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Genitourinary and gastrointestinal co-morbidities in children: The role of neural circuits in regulation of visceral function
Accepted Manuscript Genitourinary and gastrointestinal co-morbidities in children: the role of neural circuits in regulation of visceral function A.P. Malykhina, K.E. Brodie, D.T. Wilcox PII:
S1477-5131(16)30104-8
DOI:
10.1016/j.jpurol.2016.04.036
Reference:
JPUROL 2220
To appear in:
Journal of Pediatric Urology
Received Date: 18 January 2016 Accepted Date: 5 April 2016
Please cite this article as: Malykhina AP, Brodie KE, Wilcox DT, Genitourinary and gastrointestinal comorbidities in children: the role of neural circuits in regulation of visceral function, Journal of Pediatric Urology (2016), doi: 10.1016/j.jpurol.2016.04.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review article
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Genitourinary and gastrointestinal comorbidities in children: the role of neural circuits in regulation of visceral function
a
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A. P. Malykhinaa, K. E. Brodiea,b, D. T. Wilcoxa,c,*
Division of Urology, Department of Surgery, University of Colorado School of Medicine
b
Department of Pediatric Urology, Children's Hospital of Colorado, 13123 E 16th Avenue,
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Aurora, CO 80045, USA
*Corresponding author: Department of Pediatric Urology, Children's Hospital of Colorado,
777-7370.
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13123 E. 16th Avenue, B463, Aurora, CO, 80045, USA. Tel.: (+1) 720-777-3926; fax: (+1) 720-
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E-mail address: [email protected] (D. T. Wilcox)
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Summary Objective: Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. Lower urinary tract symptoms in children include overactive bladder, voiding postponement, stress
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incontinence, giggle incontinence, and dysfunctional voiding. Gastrointestinal co-morbidities, including constipation or fecal incontinence, are commonly associated with lower urinary tract (LUT) symptoms in children, often reaching 22-34%. This review summarized the potential
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mechanisms underlying functional lower urinary and gastrointestinal co-morbidities in children. It also covered the current understanding of clinical pathophysiology in the pediatric population,
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anatomy and embryological development of the pelvic organs, role of developing neural circuits in regulation of functional co-morbidities, and relevant translational animal models. Materials and methods: This was a non-systematic review of the published literature, which summarized the available clinical and translational studies on functional urologic and
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gastrointestinal co-morbidities in children, as well as neural mechanisms underlying pelvic organ ‘cross-talk’ and ‘cross-sensitization’.
Results: Co-morbidity of pediatric lower urinary and gastrointestinal dysfunctions could be
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explained by multiple factors, including a shared developmental origin, close anatomical proximity, and pelvic organ ‘cross-talk’. Daily physiological activity and viscero-visceral reflexes
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between the lower gastrointestinal and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant modulatory role of the neural pathways. Recent studies have provided evidence that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs due to a phenomenon known as pelvic organ ‘cross-sensitization’. Cross-sensitization between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs. Investigation of functional changes in nerve fibers and neurons sets certain limits in
ACCEPTED MANUSCRIPT conducting appropriate research in humans, making the use of animal models necessary to uncover the underlying mechanisms and for the development of novel therapeutic approaches for long-term symptomatic treatment of LUTD in the pediatric population.
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Conclusion: Pediatric LUTD is often complicated by gastrointestinal co-morbidities; however, the mechanisms linking bladder and bowel dysfunctions are not well understood. Clinical studies have suggested that therapeutic modulation of one system may improve the other system’s function. To
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better manage children with LUTD, the interplay between the two systems, and how co-morbid GI and voiding dysfunctions can be more specifically targeted in pediatric clinics need to be
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understood.
Keywords: Urologic and gastrointestinal co-morbidity; Pediatric bladder and bowel dysfunction;
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Neural pathways; Pelvic organ cross-talk; Pelvic organ cross-sensitization; Micturition reflex
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Introduction Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. It is characterized by a number of symptoms based on their relation to the voiding and storage phases
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of the micturition cycle. Lower urinary tract (LUT) dysfunctions in children associated with the storage symptoms include overactive bladder (changes in voiding frequency and urgency), stress and giggle incontinence, enuresis, and nocturia [1]. Voiding postponement (hesitancy, straining,
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holding maneuvers) and dysfunctional voiding (weak stream, intermittency) mainly characterize the changes in the voiding phase of the micturition cycle. The International Children’s Continence
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Society (ICCS) defines dysfunctional voiding as dysfunctional habitual contraction of the urethral sphincter during voiding; it accounts for up to 40% of pediatric urology clinic visits [1]. Large clinical databases also report the prevalence of daytime urinary incontinence in children, up to 1017% [2, 3]. Lower urinary tract symptoms that are experienced in childhood tend to linger
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throughout life, and may manifest themselves in adulthood in many different ways, ranging from urgency and frequency of micturition to the development of chronic pelvic pain syndromes [4-6]. Gastrointestinal (GI) dysfunction, constipation and/or fecal incontinence are commonly
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associated with LUTD, reaching up to 22-34% in comparison with children without constipation [7]. In addition, children with constipation have abnormal voiding parameters, even if they do not
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describe symptoms [8]. Interestingly, children who initially present to a gastroenterology clinic with GI dysfunction and those presenting with LUTD to a Pediatric Urology clinic have similar bladder and bowel symptoms, with >50% of children with LUTD having bowel dysfunction [9, 10]. Consequently, the ICCS have named this condition as Bladder and Bowel Dysfunction (BBD), previously known as dysfunctional elimination syndrome [11]. In addition, BBD has also been found in 43% of children with primary VUR [12]. Constipation associated with functional megacolon has been identified as a common etiologic factor that is related to recurrent UTI and
ACCEPTED MANUSCRIPT VUR [13]. Clinical studies have also established that urgency and risk of UTI is proportionally increased in children with chronic functional constipation [14]. Co-morbidity of pediatric lower urinary and GI dysfunctions could be explained by multiple
cross-talk via connected neural pathways [15].
