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Purpose: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis., Materials and Methods: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition., Results: Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis., Conclusions: Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral blood flow increases in the full bladder state in regions of interest typically associated with pain, emotion and/or motor control, indicating altered processing of bladder related sensations., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants., Materials and Methods: We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States., Results: Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS)., Conclusions: These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance in the processing of pain and viscerosensory signals. We identified differences in brain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome., Materials and Methods: We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands., Results: Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest in patients who reported pain during bladder filling., Conclusions: Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations and connectivity in a cortico-cerebellar network previously associated with bladder function., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We characterized urological symptoms in a subset of patients with urological chronic pelvic pain syndrome who have a high somatic symptom burden and a wide symptom distribution fitting a polysymptomatic, polysyndromic presentation pattern., Materials and Methods: A total of 81 patients with urological chronic pelvic pain syndrome enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases MAPP Research Network Study at Washington University in St. Louis and University of Alabama at Birmingham sites. They completed a symptom questionnaire to assess the somatic symptom burden and its distribution, and GUPI (Genitourinary Pain Index) to assess urological chronic pelvic pain syndrome symptoms, impact on quality of life and self-reported treatment seeking behaviors for urological chronic pelvic pain symptoms. The polysymptomatic, polysyndromic symptom pattern was defined by self-report of numerous painful and nonpainful somatic symptoms across many organ systems and by symptom categories on the polysymptomatic, polysyndromic questionnaire., Results: Patients with urological chronic pelvic pain syndrome and the symptom pattern reported more severe genitourinary pain on a Likert scale, more frequent pain in the last week and more widespread pain distribution in the genital and pelvic areas than patients with urological chronic pelvic pain syndrome without the pattern. Patients with the symptom pattern also had significantly higher scores on the GUPI pain subscale, quality of life subscale (worse) and total questionnaire scores than patients without the pattern. Patients with the pattern reported significantly more treatment seeking behavior than others., Conclusions: The polysymptomatic, polysyndromic pattern might be an important phenotypic factor to assess in the evaluation of urological chronic pelvic pain syndrome with clinical and research implications. This may be a distinct clinical subgroup among patients with urological chronic pelvic pain syndrome., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigate if subjects with interstitial cystitis/bladder pain syndrome demonstrate mechanical or thermal hyperalgesia, and whether the hyperalgesia is segmental or generalized (global)., Materials and Methods: Ten female subjects with interstitial cystitis/bladder pain syndrome and 10 age matched female controls without comorbid fibromyalgia or narcotic use were recruited for quantitative sensory testing. Using the method of limits, pressure pain and heat pain thresholds were measured. Using the method of fixed stimulus, the visual analog scale pain experienced was recorded when a fixed pressure/temperature was applied., Results: The visual analog scale pain rated by female subjects with interstitial cystitis/bladder pain syndrome was significantly higher than that rated by female control subjects when a fixed mechanical pressure (2 or 4 kg) was applied to the suprapubic (T11) area (p = 0.028). There was an up shift of the stimulus-response curve, which corresponded to the presence of mechanical hyperalgesia in the suprapubic area in interstitial cystitis/bladder pain syndrome. However, the visual analog scale pain rated by subjects with interstitial cystitis/bladder pain syndrome was not different from that rated by controls when a fixed pressure was applied at the other body sites (T1 arm, L4 leg, S2-3 sacral). No difference in visual analog scale pain rating was noted when a fixed heat stimulus (35C or 37C) was applied to any of the body sites tested (T1, T11, L4, S2). There was no difference in pressure pain thresholds or thermal pain thresholds between subjects with interstitial cystitis/bladder pain syndrome and controls., Conclusions: Female subjects with interstitial cystitis/bladder pain syndrome showed segmental hyperalgesia to mechanical pressure stimulation in the suprapubic area (T10-T12). This segmental hyperalgesia may be explained in part by spinal central sensitization., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome., Materials and Methods: Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity., Results: The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance., Conclusions: An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Previous research suggests that a failure of opioid inhibition may contribute to chronic bladder pain. We determined how acute adult and/or prior early in life exposure to bladder inflammation alters the adult content of endogenous opioid peptides in the bladder, spinal cord and blood., Materials and Methods: Inflammation was induced by intravesical administration of zymosan. Female Sprague-Dawley® rats were exposed to anesthesia only or zymosan early in life (postnatal days 14 to 16) and anesthesia only or zymosan as adults (ages 12 to 17 weeks). Thoracolumbar and lumbosacral segments of the spinal cord, and blood and bladders were collected 24 hours after adult treatment. Opioid