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Neuroscience letters  2012;534:150-154.
Previous research has suggested that early-in-life (EIL) exposure to bladder inflammation impairs the function of endogenous opioid inhibitory system(s) and may contribute to the development of chronic bladder pain. This study examined how acute adult and/or prior EIL exposure to bladder inflammation altered the inhibitory effects of systemic κ- and μ-opioid agonists on the visceromotor reflex (VMR) to urinary bladder distension (UBD). Female rats were exposed intravesically EIL (P14–P16) to either the inflammatory agent zymosan or anesthesia-alone, and then rechallenged as adults (12–17 weeks) with either anesthesia-alone or zymosan. The VMR to 60 mmHg UBD was measured after cumulative intravenous (i.v.) administration of 1 mg/kg and 4 mg/kg of either the κ-opioid agonist U50,488H or the μ-opioid agonist morphine. Morphine produced dose-dependent inhibition of the VMR to UBD in all groups, and U50,488H produced dose-dependent inhibition of the VMR to UBD in all but one group. Animals that received bladder inflammation both EIL and as adults showed significantly augmented VMRs to UBD (>100% baseline values) following 1 mg/kg of U50,488H and diminished inhibition of VMRs following 4 mg/kg of U50,488H when compared with other groups. In contrast, neither EIL nor adult bladder inflammation markedly altered the inhibition of the VMR to UBD produced by either 1 or 4 mg/kg of i.v. morphine. These data suggest EIL and adult exposure to bladder inflammation selectively decreases the inhibitory effects of κ-opioids and thereby may enhance bladder hypersensitivity in patients with painful bladder syndromes.
PMCID: PMC3558537  PMID: 23201636
Opioid; Visceral Pain; Inflammation; Painful Bladder Syndrome; Animals; Newborn
2.  Intrathecal Oxytocin Inhibits Visceromotor Reflex and Spinal Neuronal Responses to Noxious Distention of the Rat Urinary Bladder 
Background and Objectives
Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation.
Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 s; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings.
OXY doses of 0.15 μg or 1.5 μg inhibited VMRs to UBD by 37 ± 8% and 68 ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76 ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes.
These results argue that intrathecal OXY produces an OXY receptor specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.
PMCID: PMC3426637  PMID: 22878524
3.  Temporal Characteristics of Cold Pain Perception 
Neuroscience letters  2010;480(1):12-15.
Adaptation to a sustained stimulus is an important phenomenon in psychophysical experiments. When studying the response to an experimental task, the investigator has to account for the change in perceived stimulus intensity with repeated stimulus application and, if the stimulus is sustained, for the change in intensity during the presentation. An example of a sustained stimulus is the cold pressor task (CPT). The task has been used both as an experimental pain task and to study cardiovascular physiology. In functional imaging research, the CPT has been used to evaluate cognitive processing of a noxious stimulus. Investigators typically model the stimulus in a block design as a categorical (on-off) stimulus and do not account for a temporal change in stimulus perception. If the perceived stimulus changes over time, the results may be misleading.
Therefore, we characterized the time course of cold pain in human volunteers and developed a model of the temporal characteristics of perceived cold pain. Fifteen healthy participants underwent cold pain testing by immersing their right foot into a container filled with ice water (2 °C) for 30 seconds alternating with a 30 seconds immersion into a container filled with tepid water 32°C (control). Participants rated the pain intensity using an electronic slide algometer.
Using a mixed general linear model (effectively a polynomial regression model), we determined that pain ratings follow a crescendo-decrescendo pattern that can be described well using a quadratic model. We conclude that the time course of quantitative perception differs fundamentally from the time course of stimulus presentation. This may be important when looking for the physiological correlates of perception as opposed to the presence of a stimulus per se.
