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International Journal of Urology (2014) 21 (Suppl 1), 13–16
doi: 10.1111/iju.12349
Review Article
Urethral sensation: Basic mechanisms and clinical expressions Lori A Birder,1,2 Stefan de Wachter,3 James Gillespie4 and Jean Jacques Wyndaele3 Departments of 1Medicine and 2Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 3Department of Urology, University Antwerpen, Wilrijk, Belgium; and 4School of Dental Sciences, Newcastle University, Newcastle upon Tyne, UK
Abbreviations & Acronyms CGRP = calcitonin gene-related peptide CV = conduction velocity DM = diabetes mellitus EUS = external urethral sphincter LFO = low-frequency oscillations TRPA1 = transient receptor potential channel 1 TRPV1 = transient potential vanilloid receptor 1
Abstract: A prerequisite for conscious bladder control is adequate sensory input to the central nervous system, and it is well established that changes in sensory mechanisms can give rise to disturbances in bladder function. Impulses related to the desire to void are believed to course through the pelvic nerves, and those for sensation of a full bladder course through the pudendal nerves. The sense of imminent micturition most probably resides in the urethra, and the desire to void comes from stretching the bladder wall. In addition, a variety of structures play an important role in terms of urethral closure (such as the urethral epithelium, vasculature and smooth muscle) that are necessary to maintain continence. This overview will discuss mechanisms related in part to the urethra involved in activation of bladder reflexes and sensation with a discussion on the mucosa (urothelium and underlying lamina propria) and underlying cellular structures.
Correspondence: Lori A Birder Ph.D., University of Pittsburgh School of Medicine, A 1217 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA. Email: [email protected]
The uroepithelium, or urothelium, lines the renal pelvis, ureters, bladder, upper urethra and glandular ducts of the prostate, and forms the interface between the urinary space and the underlying vasculature, connective, nervous, and muscular tissues.1,2 In contrast to the urinary bladder, where the urothelium is composed of at least three layers of epithelial cells (the actual number of layers depends on the species), very little has been described regarding the urethral epithelium. Studies of different species have shown that the major part of the urinary tract is lined with a fully differentiated urothelium. Findings in cultured cells show a distinct difference in morphology of ureteral and bladder urothelial cells, supporting a difference in cell lineage. There seems to be no apparent difference between the urothelium of the trigone compared with the detrusor. This is in contrast to the proximal urethra, a region in which a complete “barrier” might not be necessary. Here, the urothelium transitions to a stratified or columnar epithelium accompanied by a lack of urothelial-specific differentiation markers.3 There are also reports of microvilli on the apical surface of the urethral epithelium. The presence of microvilli could play a role in increasing the surface area of the cell, participation in both sensory and transducer functions, and in fluid transport.4 Taken together, present evidence suggests at least three urothelial lineages: (i) those of the ureter/renal pelvis; (ii) detrusor/trigone; and (iii) bladder neck/proximal urethra. In terms of the underlying structures that are likely to contribute to function, there are similarities to that of the bladder body. For example, the urethral epithelium is likely to be part of a signaling system involving projections of the neuroendocrine cells, interstitial cells and sensory nerve endings.4–8 There is speculation that these urethral-neuroendocrine cells (sometimes termed paraneurons) could release mediators, such as serotonin, which through activation of adjacent sensory nerves can stimulate urethral reflexes.8,9 Such types of cells are not unlike that in other types of epithelia, such as the trachea, where a cell type termed “brush cells” has been described, which are likely chemo-receptive and make contact with nearby nerve fibers.10 In addition, there is also a rich vascular network located in close proximity to the urothelium.11 Given the density of this suburothelial capillary network, it is not surprising that the mucosa (which consists of the lamina propria, urothelium and underlying vascular tissue) exhibits a high metabolic rate.12 Conditions such as detrusor overactivity might result in a reduction in blood supply and hypoxia, and are likely to alter urothelial structure and bladder function. There is evidence that hypoxic conditions often correlate with increased levels of angiogenesisstimulating factors, such as vascular endothelial growth factor and hypoxia-inducible factor.13 Studies using human urothelial cells reported that stretch of human urothelial cells from patients
Received October 22 2013; accepted October 22 2013.
© 2014 The Japanese Urological Association
Key words: epithelium, instability, sensation, urethra, vasculature.