peptide content was measured using enzyme-linked immunosorbent assay., Results: Early in life bladder inflammation alone produced a chronic increase in dynorphin A (1-17) in the lumbosacral spinal cord. When early in life inflammation was followed by adult re-inflammation, spinal cord dynorphin remained unchanged but bladder dynorphin was decreased. In addition, early in life inflammation combined with adult bladder inflammation decreased endomorphin-2 content in the thoracolumbar spinal cord. Neither early in life nor adult bladder inflammation affected thoracolumbar dynorphin, serum dynorphin, lumbosacral endomorphin-2 or plasma β-endorphin., Conclusions: Several opioid peptides were measured using enzyme-linked immunosorbent assay following early in life and adult bladder inflammation. The changes observed are consistent with the view that early in life bladder inflammation alone can chronically alter spinal cord peptide content. When coupled with adult re-inflammation, these changes could set the neurochemical stage to support bladder hypersensitivity., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Painful bladder disorders vary in intensity with the menstrual cycle in women. We evaluated the influence of the correlate in rats (the estrous cycle) on the nociceptive visceromotor reflex to bladder distention in the presence/absence of inflammation and of spinal opioid blockade., Materials and Methods: We recorded visceromotor reflexes as electromyogram responses of the abdominal musculature to graded (10 to 60 mm Hg) bladder distention in anesthetized female rats in the presence of intrathecal saline or naloxone (10 μg) 1 day after receiving intravesical zymosan or anesthesia alone., Results: In saline treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. When separated into phases, rats with bladder inflammation showed complex estrous cycle effects with significantly greater visceromotor reflexes to bladder distention during metestrus and proestrus than diestrus. In naloxone treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. Naloxone enhanced the overall magnitude of visceromotor reflexes to bladder distention in the inflamed and noninflamed conditions. The magnitude of visceromotor reflexes to bladder distention in noninflamed and inflamed conditions in the presence of naloxone was estrous phase dependent in the order, estrus >metestrus >diestrus >proestrus. Similar findings were apparent on analysis of data on responses at threshold intensity (30 mm Hg)., Conclusions: Data suggest that circulating hormones present during the estrous cycle alter bladder reactivity and opioid modulatory systems to maintain constancy of input from the bladder to the central nervous system., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We assessed the effect of ovariectomy and estrogen replacement on nociceptive responses to bladder distention in a rat model., Materials and Methods: Female Sprague-Dawley rats (Harlan) underwent ovariectomy or sham surgery. Visceromotor responses (abdominal contractions) to bladder distention were determined 3 to 4 weeks later under isoflurane anesthesia. In rat subsets estrogen was chronically replaced with a subcutaneous estrogen pellet vs a placebo pellet or acutely replaced by subcutaneous injection 24 hours before testing. Effects of estrogen withdrawal were examined in another group of rats by implanting a pellet and explanting the pellet 24 hours before testing. Uterine weight was measured to assess the estrogen dose., Results: Visceromotor responses to bladder distention were significantly less vigorous in ovariectomized rats vs controls. Acute estrogen replacement increased visceromotor responses in these rats but chronic estrogen replacement did not. Sudden chronic estrogen withdrawal resulted in increased visceromotor responses. Uterine weight was consistent with the physiological estrogen dose., Conclusions: Estrogen alone was not sufficient to produce increased nociceptive responses but an acute decrease in estrogen resulted in increased visceromotor responses. These data suggest that the pronociceptive effects of estrogen may be due to a mismatch between peripheral vs central and/or genomic vs nongenomic effects of the hormone, which occur during rapidly decreasing estrogen levels., (2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We determined whether clinical observations of hypersensitivity to ice water testing, that is infusion of ice-cold saline into the bladder, in patients with painful bladder syndrome/interstitial cystitis have a parallel in a rat model of bladder hypersensitivity produced by neonatal inflammation., Materials and Methods: Rat pups were anesthetized as neonates (postnatal days 14 to 16). In some pups the bladder was inflamed by intravesical zymosan treatment. As adults, the rats were re-anesthetized and tested for abdominal muscle contractions to ice water testing, measured on electromyogram. Various neonatally treated groups of rats underwent bladder re-inflammation/no re-inflammation and/or bladder distention before ice water testing. Other control rats were treated only in adulthood., Results: Rats that underwent bladder inflammation as neonates manifested bladder hypersensitivity in adulthood, as indexed by significantly greater mean electromyogram responses during ice water testing. This bladder hypersensitivity did not require adult re-inflammation to manifest. Hypersensitivity was also observed with or without prior bladder distention, although the magnitude of electromyogram responses during ice water testing significantly correlated with the magnitude of electromyogram responses to bladder distention. Neonatally induced effects were not significantly related to estrous cycle phase. Exposure to menthol did not significantly enhance the overall magnitude of the electromyogram response to ice water testing in neonatally treated rats., Conclusions: Current results parallel those in a recent study showing that most patients with painful bladder syndrome/interstitial cystitis experience pain when undergoing ice water testing after previous urodynamic testing. These findings suggest that this animal model may be useful for understanding the etiology of and treatment for painful bladder syndrome/interstitial cystitis.