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factors, including a shared developmental origin, close anatomical proximity, and pelvic organ
This review clarified and summarized the potential mechanisms underlying pelvic organ co-
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morbidities in children, with regard to the relationship between lower urinary and colorectal dysfunctions. It covered the current understanding of clinical pathophysiology in the pediatric
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population, anatomy and embryological origins of the pelvic organs, role of neural circuits and developing neural pathways in regulation of functional co-morbidities, and available translational models with which to study the underlying mechanisms.
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Treatment options for co-morbid lower urinary tract dysfunction and gastrointestinal symptoms in children Treatment of children with BBD usually starts with a behavioral-modification program that
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consists of: timed voiding (5-7 times a day); improvement of pelvic floor relaxation by adjusted posture and breathing exercises; double voiding before bedtime; reduction in caffeine, colorants
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and carbonation from the diet; and treatment of constipation with increased fiber [16]. With behavioral modification alone, >55% of children had a significant symptom improvement, confirming the functional link between the bladder and bowel [16]. Behavioral therapy in children with bladder-sphincter dysfunction also decreased the prevalence of functional fecal incontinence by 21-30%; however, no direct correlation was found between improved functional fecal incontinence and bladder-sphincter dysfunction [17].
ACCEPTED MANUSCRIPT In children and adolescents who fail behavioral modification, there are a variety of therapeutic and physical therapies that address bladder and bowel physiology, the pelvic floor and the central nervous system [16, 18], but the mechanisms by which BBD are linked are not well understood.
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To better manage these patients, this interplay between the two organ systems and how we can more specifically target co-morbid GI and LUT dysfunction in the clinic need to be fully understand.
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Anatomical development of genitourinary and gastrointestinal systems
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In early fetal development, a close relationship between pelvic organs is evident. Both the LUT and GI systems develop from a shared cloaca. During the seventh week of gestation, the urorectal septum grows caudally, dividing the cloaca into the urogenital sinus and anorectal canal [19]. An extensive supply of nerves and vasculature forms to support the growing tissues. Numerous
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developing neural subpopulations have been identified and show distinct patterns of distribution among LUT tissues [20]. Sensory and motor nerves produce distinctive neurotransmitters and signaling molecules, however, they are anatomically indistinguishable and no data currently exist
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on the spatiotemporal distinction between these populations. The paired pelvic ganglia that develop in the LUT close to the anterior pelvic urethra also contain a mixture of both sympathetic
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and parasympathetic neurons [21].
The complex anatomy of genitourinary and GI systems rapidly changes during embryogenesis. The close developmental link between urogenital (bladder, urethra, genitalia) and distal GI (colorectum, anal canal) tracts may explain the co-occurrence of genital anomalies (ambiguous genitalia, hypospadias, chordee and micropenis in males, cleft clitoris in females) with anorectal defects [22]. Normal development and innervation of the bladder, urethra and outlet also play a
ACCEPTED MANUSCRIPT critical role in maintaining urinary continence after birth [23]. Therefore, even small perturbations in differentiation processes or timing in one tissue can translate into functional defects affecting
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the entire system, and, likely, cause long-term LUTD not only in children but also in adulthood.
Neural mechanisms controlling maturation of the micturition reflex
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Development of LUTD in children closely correlates with their psychological and emotional state. Delayed development, difficult temperament, and maternal depression/anxiety were shown
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to be associated with daytime wetting and soiling [24]. In a large epidemiologic study of a cohort of 8213 children aged 7.5-9 years, children with daytime wetting had significantly increased rates of psychological problems, especially separation anxiety, attention deficit, oppositional behavior, and conduct problems [25]. As the nervous system in children continues to develop into
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adolescence, early life interventions can affect structure and connectivity of neural circuits, and also impact on activity of central and peripheral neurons, which control bladder function [26]. Early-life bladder inflammation is also recognized to have long-term effects on voiding
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patterns. For example, women with interstitial cystitis/bladder pain syndrome reported to experience a higher incidence of childhood UTI [27]. The pain and discomfort associated with
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urination in children with UTI can adversely affect voiding behavior by negative conditioning. In addition to potential restructuring of neural circuits that control voiding, early life events could induce neural plasticity by increasing afferent signaling from the bladder to the CNS, subsequently having enduring effects on central voiding circuits. The neural mechanisms of bladder emptying undergo marked changes during the first 3 weeks of life in many mammals [28-30]. After birth, the rat pup cannot void spontaneously because
ACCEPTED MANUSCRIPT voiding is controlled by the perigenital-bladder reflex, which is triggered by the mother licking the perigenital region of the pups [29]. Although infants have a perigenital-bladder reflex as well [31], they are born with a functional bladder-bladder reflex and show spontaneous bladder emptying.
