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The Journal of Urology Sep 2016Chronic prostatitis/chronic pelvic pain syndrome causes symptoms that include the frequent and urgent need to urinate, pain or burning during urination and pain...
PURPOSE
Chronic prostatitis/chronic pelvic pain syndrome causes symptoms that include the frequent and urgent need to urinate, pain or burning during urination and pain radiating to the back, abdomen and/or colorectum. These bladder symptoms suggest that chronic prostatitis/chronic pelvic pain syndrome is associated with sensitization of adjacent organs, termed cross-organ sensitization. The objective of this study was to determine the extent of 1) changes in immunomodulatory mediators in the prostate and bladder after inflammation of the prostate and 2) bladder function and bladder afferent sensitization.
MATERIALS AND METHODS
Prostate and bladder histology, immunohistochemistry and expression of immunomodulatory targets were examined weekly after zymosan or vehicle was injected in the dorsal lobe of the mouse prostate. Cystometry, bladder and bladder afferent sensitivity were also assessed weekly.
RESULTS
Prostate inflammation induced significant up-regulation in proinflammatory and anti-inflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-10 (interleukin-10), growth factor NGF (nerve growth factor), and T-lymphocyte markers FoxP3, CD4 and CD8 in the prostate and the bladder. Notably, prostatitis significantly increased urinary voiding frequency, induced hypersensitivity to bladder distension and sensitized bladder afferents. We also examined sensory (afferent) co-innervation by injecting retrograde tracers DiI and Fast Blue in the bladder wall and the prostate, respectively. This showed that a significant proportion (approximately 17%) of dorsal root ganglion afferent somata contained tracers from the bladder and the prostate.
CONCLUSIONS
These observations support an afferent contribution to chronic prostatitis/chronic pelvic pain syndrome and cross-organ sensitization from prostate to bladder.
Topics: Animals; Blotting, Western; Chronic Disease; Cytokines; Disease Models, Animal; Ganglia, Spinal; Gene Expression Regulation; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Prostatitis; RNA; Urinary Bladder; Urinary Bladder Diseases
PubMed: 26997315
DOI: 10.1016/j.juro.2016.03.077 -
BioMed Research International 2014Understanding of the role of urothelium in regulating bladder function is continuing to evolve. While the urothelium is thought to function primarily as a barrier for... (Review)
Review
Understanding of the role of urothelium in regulating bladder function is continuing to evolve. While the urothelium is thought to function primarily as a barrier for preventing injurious substances and microorganisms from gaining access to bladder stroma and upper urinary tract, studies indicate it may also function in cell signaling events relating to voiding function. This review highlights urothelial abnormalities in bladder pain syndrome/interstitial cystitis (BPS/IC), feline interstitial cystitis (FIC), and nonneurogenic idiopathic overactive bladder (OAB). These bladder conditions are typified by lower urinary tract symptoms including urinary frequency, urgency, urgency incontinence, nocturia, and bladder discomfort or pain. Urothelial tissues and cells from affected clinical subjects and asymptomatic controls have been compared for expression of proteins and mRNA. Animal models have also been used to probe urothelial responses to injuries of the urothelium, urethra, or central nervous system, and transgenic techniques are being used to test specific urothelial abnormalities on bladder function. BPS/IC, FIC, and OAB appear to share some common pathophysiology including increased purinergic, TRPV1, and muscarinic signaling, increased urothelial permeability, and aberrant urothelial differentiation. One challenge is to determine which of several abnormally regulated signaling pathways is most important for mediating bladder dysfunction in these syndromes, with a goal of treating these conditions by targeting specific pathophysiology.
Topics: Animals; Humans; Urinary Bladder; Urinary Bladder Diseases; Urothelium
PubMed: 24900993
DOI: 10.1155/2014/865463 -
American Journal of Physiology. Renal... Feb 2021Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and...
Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at - with a peak at tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.