Urethral sensation: Introduction and basic structure
13
LA BIRDER ET AL.
diagnosed with overactive bladder resulted in greater levels of vascular endothelial growth factor as compared with control urothelium.14 In terms of bladder nerves, the densest distribution of nerves is thought to be throughout the bladder neck and the initial part of the urethra, where the nerves form a plexus adjacent to the urothelial lining. Gosling and Dixon proposed that these nerves might have a sensory function.15 In addition, there is evidence that primary afferents innervating the bladder and proximal urethra differ in terms of histological and electrophysiological properties as compared with those innervating the distal urethra.16 Some have also found that the nerve plexus is near a network of capillaries in the lamina propria region. While the urothelium in the region of the urethra is not likely to participate as a barrier, there is some evidence that these epithelial cells play a role in continence and sensation. The mucosal pathway (often referred to as a sensory web) within the proximal urethra also involves a cascade of epithelial inhibitory and stimulatory transmitters/mediators. Release of these factors are involved in a complex transduction scheme underlying the activation of bladder nerves and playing a prominent role in sensation. It has been suggested that symptoms of pain that arise from the lower urinary tract might originate principally from the bladder neck and proximal urethra. The bladder neck and proximal urethral contain the largest density of bladder nerves, and the epithelial cells that line the surface show “neuronal-like” properties including expression of proteins sensitive to chemical and physical stimuli. The proximity of afferent nerves to the epithelium suggests that epithelial cells could be targets for transmitters released from bladder nerves and/or that chemicals released by epithelial cells influence afferent nerve excitability. Thus, urethral epithelial–neural interactions (through the release of mediators) could lead to a “urethral instability” that can influence storage and voiding reflexes, and result in symptoms including urgency and pain.17 For example, it has been shown that hormone (estrogen, progesterone) receptors are expressed within the bladder neck and proximal urethra, including the epithelium. These regions are likely to be adversely affected by hormonal decline in aging, which might present with symptoms such as urinary incontinence and urgency.18,19 For some, surgical procedures (including ablation, laser surgery) have resulted in restoration of a functional uroepithelium and improvement of symptoms.20 However, the mechanisms underlying how these and other treatments might alter urethral cell–cell communication in various bladder syndromes have not been explored.
Urethra controlling or modulating bladder activity The urethra has long been considered a tube to guide urine from the bladder to the exterior side of the body. However, urethral function appears to be more complex. There are strong arguments from both animal and human studies to support the ideas that bladder control might at least partly originate or be modulated from inside the urethra. Electrical stimulation of the pudendal nerve afferents in the cat allows both inhibition and activation of the bladder, depending on the urethral location of stimulation and the frequency.21 Besides providing positive 14
feedback to ensure complete bladder emptying, urethral flow can also induce detrusor contraction in the awake ewe resembling a true micturition contraction, which is completely abandoned after applying local anesthesia.22 Both urethral flow and urethral electrical stimulation require a certain bladder volume to be able to induce the detrusor contraction, suggested some baseline bladder afferent activity. It has already been shown in humans that the sensory threshold in the bladder decreases with increasing bladder volumes, suggesting increased excitability of the afferent bladder nerves with increasing bladder volume.23 In spinal cord injured patients, electrical stimulation of the proximal and distal urethra can evoke sustained bladder contractions, at least if the bladder is partly filled.24 Furthermore, the evoked bladder contraction differs between proximal and distal urethral stimulation, suggested different underlying pathways. Once bladder contraction is elicited, urine flows through the urethra, ensuring complete emptying, as observed in animals. Also in humans, there exists such an excitatory urethro-vesical reflex. Urethral anesthetization, blocking activity in urethral afferents, leads to incomplete emptying and the need to strain in healthy volunteers.25 The receptors eliciting this reflex are considered flow receptors, although stretch receptors have been suggested to exist in the human urethra. Urethral dilation with a balloon catheter placed 1–2 cm distal from the bladder neck can evoke a bladder contraction up to 43 cm of water in healthy volunteers, which is abandoned after applying local anesthesia in the urethra.26 These observations in humans underline the complex organization and interaction of the urethral cells and nervous systems.