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The major change that occurs in children is the acquisition of voluntary control over voiding, and coordination of the bladder and external urethral sphincter. Since voiding mastery requires suppression of an involuntary reflex by voluntary control, it is possible that LUTD is actually a
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combination of immature and mature responses to the same stimulus.
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Physiological ‘cross-talk’ between the urinary bladder and distal gut Daily physiological activity and viscero-visceral reflexes between the lower GI and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant
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modulatory role of the neural pathways. In children with LUTD, rectal distension significantly, but unpredictably, affects bladder capacity, sensation and overactivity, regardless of whether the children had constipation, and independent of clinical features and baseline urodynamic findings
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[32]. Urodynamic and management protocols for LUTD that fail to recognize the effects of rectal distension may lead to unpredictable outcomes [32].
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Investigation of functional changes in nerve fibers and neurons sets certain limits for conducting appropriate research in humans, making the use of animal models unavoidable. Initial animal studies performed in rodents have established that micturition and defecation alternate under normal physiological conditions. Subsequent experiments in cats have also revealed crossinhibitory reflexes upon stimulation of either the bladder or distal gut under normal physiological conditions [33]. Both mechanical (distension) and electrical (pelvic nerve afferents) stimulation of
ACCEPTED MANUSCRIPT the colon induced inhibition of spontaneous bladder contractility and enhanced micturition threshold [34]. In these studies, the hypogastric and lumbar sympathetic nerves were cut in order to avoid peripheral adrenergic inhibition of the bladder. Additionally, the lumbar pudendal nerves
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were also sectioned so that the only afferent pathway from the bowel was via colonic branches of the pelvic nerve. These experiments confirmed that the pelvic nerve contains afferents innervating the colon and rectum, which interfere with the micturition reflex in the CNS [33, 34].
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Physiological ‘cross-talk’ between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs [15]. Three
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different but interconnected neural pathways have been described to underlie pelvic organ ‘crosstalk’. The first pathway includes the presence of sensory neurons with dichotomized axons located in dorsal root ganglia (DRG), which innervate both the urinary bladder and distal colon [35]. The number of colon-bladder convergent neurons at upper lumbar (L1-L3) and lumbosacral (L6-S2) levels varies slightly and reaches 10-20% [35]. The second level of convergence includes spinal
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interneurons where afferent inputs from the colon and urinary bladder converge on the same cell located in the dorsal horn of the spinal cord [36]. Viscero-visceral convergent neurons have
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previously been identified in lumbosacral segments of the spinal cord in cats [37], monkeys [38], and rats [39]. The number of spinal colon-bladder convergent neurons is higher in comparison with
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DRG cells, and reaches 30-35% [36]. The third pathway that underlies communication between the bladder and colon is centered on the pontine micturition center (PMC), also known as Barrington's nucleus. The main function of the PMC is to control micturition via efferent input to lumbosacral preganglionic neurons innervating the urinary bladder [40]. However, PMC neurons also receive afferent inputs from the second-order neurons in the spinal dorsal horn with bladder and colonic inputs [41]. Anatomical circuits linking the PMC with the bladder and colon provide a basis for potential functional co-modulation of both viscera by this center. Functional studies have
ACCEPTED MANUSCRIPT confirmed that colonic distension activates 73% of neurons within the PMC that previously responded to urinary bladder distension [42]. These three levels of the nervous system hierarchy, either alone or in combination, are thought to coordinate physiological ‘cross-talk’ between the
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lower urinary and GI tracts.
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Role of pelvic organ cross-sensitization in pediatric functional co-morbidities
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Urinary bladder and distal colon interact under both normal and pathological conditions; however, the directions of these interactions can change dramatically, depending on the nature and duration of applied interventions [43]. Clinical co-morbidity of genitourinary and GI dysfunctions in the pediatric population suggest that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs (colon, uterus, prostate) due
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to a phenomenon known as pelvic organ ‘cross-sensitization’ [15]. Pelvic organ cross-sensitization implies the transmission of noxious stimuli from a directly affected pelvic organ to an adjacent normal structure, resulting in the occurrence of functional (rarely structural) changes in the latter
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[15]. Just like pelvic organ ‘cross-talk’, which exists under normal physiological conditions, pelvic
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organ cross-sensitization develops mainly due to convergence of sensory information from discrete pelvic structures in the peripheral (DRG) and central (spinal cord and brain) nervous systems [15, 44]. The sequence of events leading to cross-sensitization in the pelvis includes several steps. The initial peripheral insult (inflammation, ischemia, trauma, infection) in one of the pelvic organs triggers excitation/sensitization of peripheral afferent fibers and sensory neurons. This information is further transmitted to the CNS, leading to central ‘amplification’ of noxious stimuli in the spinal
ACCEPTED MANUSCRIPT cord and brain. The CNS processes afferent signals received from the periphery and sends efferent output to the viscera, thereby modulating the function of the involved pelvic organs [15, 44].