Topics: Animals; Antigens; Autoimmune Diseases; Cystitis; Cystitis, Interstitial; Cytokines; Disease Models, Animal; Gene Expression Regulation; Mice; Mice, Transgenic; Ovalbumin; Pelvic Pain; Urinary Bladder; Urination Disorders; Urothelium
PubMed: 33308017
DOI: 10.1152/ajprenal.00290.2020 -
American Journal of Physiology.... Mar 2018Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of...
Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2 progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.
Topics: Animals; Behavior, Animal; Carboxylic Ester Hydrolases; Cystitis, Interstitial; Disease Models, Animal; Escherichia coli Infections; Female; Genetic Predisposition to Disease; Hyperalgesia; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Pain Perception; Pain Threshold; Pelvic Pain; Phenotype; Pseudorabies; Quantitative Trait Loci; Severity of Illness Index; Tumor Necrosis Factor-alpha; Urinary Bladder; Urinary Tract Infections; Vascular Endothelial Growth Factor A
PubMed: 29118019
DOI: 10.1152/ajpregu.00239.2017 -
The Pan African Medical Journal 2018A 67 years old patient has consulted for hypogastric pain, associated with a pollakiuria running for more than 12 months. The medical story reported genital prolapse,...
A 67 years old patient has consulted for hypogastric pain, associated with a pollakiuria running for more than 12 months. The medical story reported genital prolapse, some episodes of haematuria and dysuria. Pelvic ultrasound showed a voluminous image of lithiasic appearance with irregular borders. A cystotomy was performed under perimedullary anesthesia allowing the extraction of a giant bladder stone measuring 7.2 cm as major axis and 5.5 cm for small axis.
Topics: Aged; Cystotomy; Dysuria; Female; Hematuria; Humans; Pain; Ultrasonography; Urinary Bladder Calculi
PubMed: 29875910
DOI: 10.11604/pamj.2018.29.28.13701 -
American Journal of Physiology. Renal... Jun 2018Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (HS) generated by cystathionine β-synthase (CBS) or...
Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (HS) generated by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) facilitates bladder hypersensitivity. We assessed involvement of the HS pathway in protease-activated receptor 4 (PAR4)-induced bladder pain. A bladder pain model was induced by intravesical instillation of PAR4-activating peptide in mice. The role of HS in this model was evaluated by intraperitoneal preadministration of d,l-propargylglycine (PAG), aminooxyacetic acid (AOAA), or S-adenosylmethionine or the preintravesical administration of NaHS. SV-HUC-1 cells were treated in similar manners. Assessments of CBS, CSE, and macrophage migration inhibitory factor (MIF) expression, bladder voiding function, bladder inflammation, HS production, and referred bladder pain were performed. The CSE and CBS pathways existed in both mouse bladders and SV-HUC-1 cells. HS signaling was upregulated in PAR4-induced bladder pain models, and HS-generating enzyme activity was upregulated in human bladders, mouse bladders, and SV-HUC-1 cells. Pretreatment with AOAA or NaHS inhibited or promoted PAR4-induced mechanical hyperalgesia, respectively; however, PAG only partially inhibited PAR4-induced bladder pain. Treatment with PAG or AOAA decreased HS production in both mouse bladders and SV-HUC-1 cells. Pretreatment with AOAA increased MIF protein levels in bladder tissues and cells, whereas pretreatment with NaHS lowered MIF protein levels. Bladder pain triggered by the HS pathway was not accompanied by inflammation or altered micturition behavior. Thus endogenous HS generated by CBS or CSE caused referred hyperalgesia mediated through MIF in mice with PAR4-induced bladder pain, without causing bladder injury or altering micturition behavior.
