-
The Journal of Urology Jan 2022The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB). (Observational Study)
Observational Study
PURPOSE
The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB).
MATERIALS AND METHODS
Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study participants with OAB symptoms and controls were recruited from 6 U.S. tertiary referral centers. Quantitative sensory testing (QST) was performed to determine pressure pain sensitivity at the thumbnail bed and auditory sensitivity. Fixed and mixed effect multivariable linear regressions and Weibull models were used to compare QST responses between groups. Pearson correlations were used to assess the relationship between QST measures. Associations between QST and self-reported symptoms were explored with linear regression.
RESULTS
A total of 297 participants were analyzed (191 OAB, 106 controls; 76% white, 51% male). OAB cases were older than controls (57.4 vs 52.2 years, p=0.015). No significant differences in experimental thumbnail (nonbladder) pain or auditory sensitivity were detected between OAB cases and controls. Correlations between pressure and auditory derived metrics were weak to moderate overall for both groups, with some significantly stronger correlations for cases. Exploratory analyses indicated increased pressure pain and auditory sensitivity were modestly associated with greater self-reported bladder pain and pain interference with physical function.
CONCLUSIONS
As a group, no significant differences between OAB cases and controls were observed in experimental nonbladder pain or auditory sensitivity during QST. Associations between QST outcomes and clinical pain raise the possibility of centrally mediated sensory amplification in some individuals with OAB.
Topics: Adult; Aged; Cohort Studies; Female; Hearing Disorders; Humans; Male; Middle Aged; Pain; Pain Measurement; Urinary Bladder, Overactive
PubMed: 34428922
DOI: 10.1097/JU.0000000000002147 -
Molecular Neurobiology Feb 2019The periaqueductal gray matter (PAG), as one of the mostly preserved evolutionary components of the brain, is an axial structure modulating various important functions... (Review)
Review
The periaqueductal gray matter (PAG), as one of the mostly preserved evolutionary components of the brain, is an axial structure modulating various important functions of the organism, including autonomic, behavioral, pain, and micturition control. It has a critical role in urinary bladder physiology, with respect to storage and voiding of urine. The PAG has a columnar composition and has extensive connections with its cranially and caudally located components of the central nervous system (CNS). The PAG serves as the control tower of the detrusor and sphincter contractions. It serves as a bridge between the evolutionary higher decision-making brain centers and the lower centers responsible for reflexive micturition. Glutamatergic cells are the main operational neurons in the vlPAG, responsible for the reception and relay of the signals emerging from the bladder, to related brain centers. Functional imaging studies made it possible to clarify the activity of the PAG in voiding and filling phases of micturition, and its connections with various brain centers in living humans. The PAG may be affected in a wide spectrum of disorders, including multiple sclerosis (MS), migraine, stroke, Wernicke's encephalopathy, and idiopathic normal pressure hydrocephalus, all of which may have voiding dysfunction or incontinence, in certain stages of the disease. This emphasizes the importance of this structure for the basic understanding of voiding and storage disorders and makes it a potential candidate for diagnostic and therapeutic interventions.
Topics: Brain; Humans; Neural Pathways; Periaqueductal Gray; Urinary Bladder; Urinary Tract; Urinary Tract Physiological Phenomena
PubMed: 29804231
DOI: 10.1007/s12035-018-1131-8 -
PloS One 2021Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial...
BACKGROUND
Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo.
METHODOLOGY/PRINCIPAL FINDINGS
We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments.
CONCLUSIONS/SIGNIFICANCE
Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.
Topics: Adult; Animals; Antigens, Differentiation, B-Lymphocyte; Female; HMGB1 Protein; Histocompatibility Antigens Class II; Humans; Hyperalgesia; Macrophage Migration-Inhibitory Factors; Male; Mice; Mice, Inbred C57BL; Receptors, CXCR4; Receptors, Immunologic; Receptors, Thrombin; Urinary Bladder; Young Adult
PubMed: 34424927
DOI: 10.1371/journal.pone.0255975 -
Stem Cell Reviews and Reports Feb 2020Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue... (Review)
Review
Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue regeneration. Mesenchymal stem cells are multipotent progenitor cells with enhanced proliferation and differentiation capabilities and less tumorigenicity than conventional adult stem cells; these cells are also easier to acquire. Bladder dysfunction is often chronic in nature with limited treatment modalities due to its undetermined pathophysiology. Most treatments focus on symptom alleviation rather than pathognomonic changes repair. The potential of stem cell therapy for bladder dysfunction has been reported in preclinical models for stress urinary incontinence, overactive bladder, detrusor underactivity, and interstitial cystitis/bladder pain syndrome. Despite these findings, however, stem cell therapy is not yet available for clinical use. Only one pilot study on detrusor underactivity and a handful of clinical trials on stress urinary incontinence have reported the effects of stem cell treatment. This limitation may be due to stem cell function loss following ex vivo expansion, poor in vivo engraftment or survival after transplantation, or a lack of understanding of the precise mechanisms of action underlying therapeutic outcomes and in vivo behavior of stem cells administered to target organs. Efficacy comparisons with existing treatment modalities are also needed for the successful clinical application of stem cell therapies. This review describes the current status of stem cell research on treating bladder dysfunction and suggests future directions to facilitate clinical applications of this promising treatment modality, particularly for bladder dysfunction.