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Translational animal models for cross-sensitization studies
Several animal models have been established to study the mechanisms of colon-bladder crosssensitization triggered by a noxious insult applied either to the distal colon or to the urinary
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bladder (reviewed in [15, 44]). Intracolonic application of 2,4,6-trinitrobenzene sulfonic acid
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(TNBS) is a well-established model of colonic inflammation that is induced by a single intraluminal administration of TNBS, with no requirements for previous sensitization of the animal [45]. After recovery from inflammation (12-15 days later), neither the colon nor the urinary bladder has any detectable histological or biochemical changes. Studies using TNBS-induced colitis have determined a significant increase in bladder contractility by almost 70% in the
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presence of acute colitis [46]. Additionally, the bladder develops signs of neurogenic dysfunction, as shown by hyperactivity of bladder afferent fibers [47], hyperexcitability of bladder projecting sensory [15] and spinal [36] neurons, increased release of pro-inflammatory neuropeptides in the
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urinary bladder [48, 49], and changes in detrusor contractility in vivo and in vitro [50, 51]. Acute
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TNBS-induced colitis also leads to early onset of micturition and decreased intermicturition interval in mice [52]. Local segmental irradiation of the colon has been shown to induce the occurrence of detrusor overactivity detected by cystometric evaluations in rats [53]. In the model of colonic irritation with intraluminal mustard oil in rats, vascular permeability in the normal bladder significantly increased after colonic treatment [54]. This effect was attenuated by transection of the hypogastric nerve [54], suggesting the importance of neural connections. Other studies have also established a diminution of colon/bladder cross-sensitization upon denervation of
ACCEPTED MANUSCRIPT the urinary bladder [47]. A recent study [55] demonstrated that TNBS-induced colitis in rats caused increased pain sensitivity in the bladder and urethra via activation of C-fiber afferents, demonstrating that not only is cross-sensitization a cause of bladder overactivity but also of LUT
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urgency and/or pain. Early-in-life exposure to noxious stimuli has been reported to enhance the vulnerability of the organism to subsequent pathological challenges in the adult life, by producing long-lasting
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neuroanatomical and neurophysiological changes in the nociceptive system [56]. For example, transient bladder inflammation in neonatal rats causes an increased visceromotor response to
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urinary bladder distension in adulthood [57]. Involved mechanisms may be associated with impaired development of the spinal opioid system, suggesting that the neonatal insult may permanently alter the central modulatory pathway, which could lead to later onset of cross-organ (viscero-visceral and viscero-somatic) secondary hyperalgesia [58]. Clinical studies have also reported a correlation between LUTD and function of the pelvic floor muscles. For instance,
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spastic pelvic floor syndrome is considered to be a contributing factor to the management of functional constipation in children [59-61], suggesting the presence of not only viscero-visceral but
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also viscero-somatic cross-talk in the pelvis.
In additional to peripheral innervation, CNS circuits are also critical for modifying urinary
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activity to best coordinate voiding patterns with other behaviors. For example, non-micturition contractions that develop with partial bladder outlet obstruction impact on cortical activity and have potential effects on sleep and cognitive function [62]. In the opposing direction, psychosocial stressors can affect activity of PMC neurons involved in micturition to produce voiding dysfunctions in experimental animals and humans [63, 64]. These examples underscore the importance of understanding how the brain processes sensory feedback from the bladder and, in turn, how it regulates bladder function.
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Conclusions
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In children with LUTD, urinary symptoms often coincide with GI co-morbidities and vice versa, and therapeutic modulation of one system may improve the other system’s function. Despite the integral role of the nervous system in the regulation of voiding, and its potential role in LUTD, the underlying mechanisms are not well understood and have not been well studied. In considering
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the basis of prevalent urological disorders, dysfunctions of neural regulation have largely been
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ignored, despite evidence that many aspects of these disorders originate from altered functions of both peripheral and central nervous systems. A better understanding of the basic pathophysiology of these disorders can have a large impact by improving diagnoses and guiding the development of novel treatments. Knowledge of the neuropharmacology of developing spinal reflexes that control voiding, and of neurotransmitter systems involved in the afferent branch of this reflex, is a relevant
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the pediatric population.
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step in the development of new and safer drugs for long-term symptomatic treatment of LUTD in
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Conflict of interest: Nil.
Funding: The study was supported by the AEF grants from the UCD Department of Surgery (to DTW and APM), NIH DK095817 grant (to APM), and the Ponzio Family Chair in Pediatric Urology (DTW).