PMCID: PMC3708606  PMID: 20493237
Pain; Rating; Cold; Sensory Adaptation; Imaging
4.  Neonatal Bladder Inflammation Produces Functional Changes and Alters Neuropeptide Content in Bladders of Adult Female Rats 
Neonatal bladder inflammation has been demonstrated to produce hypersensitivity to bladder re-inflammation as an adult. The purpose of this study was to investigate the effects of neonatal urinary bladder inflammation on adult bladder function and structure. Female Sprague-Dawley rats were treated on postnatal days 14-16 with intravesical zymosan or anesthesia alone. At 12-16 weeks of age, micturition frequency and cystometrograms were measured. Similarly treated rats had their bladders removed for measurement of plasma extravasation following intravesical mustard oil, for neuropeptide analysis (CGRP or SubP), or for detailed histological examination. Rats treated with zymosan as neonates exhibited increased micturition frequency, reduced micturition volume thresholds, greater extravasation of Evan's Blue following intravesical mustard oil administration, and greater total bladder content of CGRP and SubP. In contrast, there were no quantitative histological changes in the thickness, fibrosis or mast cells of bladder tissue due to neonatal zymosan treatments. Functional changes in urologic systems observed in adulthood, coupled with the increased neuropeptide content and neurogenic plasma extravasation in adult bladders, suggest that the neonatal bladder inflammation treatment enhanced the number, function and/or neurochemical content of primary afferent neurons. These data support the hypothesis that insults to the urologic system in infancy may contribute to the development of adult bladder hypersensitivity.
Inflammation of the bladder early in life in the rat has multiple sequelae including laboratory measures that suggest an alteration of the neurophysiological substrates related to the bladder. Some painful bladder syndromes in humans have similar characteristics and so may be due to similar mechanisms.
PMCID: PMC2835826  PMID: 19945355
developmental; visceral nociception; hyperalgesia; interstitial cystitis
Brain research  2011;1386:118-126.
This investigation examined the effect of footshock on responses of 283 spinal dorsal horn neurons (DHNs) to urinary bladder distension (UBD). Female rats were treated with seven daily sessions of footshock (chronic footshock, CFS), six accommodation sessions followed by one exposure to footshock (acute footshock, AFS), or handled similarly without receiving any footshock (no footshock, NFS). After the final footshock or NFS session, rats were anesthetized, a laminectomy performed and extracellular single-unit recordings of L6-S1 DHNs obtained in intact or spinalized preparations. Neurons were classified as Type I - inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II - not inhibited by HNCS - and characterized for spontaneous activity and for neuronal discharges evoked by graded UBD. A differential effect of footshock-induced stress was noted on neuronal subgroups. In intact preparations, Type I neurons were less responsive to UBD after either chronic or acute stress, while Type II neurons demonstrated significantly augmented responses to UBD. This enhanced neuronal responsiveness to UBD was present in spinalized preparations following exposure to CFS but not AFS. Type I neurons were still less responsive to stress in spinalized preparations following CFS and AFS. This study provides further evidence that (1) at least two populations of spinal neurons exist which encode for visceral stimuli and are likely to have distinct roles in visceral nociception, and that (2) the chronic stress-induced enhancement of DHN responses to UBD involves changes in at the spinal level while the acute stress effects are dependent on a supraspinal substrate.
PMCID: PMC3086680  PMID: 21376017
visceral; urinary bladder; cystitis; stress; spinal
6.  Effects of Nicotine on Spinal Cord Injury Pain 
One factor affecting spinal cord injury (SCI)–related pain may be nicotine. Case reports have described a worsening of neuropathic pain from smoking and relief from abstinence. Neurobiological correlates also implicate the potential effect of nicotine on SCI-related pain.
The current study employed a randomized, placebo-controlled crossover design to examine the effect of nicotine exposure on subtypes of SCI-related pain among smokers and nonsmokers.
Whereas nonsmokers with SCI showed a reduction in mixed forms of pain following nicotine exposure, smokers with SCI showed a converse increase in pain with regard to both mixed and neuropathic forms of pain. The exacerbation of pain in chronic nicotine or tobacco users may not only elucidate possible pain mechanisms but may also be of use in smoking cessation counseling among those with SCI.
PMCID: PMC3584761  PMID: 23459459
neuropathic pain; nicotine; pain; smoking; spinal cord injury; randomized controlled trial
7.  Effects of acute adult and early-in-life bladder inflammation on bladder neuropeptides in adult female rats 
BMC Urology  2011;11:18.
The purpose of the present study was to determine how acute adult and/or prior early-in life (EIL; P14-P16) exposure to bladder inflammation affects bladder content of calcitonin gene related peptide (CGRP) and substance P (SP). Estrous cycle influences were also studied in the adult-treatment conditions.
In Experiment 1, intravesical zymosan or isoflurane anesthesia alone was administered to adult female rats. Bladders and serum were collected 24 hours later during each phase of the estrous cycle. In Experiment 2, zymosan or anesthesia alone was administered EIL and as adults, with bladder tissue collection 24 h later.