Topics: Cell Self Renewal; Cell- and Tissue-Based Therapy; Chemokines; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Regeneration; Urinary Bladder; Urinary Bladder Diseases; Urinary Incontinence, Stress
PubMed: 31758372
DOI: 10.1007/s12015-019-09922-2 -
The Journal of Urology Jul 2016Chronic bladder pain is a debilitating condition often accompanied by alterations in affective and autonomic function. Many symptoms associated with chronic bladder pain... (Review)
Review
PURPOSE
Chronic bladder pain is a debilitating condition often accompanied by alterations in affective and autonomic function. Many symptoms associated with chronic bladder pain are mediated by the central nervous system. In this review data from preclinical animal models and human neuroimaging studies were analyzed and a theoretical supraspinal bladder pain network was generated.
MATERIALS AND METHODS
We comprehensively reviewed the literature using PubMed® and Google Scholar™. Relevant reviews and original research articles, and the cited references were summarized and then organized on a neuroanatomical basis.
RESULTS
The brain loci the most predominant in the bladder pain literature are the thalamus, parabrachial nucleus, cerebral cortex, amygdala, hypothalamus, periaqueductal gray and rostral ventromedial medulla. This review highlights each of these regions, discussing the molecular and physiological changes that occur in each in the context of bladder pain.
CONCLUSIONS
A complex network of brain loci is involved in bladder pain modulation. Studying these brain regions and the changes that they undergo during the transition from acute to chronic bladder pain will provide novel therapeutic strategies for patients with chronic bladder pain diseases such as interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome.
Topics: Animals; Brain; Chronic Pain; Humans; Neuroimaging; Pain Perception; Pelvic Pain; Urinary Bladder Diseases
PubMed: 26905019
DOI: 10.1016/j.juro.2015.10.198 -
Journal of Education & Teaching in... Oct 2020A bladder diverticulum can be the consequence of a congenital abnormality or acquired as a result of trauma, infection, or outlet obstruction. Many are asymptomatic, but...
UNLABELLED
A bladder diverticulum can be the consequence of a congenital abnormality or acquired as a result of trauma, infection, or outlet obstruction. Many are asymptomatic, but some may present with complications such as urinary tract infection, hematuria, or urinary retention. A 76-year-old male presented to the emergency department (ED) for the second visit in one week with a chief complaint of urinary retention and lower abdominal pain. He had not voided since the prior night, when he had presented to the ED for the same compliant. During his initial visit, his symptoms were relieved by insertion of an in-&-out foley catheter. Point of Care Ultrasound (POCUS) of the bladder showed the appearance of two enlarged vertically aligned "bladders" with a central connection, concerning for a bladder diverticulum. Patient's cause of bladder diverticulum was found to be secondary to outlet obstruction, specifically benign prostatic hypertrophy (BPH). An indwelling foley catheter was inserted, and the patient was discharged home with instructions for urology follow up. The purpose of this report is to describe an anatomical anomaly of a bladder diverticulum presenting incidentally on Point of Care Ultrasound during routine workup of urinary retention.
TOPICS
Urinary bladder diverticulum, urinary retention, benign prostatic hypertrophy, POCUS, case report.
PubMed: 37465333
DOI: 10.21980/J8635C -
Urology Dec 2021To further examine anesthetic bladder capacity as a biomarker for interstitial cystitis/bladder pain syndrome (IC/BPS) patient subtypes, we evaluated demographic and...
OBJECTIVE
To further examine anesthetic bladder capacity as a biomarker for interstitial cystitis/bladder pain syndrome (IC/BPS) patient subtypes, we evaluated demographic and clinical characteristics in a large and heterogeneous female patient cohort.
MATERIAL AND METHODS
This is a retrospective review of data from women (n = 257) diagnosed with IC/BPS who were undergoing therapeutic bladder hydrodistention (HOD). Assessments included medical history and physical examination, validated questionnaire scores, and anesthetic BC. Linear regression analyses were computed to model the relationship between anesthetic BC and patient demographic data, symptoms, and diagnoses. Variables exhibiting suggestive correlations (P ≤ .1) were candidates for a multiple linear regression analysis and were retained if significant (P ≤ .05).
RESULTS
Multiple regression analysis identified a positive correlation between BC and endometriosis (P = .028) as well as negative correlations between BC and both ICSI score (P < .001) and the presence of Hunner's lesions (P < .001). There were higher average numbers of pelvic pain syndrome (PPS) diagnoses (P = .006) and neurologic, autoimmune, or systemic pain (NASP) diagnoses (P = .003) in IC/BPS patients with a non-low BC, but no statistical difference in the duration of diagnosis between patients with low and non-low BC (P = .118).