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ACCEPTED MANUSCRIPT the effects of early-in-life experience with bladder inflammation. The journal of pain: official journal of the American Pain Society 2007; 8(12):914-23. Kuijpers JH, Bleijenberg G. [Spastic pelvic floor syndrome, a cause of constipation]. Nederlands tijdschrift voor geneeskunde 1985;129(34):1624-8.
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S1477-5131(16)30104-8
DOI:
10.1016/j.jpurol.2016.04.036
Reference:
JPUROL 2220
To appear in:
Journal of Pediatric Urology
Received Date: 18 January 2016 Accepted Date: 5 April 2016
Please cite this article as: Malykhina AP, Brodie KE, Wilcox DT, Genitourinary and gastrointestinal comorbidities in children: the role of neural circuits in regulation of visceral function, Journal of Pediatric Urology (2016), doi: 10.1016/j.jpurol.2016.04.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review article
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Genitourinary and gastrointestinal comorbidities in children: the role of neural circuits in regulation of visceral function
a
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A. P. Malykhinaa, K. E. Brodiea,b, D. T. Wilcoxa,c,*
Division of Urology, Department of Surgery, University of Colorado School of Medicine
b
Department of Pediatric Urology, Children's Hospital of Colorado, 13123 E 16th Avenue,
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Aurora, CO 80045, USA
*Corresponding author: Department of Pediatric Urology, Children's Hospital of Colorado,
777-7370.
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13123 E. 16th Avenue, B463, Aurora, CO, 80045, USA. Tel.: (+1) 720-777-3926; fax: (+1) 720-
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E-mail address: [email protected] (D. T. Wilcox)
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Summary Objective: Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. Lower urinary tract symptoms in children include overactive bladder, voiding postponement, stress
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incontinence, giggle incontinence, and dysfunctional voiding. Gastrointestinal co-morbidities, including constipation or fecal incontinence, are commonly associated with lower urinary tract (LUT) symptoms in children, often reaching 22-34%. This review summarized the potential
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mechanisms underlying functional lower urinary and gastrointestinal co-morbidities in children. It also covered the current understanding of clinical pathophysiology in the pediatric population,
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anatomy and embryological development of the pelvic organs, role of developing neural circuits in regulation of functional co-morbidities, and relevant translational animal models. Materials and methods: This was a non-systematic review of the published literature, which summarized the available clinical and translational studies on functional urologic and
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gastrointestinal co-morbidities in children, as well as neural mechanisms underlying pelvic organ ‘cross-talk’ and ‘cross-sensitization’.
Results: Co-morbidity of pediatric lower urinary and gastrointestinal dysfunctions could be
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explained by multiple factors, including a shared developmental origin, close anatomical proximity, and pelvic organ ‘cross-talk’. Daily physiological activity and viscero-visceral reflexes
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between the lower gastrointestinal and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant modulatory role of the neural pathways. Recent studies have provided evidence that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs due to a phenomenon known as pelvic organ ‘cross-sensitization’. Cross-sensitization between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs. Investigation of functional changes in nerve fibers and neurons sets certain limits in
ACCEPTED MANUSCRIPT conducting appropriate research in humans, making the use of animal models necessary to uncover the underlying mechanisms and for the development of novel therapeutic approaches for long-term symptomatic treatment of LUTD in the pediatric population.
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Conclusion: Pediatric LUTD is often complicated by gastrointestinal co-morbidities; however, the mechanisms linking bladder and bowel dysfunctions are not well understood. Clinical studies have suggested that therapeutic modulation of one system may improve the other system’s function. To
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better manage children with LUTD, the interplay between the two systems, and how co-morbid GI and voiding dysfunctions can be more specifically targeted in pediatric clinics need to be
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understood.
Keywords: Urologic and gastrointestinal co-morbidity; Pediatric bladder and bowel dysfunction;
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Neural pathways; Pelvic organ cross-talk; Pelvic organ cross-sensitization; Micturition reflex
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Introduction Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. It is characterized by a number of symptoms based on their relation to the voiding and storage phases
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of the micturition cycle. Lower urinary tract (LUT) dysfunctions in children associated with the storage symptoms include overactive bladder (changes in voiding frequency and urgency), stress and giggle incontinence, enuresis, and nocturia [1]. Voiding postponement (hesitancy, straining,
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holding maneuvers) and dysfunctional voiding (weak stream, intermittency) mainly characterize the changes in the voiding phase of the micturition cycle. The International Children’s Continence
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Society (ICCS) defines dysfunctional voiding as dysfunctional habitual contraction of the urethral sphincter during voiding; it accounts for up to 40% of pediatric urology clinic visits [1]. Large clinical databases also report the prevalence of daytime urinary incontinence in children, up to 1017% [2, 3]. Lower urinary tract symptoms that are experienced in childhood tend to linger
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throughout life, and may manifest themselves in adulthood in many different ways, ranging from urgency and frequency of micturition to the development of chronic pelvic pain syndromes [4-6]. Gastrointestinal (GI) dysfunction, constipation and/or fecal incontinence are commonly
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associated with LUTD, reaching up to 22-34% in comparison with children without constipation [7]. In addition, children with constipation have abnormal voiding parameters, even if they do not
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describe symptoms [8]. Interestingly, children who initially present to a gastroenterology clinic with GI dysfunction and those presenting with LUTD to a Pediatric Urology clinic have similar bladder and bowel symptoms, with >50% of children with LUTD having bowel dysfunction [9, 10]. Consequently, the ICCS have named this condition as Bladder and Bowel Dysfunction (BBD), previously known as dysfunctional elimination syndrome [11]. In addition, BBD has also been found in 43% of children with primary VUR [12]. Constipation associated with functional megacolon has been identified as a common etiologic factor that is related to recurrent UTI and
ACCEPTED MANUSCRIPT VUR [13]. Clinical studies have also established that urgency and risk of UTI is proportionally increased in children with chronic functional constipation [14]. Co-morbidity of pediatric lower urinary and GI dysfunctions could be explained by multiple
cross-talk via connected neural pathways [15].