In general, Experiment 1 showed that bladder content of both CGRP and SP was increased by inflammation. This effect was significant when data were collapsed across all phases of the estrous cycle, but was only significant during proestrus when individual comparisons were made during each phase of estrous. Also, adult bladder inflammation significantly reduced estradiol levels. In Experiment 2, bladder content of CGRP and SP was significantly increased in rats receiving EIL and/or adult inflammation. Bladder weights were also significantly increased by inflammation.
These data indicate that bladder CGRP and SP are maximally increased during the proestrus phase of the estrous cycle in inflamed adult female rats. EIL exposure to bladder inflammation alone can also produce an increase in CGRP and SP lasting into adulthood. Therefore, EIL experience with bladder inflammation may predispose an organism to experience a painful bladder disorder as an adult by increasing primary afferent content of CGRP and/or SP.
PMCID: PMC3171712  PMID: 21843346
8.  Effect of Estrogen on Bladder Nociception in Rats 
The Journal of urology  2010;183(3):1201-1205.
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.
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.
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.
PMCID: PMC3094858  PMID: 20096872
estrogens; ovary; pain; ovariectomy; rats; Sprague-Dawley
11.  Effects of Oxytocin and Prolactin on Stress-Induced Bladder Hypersensitivity in Female Rats 
Anecdotal evidence suggests that chronic bladder pain improves while breastfeeding. The present study sought to identify potential mechanisms for such a phenomenon by investigating the effects of the lactogenic hormones prolactin (PL) and oxytocin (OXY) in a rat model of bladder nociception. Lactating rats were less sensitive to urinary bladder distension (UBD) than controls. In investigating potential antinociceptive and anxiolytic roles for these hormones, we found exposure to a footshock paradigm (STRESS groups) produced bladder hypersensitivity in saline-treated rats, manifested as significantly higher electromyographical (EMG) responses to UBD, compared to rats exposed to a non-footshock paradigm (SHAM groups). This hypersensitivity was attenuated by the intraperitoneal administration of OXY prior to footshock in the STRESS-OXY group. The administration of PL augmented EMG responses in the SHAM-PL group but had no effect on the responses of the STRESS-PL group. In the absence of behavioral pretreatment, OXY attenuated UBD-evoked responses while PL had no effect. Moreover, OXY-treated rats spent more time in the open arm of an elevated plus maze compared to saline-treated rats suggesting anxiolysis. These studies suggest the potential for systemic OXY, but not PL, as an analgesic and anxiolytic treatment for painful bladder disorders such as interstitial cystitis.
PMCID: PMC2757490  PMID: 19595642
oxytocin; prolactin; nociception; pain; stress; anxiety; bladder
12.  Rostral Ventral Medulla Modulation of the Visceromotor Reflex Evoked by Urinary Bladder Distension in Female Rats 
The present studies examined the involvement of the rostral ventral medulla (RVM) in modulating the visceromotor response (VMR) evoked by urinary bladder distension (UBD) in adult female rats. The VMR was indexed by electromyographic (EMG) responses of the abdominal external oblique muscle to UBD. Experiment 1 showed that the predominant effect of electrical stimulation of the RVM in normal rats was to produce intensity-dependent inhibition of the VMR (54% of sites sampled). Facilitatory, biphasic, or no effects were obtained at the remaining sites. Experiment 2 showed that RVM-induced inhibition of the VMR was significantly attenuated by intraperitoneal (i.p.) administration of naloxone, but not saline vehicle. In Experiment 3, we examined the effect of lesions of the RVM in rats with inflamed bladders since previous research has shown that an endogenous opioid inhibitory system is engaged by bladder inflammation. Electrolytic lesions of the RVM, but not sham-lesions of the RVM, significantly increased the VMR to graded UBD in rats with augmented VMRs induced by prior inflammation of the bladder. The present data suggest that the RVM can inhibit the VMR to UBD acting in part via an opioid inhibitory system and that bladder inflammation can recruit the RVM to produce a net inhibitory effect on the VMR to UBD.