Purpose: Using psychophysical methods we compared the effect of the menstrual cycle on bladder sensation in subjects with the diagnosis of interstitial cystitis (IC) and in controls., Materials and Methods: Female participants with normal menstrual cycles, including 7 with IC and 8 healthy controls, were recruited into this study. They completed daily diaries related to bladder pain and other body pain, and tracked daily micturition frequency. In a subset formal psychophysical testing of thermal and ischemic pain was performed at 2 times of the menstrual cycle, corresponding to the luteal and follicular phases. Cystometrograms were performed at the same time., Results: Subjects with IC had higher pain scores and frequency than controls throughout the entire menstrual cycle. Pain scores were highest in the perimenstrual period in subjects with IC and controls. Micturition frequency was highest in the perimenstrual period in subjects with IC. Cystometric evaluation of a first need to void and the evocation of bladder pain demonstrated that lower intravesical volume and pressure were necessary to evoke bladder pain during the follicular period than during the luteal period in subjects with IC, although there was no effect on the first need to void., Conclusions: These findings are consistent with clinical lore that suggests a perimenstrual flare in pain in subjects with IC. To our knowledge it also demonstrates for the first time a menstrual cycle effect on bladder sensory function in subjects with IC. This suggests a potential role of gonadal hormones on bladder sensory processing and, therefore, a potential role for hormonal modulation as a therapeutic modality in this patient population.

Purpose: We quantified differences in somatic and visceral sensation in healthy subjects and subjects with interstitial cystitis (IC)., Materials and Methods: A total of 13 subjects with IC and 13 healthy subjects answered psychological questionnaires and underwent psychophysical testing of thermal and pressure thresholds for sensation as well as the ischemic forearm test of pain tolerance. A subset of subjects also underwent bladder sensory testing with the determination of 3 consecutive cystometrograms. Ratings of intensity and unpleasantness were determined., Results: Subjects with IC were significantly more sensitive to deep tissue measures of sensation related to pressure, ischemia and bladder than healthy subjects. Cutaneous thermal pain measures were similar in the 2 groups. Psychological measures indicated higher reactivity in subjects with IC., Conclusions: Similar to other visceral pain disorders, such as irritable bowel syndrome, hypersensitivity to somatic stimuli was noted in subjects with IC. This suggests altered central mechanisms in the processing of sensory events from the bladder.

Purpose: A mouse model of bladder distension (UBD) induced acute visceral nociception was characterized. Murine models of nociception may allow for the investigation of mechanisms of pain and analgesia through the use of genetic models., Materials and Methods: Isoflurane anesthetized, spontaneously breathing female C3H/J mice had 24 gauge intravesical catheters transurethrally placed and electrodes implanted in the abdominal musculature and in upper limbs for electromyograms and electrocardiograms., Results: UBD (10 to 80 mm Hg for 20 seconds, phasic air distention) produced reliable, reproducible visceromotor responses (VMRs), that is increased abdominal muscle activity, which were graded with graded UBD. Heart rate and respiratory responses were reliable but not reproducible. Subcutaneous morphine (1 to 4 mg/kg) and intravesical lidocaine (500 microg) produced reversible VMR inhibition. Inflammation produced by intravesical mustard oil (2.5% for 15 minutes with an olive oil control) produced a marked increase in sensitivity to UBD with more robust responses evoked by lower UBD intensities. VMRs were present in decerebrate but not in spinal cord transected mice. Unanesthetized mice had similar responses to UBD but with lower pressure thresholds for VMRs., Conclusions: These findings suggest the usefulness of the current model system for the study of bladder nociception. In mice UBD evoked VMRs are spinobulbospinal reflexes that are reliable and reproducible, graded in relation to the stimulus, inhibited by analgesics and augmented by the presence of inflammation. Together these data strongly support the use of this model because it may allow the assessment of pharmacogenetic differences among murine strains and the use of transgenic technologies.

Purpose: We assessed the usefulness of cardiovascular and visceromotor responses to bladder distention as measures of acute visceral nociception in rats by determining the reliability of these responses., Materials and Methods: Halothane anesthetized male and female Sprague-Dawley rats were acutely instrumented with tracheal, jugular venous, carotid arterial and bladder cannulas. Wires were inserted into the abdominal musculature to enable myoelectrical activity measurement. Anesthesia was decreased until flexion reflexes were present. Repeat phasic and graded bladder distention was administered, and arterial blood pressure and abdominal electromyography activity were continuously monitored. We determined the effects of gender, vaginal smear estrous cycle stage and drug treatment on the measured responses., Results: Bladder distention produced reliable pressor and visceromotor (abdominal contractile) responses. There was great inter-animal variability in response vigor but good reproducibility was noted within individual animals. During slow bladder filling bladder contractions were not noted at this level of anesthesia. Sex differences included a more vigorous reflex response in females than in males, which was most vigorous in females in proestrus. Repeat bladder distention led to increasingly vigorous pressor responses and the improved reliability of visceromotor responses. Intravenous morphine and lidocaine dose dependently inhibited the reflex responses., Conclusions: Pressor and visceromotor responses to bladder distention in halothane anesthetized rats are reliable measures of acute bladder nociception that may prove useful for analgesic screening and in studies of hormonal effects on nociception.