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factors, including a shared developmental origin, close anatomical proximity, and pelvic organ
This review clarified and summarized the potential mechanisms underlying pelvic organ co-
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morbidities in children, with regard to the relationship between lower urinary and colorectal dysfunctions. It covered the current understanding of clinical pathophysiology in the pediatric
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population, anatomy and embryological origins of the pelvic organs, role of neural circuits and developing neural pathways in regulation of functional co-morbidities, and available translational models with which to study the underlying mechanisms.
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Treatment options for co-morbid lower urinary tract dysfunction and gastrointestinal symptoms in children Treatment of children with BBD usually starts with a behavioral-modification program that
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consists of: timed voiding (5-7 times a day); improvement of pelvic floor relaxation by adjusted posture and breathing exercises; double voiding before bedtime; reduction in caffeine, colorants
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and carbonation from the diet; and treatment of constipation with increased fiber [16]. With behavioral modification alone, >55% of children had a significant symptom improvement, confirming the functional link between the bladder and bowel [16]. Behavioral therapy in children with bladder-sphincter dysfunction also decreased the prevalence of functional fecal incontinence by 21-30%; however, no direct correlation was found between improved functional fecal incontinence and bladder-sphincter dysfunction [17].
ACCEPTED MANUSCRIPT In children and adolescents who fail behavioral modification, there are a variety of therapeutic and physical therapies that address bladder and bowel physiology, the pelvic floor and the central nervous system [16, 18], but the mechanisms by which BBD are linked are not well understood.
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To better manage these patients, this interplay between the two organ systems and how we can more specifically target co-morbid GI and LUT dysfunction in the clinic need to be fully understand.
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Anatomical development of genitourinary and gastrointestinal systems
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In early fetal development, a close relationship between pelvic organs is evident. Both the LUT and GI systems develop from a shared cloaca. During the seventh week of gestation, the urorectal septum grows caudally, dividing the cloaca into the urogenital sinus and anorectal canal [19]. An extensive supply of nerves and vasculature forms to support the growing tissues. Numerous
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developing neural subpopulations have been identified and show distinct patterns of distribution among LUT tissues [20]. Sensory and motor nerves produce distinctive neurotransmitters and signaling molecules, however, they are anatomically indistinguishable and no data currently exist
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on the spatiotemporal distinction between these populations. The paired pelvic ganglia that develop in the LUT close to the anterior pelvic urethra also contain a mixture of both sympathetic
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and parasympathetic neurons [21].
The complex anatomy of genitourinary and GI systems rapidly changes during embryogenesis. The close developmental link between urogenital (bladder, urethra, genitalia) and distal GI (colorectum, anal canal) tracts may explain the co-occurrence of genital anomalies (ambiguous genitalia, hypospadias, chordee and micropenis in males, cleft clitoris in females) with anorectal defects [22]. Normal development and innervation of the bladder, urethra and outlet also play a
ACCEPTED MANUSCRIPT critical role in maintaining urinary continence after birth [23]. Therefore, even small perturbations in differentiation processes or timing in one tissue can translate into functional defects affecting
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the entire system, and, likely, cause long-term LUTD not only in children but also in adulthood.
Neural mechanisms controlling maturation of the micturition reflex
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Development of LUTD in children closely correlates with their psychological and emotional state. Delayed development, difficult temperament, and maternal depression/anxiety were shown
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to be associated with daytime wetting and soiling [24]. In a large epidemiologic study of a cohort of 8213 children aged 7.5-9 years, children with daytime wetting had significantly increased rates of psychological problems, especially separation anxiety, attention deficit, oppositional behavior, and conduct problems [25]. As the nervous system in children continues to develop into
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adolescence, early life interventions can affect structure and connectivity of neural circuits, and also impact on activity of central and peripheral neurons, which control bladder function [26]. Early-life bladder inflammation is also recognized to have long-term effects on voiding
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patterns. For example, women with interstitial cystitis/bladder pain syndrome reported to experience a higher incidence of childhood UTI [27]. The pain and discomfort associated with
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urination in children with UTI can adversely affect voiding behavior by negative conditioning. In addition to potential restructuring of neural circuits that control voiding, early life events could induce neural plasticity by increasing afferent signaling from the bladder to the CNS, subsequently having enduring effects on central voiding circuits. The neural mechanisms of bladder emptying undergo marked changes during the first 3 weeks of life in many mammals [28-30]. After birth, the rat pup cannot void spontaneously because
ACCEPTED MANUSCRIPT voiding is controlled by the perigenital-bladder reflex, which is triggered by the mother licking the perigenital region of the pups [29]. Although infants have a perigenital-bladder reflex as well [31], they are born with a functional bladder-bladder reflex and show spontaneous bladder emptying.