Topics: Alkynes; Aminooxyacetic Acid; Analgesics; Animals; Cell Line; Cystathionine gamma-Lyase; Cystitis, Interstitial; Disease Models, Animal; Enzyme Inhibitors; Female; Glycine; Humans; Hydrogen Sulfide; Hyperalgesia; Intramolecular Oxidoreductases; Ligands; Lyases; Macrophage Migration-Inhibitory Factors; Mice, Inbred C57BL; Pain Threshold; Receptors, Thrombin; Signal Transduction; Sulfides; Urinary Bladder
PubMed: 29357418
DOI: 10.1152/ajprenal.00526.2017 -
Neurourology and Urodynamics Jun 2011Interstitial cystitis (painful bladder syndrome / interstitial cystitis; PBS/IC) is a persistent pain syndrome affecting the urinary bladder with symptoms including... (Review)
Review
Interstitial cystitis (painful bladder syndrome / interstitial cystitis; PBS/IC) is a persistent pain syndrome affecting the urinary bladder with symptoms including urinary frequency, bladder pain and nocturia.(–6) Various animal models have been studied, most of which mimic some aspect of the human condition of interest to the investigator(s). This review will provide examples of various animal models including those incorporating chronic stress, thought to produce features that share similarities to that of PBS/IC patients, whose symptoms are often exacerbated by various stressors. (–12) This review also provides evidence that patients with PBS/IC exhibit abnormalities within the bladder epithelium (or urothelium), even though a consistent relationship of such changes with symptom severity has not been demonstrated. These changes include alterations in urothelial integrity, differentiation and/or proliferation as well as changes in ‘sensory’ function (altered expression or sensitivity of receptors and ion channels). Establishing a diagnostic ‘indicator’ with a high degree of correlation in this syndrome would be of value in terms of disease status, diagnosis and treatment. There have been reports of a number of factors/mediators altered in PBS/IC. However, the lack of a validated biomarker and a well-defined etiology for this syndrome introduces a number of complications, including diagnostic confidence, choice of appropriate animal models to study basic mechanism with the goal toward treatment, and rational therapies. It is also becoming increasingly apparent that patients with PBS/IC often overlap or share symptoms commonly associated with other persistent pain disorders. These include (but are not limited to) irritable bowel syndrome (IBS), non-cardiac chest pain, fibromyalgia and even overactive bladder syndrome (OAB).(–18) Such types of changes are not limited to the urinary bladder, however, as reports of alterations in epithelial signaling/barrier function have been described in patients diagnosed with a wider variety of syndromes, including functional and inflammatory bowel disorders such as irritable bowel syndrome (IBS), gastrointestinal esophageal reflux disease (GERD) and asthma.(–21) These and other findings suggest that changes within the epithelium (barrier as well as signaling functions) may be a common occurrence that may contribute to peripheral mechanisms of hypersensitivity in a number of disorders.
Topics: Afferent Pathways; Animals; Comorbidity; Cystitis, Interstitial; Disease Models, Animal; Humans; Mechanotransduction, Cellular; Pain Threshold; Urinary Bladder; Urothelium
PubMed: 21661011
DOI: 10.1002/nau.21109 -
European Journal of Pharmacology Mar 2023and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain...
BACKGROUND
and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall.
EXPERIMENTAL APPROACH
The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice.
KEY RESULTS
PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3.
CONCLUSION AND IMPLICATIONS
PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP.
Topics: Animals; Cricetinae; Humans; Mice; Calcium; Cricetulus; Fura-2; Ganglia, Spinal; HEK293 Cells; Menthol; Pain; Phenazopyridine; Sensory Receptor Cells; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; Urinary Bladder
PubMed: 36657655
DOI: 10.1016/j.ejphar.2023.175512 -
American Journal of Physiology. Renal... Jan 2022Urinary tract infections (UTIs) cause bladder hyperactivity and pelvic pain, but the underlying causes of these symptoms remain unknown. We investigated whether afferent...