Histological, anatomical and physiological data In older literature on histology, several different sensory nerve endings/receptors in the lower urinary tract have been described in different species.27 In following years, in the cat, only Vater Pacini bodies and slow adapting nerve endings were mentioned.28 Others give only free nerve endings,29,30 including in humans. In the urethra, mucosal slow adapting receptors and in the urethral serosa Vater Pacini bodies would be present in different types of animals.31–35 Mostly A delta fibers would be present in the posterior urethra. However, it is likely that other types of nerve fibers also play a role. In a cat experiment, Bahns et al. explored mostly single and some multi-units in the afferent axons.36 The receptive fields were found on the surface of the urethra. Two-thirds were thin myelinated (CV 3–15 m/s), the rest presumably unmyelinated (CV
International Journal of Urology (2014) 21 (Suppl 1), 13–16
doi: 10.1111/iju.12349
Review Article
Urethral sensation: Basic mechanisms and clinical expressions Lori A Birder,1,2 Stefan de Wachter,3 James Gillespie4 and Jean Jacques Wyndaele3 Departments of 1Medicine and 2Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 3Department of Urology, University Antwerpen, Wilrijk, Belgium; and 4School of Dental Sciences, Newcastle University, Newcastle upon Tyne, UK
Abbreviations & Acronyms CGRP = calcitonin gene-related peptide CV = conduction velocity DM = diabetes mellitus EUS = external urethral sphincter LFO = low-frequency oscillations TRPA1 = transient receptor potential channel 1 TRPV1 = transient potential vanilloid receptor 1
Abstract: A prerequisite for conscious bladder control is adequate sensory input to the central nervous system, and it is well established that changes in sensory mechanisms can give rise to disturbances in bladder function. Impulses related to the desire to void are believed to course through the pelvic nerves, and those for sensation of a full bladder course through the pudendal nerves. The sense of imminent micturition most probably resides in the urethra, and the desire to void comes from stretching the bladder wall. In addition, a variety of structures play an important role in terms of urethral closure (such as the urethral epithelium, vasculature and smooth muscle) that are necessary to maintain continence. This overview will discuss mechanisms related in part to the urethra involved in activation of bladder reflexes and sensation with a discussion on the mucosa (urothelium and underlying lamina propria) and underlying cellular structures.
Correspondence: Lori A Birder Ph.D., University of Pittsburgh School of Medicine, A 1217 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA. Email: [email protected]
The uroepithelium, or urothelium, lines the renal pelvis, ureters, bladder, upper urethra and glandular ducts of the prostate, and forms the interface between the urinary space and the underlying vasculature, connective, nervous, and muscular tissues.1,2 In contrast to the urinary bladder, where the urothelium is composed of at least three layers of epithelial cells (the actual number of layers depends on the species), very little has been described regarding the urethral epithelium. Studies of different species have shown that the major part of the urinary tract is lined with a fully differentiated urothelium. Findings in cultured cells show a distinct difference in morphology of ureteral and bladder urothelial cells, supporting a difference in cell lineage. There seems to be no apparent difference between the urothelium of the trigone compared with the detrusor. This is in contrast to the proximal urethra, a region in which a complete “barrier” might not be necessary. Here, the urothelium transitions to a stratified or columnar epithelium accompanied by a lack of urothelial-specific differentiation markers.3 There are also reports of microvilli on the apical surface of the urethral epithelium. The presence of microvilli could play a role in increasing the surface area of the cell, participation in both sensory and transducer functions, and in fluid transport.4 Taken together, present evidence suggests at least three urothelial lineages: (i) those of the ureter/renal pelvis; (ii) detrusor/trigone; and (iii) bladder neck/proximal urethra. In terms of the underlying structures that are likely to contribute to function, there are similarities to that of the bladder body. For example, the urethral epithelium is likely to be part of a signaling system involving projections of the neuroendocrine cells, interstitial cells and sensory nerve endings.4–8 There is speculation that these urethral-neuroendocrine cells (sometimes termed paraneurons) could release mediators, such as serotonin, which through activation of adjacent sensory nerves can stimulate urethral reflexes.8,9 Such types of cells are not unlike that in other types of epithelia, such as the trachea, where a cell type termed “brush cells” has been described, which are likely chemo-receptive and make contact with nearby nerve fibers.10 In addition, there is also a rich vascular network located in close proximity to the urothelium.11 Given the density of this suburothelial capillary network, it is not surprising that the mucosa (which consists of the lamina propria, urothelium and underlying vascular tissue) exhibits a high metabolic rate.12 Conditions such as detrusor overactivity might result in a reduction in blood supply and hypoxia, and are likely to alter urothelial structure and bladder function. There is evidence that hypoxic conditions often correlate with increased levels of angiogenesisstimulating factors, such as vascular endothelial growth factor and hypoxia-inducible factor.13 Studies using human urothelial cells reported that stretch of human urothelial cells from patients
Received October 22 2013; accepted October 22 2013.
© 2014 The Japanese Urological Association
Key words: epithelium, instability, sensation, urethra, vasculature.