PMCID: PMC2576287  PMID: 18619908
bladder; rostral ventromedial medulla; visceromotor reflex; pain; inhibition
13.  Footshock-Induced Urinary Bladder Hypersensitivity: Role of Spinal Corticotropin-Releasing Factor Receptors 
Stress-induced hyperalgesia (SIH), a common clinical observation associated with multiple painful diseases including functional urinary disorders, presently has no mechanistic explanation. Using a Footshock treatment, a classical stressor, to magnify physiological responses in a model of urinary bladder pain, we examined one potential group of mediators of SIH, the corticotropin-releasing factor (CRF)-related neuropeptides. Exposure to a Footshock treatment produced bladder hypersensitivity in female Sprague Dawley rats, manifested as significantly more vigorous visceromotor responses (VMRs) to urinary bladder distension (UBD) compared to rats that were exposed to a Non-footshock treatment. This bladder hypersensitivity was significantly attenuated by blocking spinal CRF2 receptors but not CRF1 receptors. Furthermore, spinal administration of urocortin 2, a CRF2 receptor agonist, augmented UBD-evoked VMRs in a way similar to what was observed following exposure to Footshock, an effect significantly attenuated by pretreatment with spinal aSVG30, a CRF2 receptor antagonist. Surprisingly, neither spinal administration of CRF nor the CRF1 receptor antagonist, antalarmin, had an effect on bladder nociceptive responses. The results of the present study not only provide further support for a role of stress in the exacerbation of bladder pain, but also implicate spinal urocortins and their endogenous receptor, the CRF2 receptor, as potential mediators of this effect.
This study presents evidence that spinal urocortins and CRF2 receptors are involved in stress-induced hypersensitivity related to the urinary bladder. This provides a basis for investigating how urocortins mediate SIH, ultimately leading to more effective treatment options for patients suffering from painful bladder syndromes as well as stress-exacerbated chronic pain.
PMCID: PMC2579943  PMID: 18632307
Urinary bladder; hypersensitivity; visceral; urocortin; corticotropin-releasing factor
14.  Inflammation and enhanced nociceptive responses to bladder distension produced by intravesical zymosan in the rat 
BMC Urology  2006;6:2.
Mycotic infections of the bladder produce pain and inflammatory changes. The present study examined the inflammatory and nociceptive effects of the yeast cell wall component, zymosan, when admininstered into the urinary bladder in order to characterize this form of bladder sensitization.
Parametric analyses of the time-course (0–48 hr) and concentration (0–2% solutions) variables associated with intravesical zymosan-induced bladder inflammation were performed in female rats. Plasma extravasation of Evan's Blue dye was used as a measure of tissue inflammation. Cardiovascular and visceromotor responses to urinary bladder distension were used as measures of nociception.
Zymosan-induced bladder inflammation, as indexed by plasma extravasation of Evan's Blue, was significantly greater in rats treated with either 1 or 2% solutions as compared to either 0.1 or 0.5% zymosan solutions. In time-course studies (1 – 48 hr post-treatment), 1% zymosan-induced inflammation progressively increased with time following administration, was greatest at 24 hr and began to normalize by 48 hr. In the studies of inflammation-induced changes in nociception, arterial blood pressure (ABP) and visceromotor responses to graded distension of the urinary bladder were significantly increased relative to controls 24 hr after zymosan administration.
These studies provide important time-course and solution concentration parameters for studies of zymosan-induced inflammation of the bladder and suggest utility of this model for the study of bladder-related pain.
PMCID: PMC1395324  PMID: 16469099
15.  Visceral Pain and Life Quality in Persons With Spinal Cord Injury: A Brief Report 
Few studies have examined the prevalence of visceral pain in persons with spinal cord injury (SCI), and virtually no studies have looked at the relationship between visceral pain and self-reported quality of life. We examined the frequency of reported visceral pain at 5, 10, and 15 years after injury to determine whether the presence of visceral pain is related to quality of life, and to determine to what extent visceral pain should be of concern to clinicians treating patients with SCI.
Visceral pain and quality of life in persons with SCI were compared from a combined Craig Hospital and National Model SCI Systems database at 5 (N = 33), 10 (N = 132), and 15 (N = 96) years after injury.
The rates of visceral pain increased at each measurement (10% at year 5, 22% at year 10, and 32% at year 15); although these numbers reflect cross-sectional data, they do show a clear statistical change. Only a limited true longitudinal sample was available, but at 10 years after injury, individuals who had reported visceral pain at any time reported a significantly lower quality of life than those never experiencing visceral pain, F1,188 = 3.95, P < 0.05.
Although visceral pain may not be as prevalent as the more researched neuropathic and musculoskeletal subtypes of pain, it may account for a higher percentage of people with SCI who report pain than previously recognized. More quantitative and longitudinal research is needed to examine the relationship of visceral pain with overall quality of life and to pursue interventions.
PMCID: PMC1864904  PMID: 16396385
Spinal cord injuries; Visceral pain; Quality of life

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