Urinary tract infections (UTIs) cause bladder hyperactivity and pelvic pain, but the underlying causes of these symptoms remain unknown. We investigated whether afferent sensitization contributes to the bladder overactivity and pain observed in mice suffering from experimentally induced bacterial cystitis. Inoculation of mouse bladders with the uropathogenic strain UTI89 caused pelvic allodynia, increased voiding frequency, and prompted an acute inflammatory process marked by leukocytic infiltration and edema of the mucosa. Compared with controls, isolated bladder sensory neurons from UTI-treated mice exhibited a depolarized resting membrane potential, lower action potential threshold and rheobase, and increased firing in response to suprathreshold stimulation. To determine whether bacterial virulence factors can contribute to the sensitization of bladder afferents, neurons isolated from naïve mice were incubated with supernatants collected from bacterial cultures with or depleted of lipopolysaccharide (LPS). Supernatants containing LPS prompted the sensitization of bladder sensory neurons with both tetrodotoxin (TTX)-resistant and TTX-sensitive action potentials. However, bladder sensory neurons with TTX-sensitive action potentials were not affected by bacterial supernatants depleted of LPS. Unexpectedly, ultrapure LPS increased the excitability only of bladder sensory neurons with TTX-resistant action potentials, but the supplementation of supernatants depleted of LPS with ultrapure LPS resulted in the sensitization of both population of bladder sensory neurons. In summary, the results of our study indicate that multiple virulence factors released from UTI89 act on bladder sensory neurons to prompt their sensitization. These sensitized bladder sensory neurons mediate, at least in part, the bladder hyperactivity and pelvic pain seen in mice inoculated with UTI89. Urinary tract infection (UTI) produced by uropathogenic (UPEC) promotes sensitization of bladder afferent sensory neurons with tetrodotoxin-resistant and tetrodotoxin-sensitive action potentials. Lipopolysaccharide and other virulence factors produced by UPEC contribute to the sensitization of bladder afferents in UTI. In conclusion, sensitized afferents contribute to the voiding symptoms and pelvic pain present in mice bladder inoculated with UPEC.
Topics: Action Potentials; Animals; Cystitis, Interstitial; Disease Models, Animal; Escherichia coli Infections; Female; Mice, Inbred C57BL; Neurons, Afferent; Urinary Bladder; Urinary Tract Infections; Urodynamics; Uropathogenic Escherichia coli; Virulence; Virulence Factors; Mice
PubMed: 34779263
DOI: 10.1152/ajprenal.00167.2021 -
BMC Urology Mar 2023To better understand the sensation of bladder "pressure" and "discomfort", and how they are similar or distinct from the "pain" and "urgency" symptoms in IC/BPS and OAB.
BACKGROUND
To better understand the sensation of bladder "pressure" and "discomfort", and how they are similar or distinct from the "pain" and "urgency" symptoms in IC/BPS and OAB.
METHODS
IC/BPS and OAB patients rated their bladder pain, pressure, discomfort, and urinary urgency on separate 0-10 numeric rating scales (NRS). Their NRS ratings were compared between IC/BPS and OAB, and Pearson correlations were performed.
RESULTS
Among IC/BPS patients (n = 27), their mean numeric ratings of pain, pressure, discomfort, and urinary urgency were almost identical (6.6 ± 2.1, 6.0 ± 2.5, 6.5 ± 2.2, and 6.0 ± 2.8 respectively). The three-way correlations between pain, pressure, or discomfort were very strong (all > 0.77). Among OAB patients (n = 51), their mean numeric ratings of pain, pressure, and discomfort (2.0 ± 2.6, 3.4 ± 2.9, 3.4 ± 2.9) were significantly lower than urgency (6.1 ± 2.6, p < 0.001). The correlations between urgency and pain, and between urgency and pressure were weak in OAB (0.21 and 0.26). The correlation between urgency and discomfort was moderate in OAB (0.45). The most bothersome symptom of IC/BPS was bladder/pubic pain, while the most bothersome symptom of OAB was urinary urgency and daytime frequency.
CONCLUSIONS
IC/BPS patients interpreted bladder pain, pressure, or discomfort as the similar concepts and rated their intensity similarly. It is unclear whether pressure or discomfort provide additional information beyond pain in IC/BPS. Discomfort may also be confused with urgency in OAB. We should re-examine the descriptors pressure or discomfort in the IC/BPS case definition.
Topics: Humans; Urinary Bladder, Overactive; Urinary Bladder; Cystitis, Interstitial; Pelvic Pain
PubMed: 36997906
DOI: 10.1186/s12894-022-01164-8