Urethral sensation: Introduction and basic structure
13
LA BIRDER ET AL.
diagnosed with overactive bladder resulted in greater levels of vascular endothelial growth factor as compared with control urothelium.14 In terms of bladder nerves, the densest distribution of nerves is thought to be throughout the bladder neck and the initial part of the urethra, where the nerves form a plexus adjacent to the urothelial lining. Gosling and Dixon proposed that these nerves might have a sensory function.15 In addition, there is evidence that primary afferents innervating the bladder and proximal urethra differ in terms of histological and electrophysiological properties as compared with those innervating the distal urethra.16 Some have also found that the nerve plexus is near a network of capillaries in the lamina propria region. While the urothelium in the region of the urethra is not likely to participate as a barrier, there is some evidence that these epithelial cells play a role in continence and sensation. The mucosal pathway (often referred to as a sensory web) within the proximal urethra also involves a cascade of epithelial inhibitory and stimulatory transmitters/mediators. Release of these factors are involved in a complex transduction scheme underlying the activation of bladder nerves and playing a prominent role in sensation. It has been suggested that symptoms of pain that arise from the lower urinary tract might originate principally from the bladder neck and proximal urethra. The bladder neck and proximal urethral contain the largest density of bladder nerves, and the epithelial cells that line the surface show “neuronal-like” properties including expression of proteins sensitive to chemical and physical stimuli. The proximity of afferent nerves to the epithelium suggests that epithelial cells could be targets for transmitters released from bladder nerves and/or that chemicals released by epithelial cells influence afferent nerve excitability. Thus, urethral epithelial–neural interactions (through the release of mediators) could lead to a “urethral instability” that can influence storage and voiding reflexes, and result in symptoms including urgency and pain.17 For example, it has been shown that hormone (estrogen, progesterone) receptors are expressed within the bladder neck and proximal urethra, including the epithelium. These regions are likely to be adversely affected by hormonal decline in aging, which might present with symptoms such as urinary incontinence and urgency.18,19 For some, surgical procedures (including ablation, laser surgery) have resulted in restoration of a functional uroepithelium and improvement of symptoms.20 However, the mechanisms underlying how these and other treatments might alter urethral cell–cell communication in various bladder syndromes have not been explored.
Urethra controlling or modulating bladder activity The urethra has long been considered a tube to guide urine from the bladder to the exterior side of the body. However, urethral function appears to be more complex. There are strong arguments from both animal and human studies to support the ideas that bladder control might at least partly originate or be modulated from inside the urethra. Electrical stimulation of the pudendal nerve afferents in the cat allows both inhibition and activation of the bladder, depending on the urethral location of stimulation and the frequency.21 Besides providing positive 14
feedback to ensure complete bladder emptying, urethral flow can also induce detrusor contraction in the awake ewe resembling a true micturition contraction, which is completely abandoned after applying local anesthesia.22 Both urethral flow and urethral electrical stimulation require a certain bladder volume to be able to induce the detrusor contraction, suggested some baseline bladder afferent activity. It has already been shown in humans that the sensory threshold in the bladder decreases with increasing bladder volumes, suggesting increased excitability of the afferent bladder nerves with increasing bladder volume.23 In spinal cord injured patients, electrical stimulation of the proximal and distal urethra can evoke sustained bladder contractions, at least if the bladder is partly filled.24 Furthermore, the evoked bladder contraction differs between proximal and distal urethral stimulation, suggested different underlying pathways. Once bladder contraction is elicited, urine flows through the urethra, ensuring complete emptying, as observed in animals. Also in humans, there exists such an excitatory urethro-vesical reflex. Urethral anesthetization, blocking activity in urethral afferents, leads to incomplete emptying and the need to strain in healthy volunteers.25 The receptors eliciting this reflex are considered flow receptors, although stretch receptors have been suggested to exist in the human urethra. Urethral dilation with a balloon catheter placed 1–2 cm distal from the bladder neck can evoke a bladder contraction up to 43 cm of water in healthy volunteers, which is abandoned after applying local anesthesia in the urethra.26 These observations in humans underline the complex organization and interaction of the urethral cells and nervous systems.
Histological, anatomical and physiological data In older literature on histology, several different sensory nerve endings/receptors in the lower urinary tract have been described in different species.27 In following years, in the cat, only Vater Pacini bodies and slow adapting nerve endings were mentioned.28 Others give only free nerve endings,29,30 including in humans. In the urethra, mucosal slow adapting receptors and in the urethral serosa Vater Pacini bodies would be present in different types of animals.31–35 Mostly A delta fibers would be present in the posterior urethra. However, it is likely that other types of nerve fibers also play a role. In a cat experiment, Bahns et al. explored mostly single and some multi-units in the afferent axons.36 The receptive fields were found on the surface of the urethra. Two-thirds were thin myelinated (CV 3–15 m/s), the rest presumably unmyelinated (CV