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The major change that occurs in children is the acquisition of voluntary control over voiding, and coordination of the bladder and external urethral sphincter. Since voiding mastery requires suppression of an involuntary reflex by voluntary control, it is possible that LUTD is actually a
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combination of immature and mature responses to the same stimulus.
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Physiological ‘cross-talk’ between the urinary bladder and distal gut Daily physiological activity and viscero-visceral reflexes between the lower GI and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant
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modulatory role of the neural pathways. In children with LUTD, rectal distension significantly, but unpredictably, affects bladder capacity, sensation and overactivity, regardless of whether the children had constipation, and independent of clinical features and baseline urodynamic findings
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[32]. Urodynamic and management protocols for LUTD that fail to recognize the effects of rectal distension may lead to unpredictable outcomes [32].
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Investigation of functional changes in nerve fibers and neurons sets certain limits for conducting appropriate research in humans, making the use of animal models unavoidable. Initial animal studies performed in rodents have established that micturition and defecation alternate under normal physiological conditions. Subsequent experiments in cats have also revealed crossinhibitory reflexes upon stimulation of either the bladder or distal gut under normal physiological conditions [33]. Both mechanical (distension) and electrical (pelvic nerve afferents) stimulation of
ACCEPTED MANUSCRIPT the colon induced inhibition of spontaneous bladder contractility and enhanced micturition threshold [34]. In these studies, the hypogastric and lumbar sympathetic nerves were cut in order to avoid peripheral adrenergic inhibition of the bladder. Additionally, the lumbar pudendal nerves
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were also sectioned so that the only afferent pathway from the bowel was via colonic branches of the pelvic nerve. These experiments confirmed that the pelvic nerve contains afferents innervating the colon and rectum, which interfere with the micturition reflex in the CNS [33, 34].
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Physiological ‘cross-talk’ between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs [15]. Three
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different but interconnected neural pathways have been described to underlie pelvic organ ‘crosstalk’. The first pathway includes the presence of sensory neurons with dichotomized axons located in dorsal root ganglia (DRG), which innervate both the urinary bladder and distal colon [35]. The number of colon-bladder convergent neurons at upper lumbar (L1-L3) and lumbosacral (L6-S2) levels varies slightly and reaches 10-20% [35]. The second level of convergence includes spinal
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interneurons where afferent inputs from the colon and urinary bladder converge on the same cell located in the dorsal horn of the spinal cord [36]. Viscero-visceral convergent neurons have
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previously been identified in lumbosacral segments of the spinal cord in cats [37], monkeys [38], and rats [39]. The number of spinal colon-bladder convergent neurons is higher in comparison with
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DRG cells, and reaches 30-35% [36]. The third pathway that underlies communication between the bladder and colon is centered on the pontine micturition center (PMC), also known as Barrington's nucleus. The main function of the PMC is to control micturition via efferent input to lumbosacral preganglionic neurons innervating the urinary bladder [40]. However, PMC neurons also receive afferent inputs from the second-order neurons in the spinal dorsal horn with bladder and colonic inputs [41]. Anatomical circuits linking the PMC with the bladder and colon provide a basis for potential functional co-modulation of both viscera by this center. Functional studies have
ACCEPTED MANUSCRIPT confirmed that colonic distension activates 73% of neurons within the PMC that previously responded to urinary bladder distension [42]. These three levels of the nervous system hierarchy, either alone or in combination, are thought to coordinate physiological ‘cross-talk’ between the
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lower urinary and GI tracts.
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Role of pelvic organ cross-sensitization in pediatric functional co-morbidities
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Urinary bladder and distal colon interact under both normal and pathological conditions; however, the directions of these interactions can change dramatically, depending on the nature and duration of applied interventions [43]. Clinical co-morbidity of genitourinary and GI dysfunctions in the pediatric population suggest that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs (colon, uterus, prostate) due
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to a phenomenon known as pelvic organ ‘cross-sensitization’ [15]. Pelvic organ cross-sensitization implies the transmission of noxious stimuli from a directly affected pelvic organ to an adjacent normal structure, resulting in the occurrence of functional (rarely structural) changes in the latter
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[15]. Just like pelvic organ ‘cross-talk’, which exists under normal physiological conditions, pelvic
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organ cross-sensitization develops mainly due to convergence of sensory information from discrete pelvic structures in the peripheral (DRG) and central (spinal cord and brain) nervous systems [15, 44]. The sequence of events leading to cross-sensitization in the pelvis includes several steps. The initial peripheral insult (inflammation, ischemia, trauma, infection) in one of the pelvic organs triggers excitation/sensitization of peripheral afferent fibers and sensory neurons. This information is further transmitted to the CNS, leading to central ‘amplification’ of noxious stimuli in the spinal
ACCEPTED MANUSCRIPT cord and brain. The CNS processes afferent signals received from the periphery and sends efferent output to the viscera, thereby modulating the function of the involved pelvic organs [15, 44].