CONCLUSION
These data, generated from a large IC/BPS patient cohort, provide additional evidence that higher BC correlates with higher numbers of non-bladder-centric syndromes while lower BC correlates more closely with bladder-specific pathology. Taken together, the results support the concept of clinical subgroups in IC/BPS.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anesthetics; Autoimmune Diseases; Biomarkers; Cystitis, Interstitial; Endometriosis; Female; Humans; Lower Urinary Tract Symptoms; Middle Aged; Nervous System Diseases; Organ Size; Pelvic Pain; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Syndrome; Time Factors; Urinary Bladder; Young Adult
PubMed: 34303757
DOI: 10.1016/j.urology.2021.07.009 -
Current Topics in Membranes 2022Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a urologic, chronic pelvic pain syndrome characterized by pelvic pain, pressure, or discomfort with urinary... (Review)
Review
Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a urologic, chronic pelvic pain syndrome characterized by pelvic pain, pressure, or discomfort with urinary symptoms. Symptom exacerbation (flare) is common with multiple, perceived triggers including stress. Multiple transient receptor potential (TRP) channels (TRPA1, TRPV1, TRPV4) expressed in the bladder have specific tissue distributions in the lower urinary tract (LUT) and are implicated in bladder disorders including overactive bladder (OAB) and BPS/IC. TRPV4 channels are strong candidates for mechanosensors in the urinary bladder and TRPV4 antagonists are promising therapeutic agents for OAB. In this perspective piece, we address the current knowledge of TRPV4 distribution and function in the LUT and its plasticity with injury or disease with an emphasis on BPS/IC. We review our studies that extend the knowledge of TRPV4 in urinary bladder function by focusing on (i) TRPV4 involvement in voiding dysfunction, pelvic pain, and non-voiding bladder contractions in NGF-OE mice; (ii) distention-induced luminal ATP release mechanisms and (iii) involvement of TRPV4 and vesicular release mechanisms. Finally, we review our lamina propria studies in postnatal rat studies that demonstrate: (i) the predominance of the TRPV4+ and PDGFRα+ lamina propria cellular network in early postnatal rats; (ii) the ability of exogenous mediators (i.e., ATP, TRPV4 agonist) to activate and increase the number of lamina propria cells exhibiting active Ca events; and (iii) the ability of ATP and TRPV4 agonist to increase the rate of integrated Ca activity corresponding to coupled lamina propria network events and the formation of propagating wavefronts.
Topics: Adenosine Triphosphate; Animals; Mice; Nerve Growth Factor; Pelvic Pain; Rats; Receptor, Platelet-Derived Growth Factor alpha; TRPV Cation Channels; Transient Receptor Potential Channels; Urinary Bladder; Urinary Bladder, Overactive
PubMed: 36210154
DOI: 10.1016/bs.ctm.2022.06.002 -
Pain Jan 2022Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that...
Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.
Topics: Adolescent; Adult; Child; Chronic Pain; Female; Humans; Pain Threshold; Pelvic Pain; Reproducibility of Results; Urinary Bladder; Young Adult
PubMed: 34086630
DOI: 10.1097/j.pain.0000000000002311 -
World Journal of Gastroenterology Dec 2022Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory...
BACKGROUND
Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory pathways, it is likely that those syndromes involve a cross-sensitization of the bladder and the colon. The precise pathophysiology remains poorly understood.
AIM
To develop a model of chronic bladder-colon cross-sensitization and to investigate the mech-anisms involved.
METHODS
Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia. Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions. Myeloperoxidase, used as a marker of colorectal inflammation, was measured in the colon, and colorectal permeability was measured using chambers. c-Fos protein expression, used as a marker of neuronal activation, was assessed in the spinal cord (L6-S1 level) using immunohistochemistry. Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord. The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot.
RESULTS
Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid saline ( < 0.0001). This effect started 1 h post-injection and lasted up to 7 d post-injection. No increased permeability or inflammation was shown in the bladder or colon 7 d post-injection. Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord ( < 0.0001). In green fluorescent protein on the fractalkine receptor-positive mice, intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord ( < 0.0001). NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection ( = 0.007 and 0.023 respectively). Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline, a microglia inhibitor, by intracerebroventricular injection of CP-99994 dihydrochloride, a NK1 antagonist, and by intracerebroventricular injection of SB203580, a MAPK-p38 inhibitor.
CONCLUSION
We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice. Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension, mediated by neuroglial interactions, MAPK-p38 phosphorylation and the NK1 receptor.
Topics: Animals; Male; Mice; Rats; CX3C Chemokine Receptor 1; Green Fluorescent Proteins; Inflammation; Mice, Inbred C57BL; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Spinal Cord; Urinary Bladder; Visceral Pain; Colon; Hyperalgesia; Chronic Pain; Microglia
PubMed: 36632316
DOI: 10.3748/wjg.v28.i48.6935