8592
                01 July 2013
                05 August 2013
                05 August 2013
                : 9
                : 3
                : 224-233
                Affiliations
                Uro-physiology Research Group; The Dental and Medical School; Newcastle University; Newcastle upon Tyne, England
                Author notes
                [* ]Correspondence to: James I Gillespie, Email: james.gillespie@ 123456ncl.ac.uk
                Article
                2013ORG0032R 25895
                10.4161/org.25895
                3896594
                23917648
                ffa0f77f-f7a1-45f4-9286-88c6daad0f23
                Copyright © 2013 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 28 June 2013
                : 17 July 2013
                : 23 July 2013
                Categories
                Special Focus Review

                Molecular biology
                bladder,sensation,afferent nerves,modulation,pharmacology
                Molecular biology
                bladder, sensation, afferent nerves, modulation, pharmacology

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