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Translational animal models for cross-sensitization studies
Several animal models have been established to study the mechanisms of colon-bladder crosssensitization triggered by a noxious insult applied either to the distal colon or to the urinary
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bladder (reviewed in [15, 44]). Intracolonic application of 2,4,6-trinitrobenzene sulfonic acid
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(TNBS) is a well-established model of colonic inflammation that is induced by a single intraluminal administration of TNBS, with no requirements for previous sensitization of the animal [45]. After recovery from inflammation (12-15 days later), neither the colon nor the urinary bladder has any detectable histological or biochemical changes. Studies using TNBS-induced colitis have determined a significant increase in bladder contractility by almost 70% in the
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presence of acute colitis [46]. Additionally, the bladder develops signs of neurogenic dysfunction, as shown by hyperactivity of bladder afferent fibers [47], hyperexcitability of bladder projecting sensory [15] and spinal [36] neurons, increased release of pro-inflammatory neuropeptides in the
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urinary bladder [48, 49], and changes in detrusor contractility in vivo and in vitro [50, 51]. Acute
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TNBS-induced colitis also leads to early onset of micturition and decreased intermicturition interval in mice [52]. Local segmental irradiation of the colon has been shown to induce the occurrence of detrusor overactivity detected by cystometric evaluations in rats [53]. In the model of colonic irritation with intraluminal mustard oil in rats, vascular permeability in the normal bladder significantly increased after colonic treatment [54]. This effect was attenuated by transection of the hypogastric nerve [54], suggesting the importance of neural connections. Other studies have also established a diminution of colon/bladder cross-sensitization upon denervation of
ACCEPTED MANUSCRIPT the urinary bladder [47]. A recent study [55] demonstrated that TNBS-induced colitis in rats caused increased pain sensitivity in the bladder and urethra via activation of C-fiber afferents, demonstrating that not only is cross-sensitization a cause of bladder overactivity but also of LUT
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urgency and/or pain. Early-in-life exposure to noxious stimuli has been reported to enhance the vulnerability of the organism to subsequent pathological challenges in the adult life, by producing long-lasting
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neuroanatomical and neurophysiological changes in the nociceptive system [56]. For example, transient bladder inflammation in neonatal rats causes an increased visceromotor response to
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urinary bladder distension in adulthood [57]. Involved mechanisms may be associated with impaired development of the spinal opioid system, suggesting that the neonatal insult may permanently alter the central modulatory pathway, which could lead to later onset of cross-organ (viscero-visceral and viscero-somatic) secondary hyperalgesia [58]. Clinical studies have also reported a correlation between LUTD and function of the pelvic floor muscles. For instance,
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spastic pelvic floor syndrome is considered to be a contributing factor to the management of functional constipation in children [59-61], suggesting the presence of not only viscero-visceral but
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also viscero-somatic cross-talk in the pelvis.
In additional to peripheral innervation, CNS circuits are also critical for modifying urinary
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activity to best coordinate voiding patterns with other behaviors. For example, non-micturition contractions that develop with partial bladder outlet obstruction impact on cortical activity and have potential effects on sleep and cognitive function [62]. In the opposing direction, psychosocial stressors can affect activity of PMC neurons involved in micturition to produce voiding dysfunctions in experimental animals and humans [63, 64]. These examples underscore the importance of understanding how the brain processes sensory feedback from the bladder and, in turn, how it regulates bladder function.
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Conclusions
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In children with LUTD, urinary symptoms often coincide with GI co-morbidities and vice versa, and therapeutic modulation of one system may improve the other system’s function. Despite the integral role of the nervous system in the regulation of voiding, and its potential role in LUTD, the underlying mechanisms are not well understood and have not been well studied. In considering
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the basis of prevalent urological disorders, dysfunctions of neural regulation have largely been
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ignored, despite evidence that many aspects of these disorders originate from altered functions of both peripheral and central nervous systems. A better understanding of the basic pathophysiology of these disorders can have a large impact by improving diagnoses and guiding the development of novel treatments. Knowledge of the neuropharmacology of developing spinal reflexes that control voiding, and of neurotransmitter systems involved in the afferent branch of this reflex, is a relevant
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the pediatric population.
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step in the development of new and safer drugs for long-term symptomatic treatment of LUTD in
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Conflict of interest: Nil.
Funding: The study was supported by the AEF grants from the UCD Department of Surgery (to DTW and APM), NIH DK095817 grant (to APM), and the Ponzio Family Chair in Pediatric Urology (DTW).
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