Stress-induced bladder hypersensitivity: Effect of corticotropin releasing factor receptors assessed by spinal neurophysiology and neurochemistry.

Corticotropin releasing factor (CRF) receptors have been implicated in stress-induced hyperalgesia. The present study examined the role of CRF receptors Type 1&2 (CRFR1, CRFR2) in stress-induced bladder hyperalgesia in female rats by quantifying changes in receptor and agonist content following chronic (CFS, 7 daily episodes), acute (AFS, single episode) and control (NFS, no episodes) footshock protocols. ELISAs demonstrated that CFS lead to an increase in spinal thoracolumbar and lumbosacral spinal cord CRFR2 content and a decrease in lumbosacral spinal cord CRFR1 content. Content of the endogenous CRFR2 agonist, urocortin 2, was also increased in lumbosacral spinal cord and bladder tissues of CFS-pretreated rats, but urocortin 3 was decreased. Correlative single unit studies of lumbosacral dorsal horn neurons excited by bladder distension, in anesthetized rats that had undergone CFS, AFS or NFS protocols, used a before-after methodology with administration of a CRFR1 antagonist (antalarmin, 24 µg), CRFR2 antagonist (aSVG30, 12 µg) or normal saline topically to the exposed spinal cord following primary characterization. aSVG30 produced a reduction of neuronal responses evoked by bladder distension in CFS-pretreated rats but no statistically significant effects of aSVG30, antalarmin or vehicle were noted in other groups tested with the exception that antalarmin had an inhibitory effect on spontaneous activity in NFS-pretreated rats. The present findings are consistent with previous experiments using reflex responses to bladder distension as endpoints and further support a role for CRFR2-related mechanisms in stress-induced bladder hypersensitivity. This suggests CRFR2 antagonists may have efficacy in the treatment of bladder pain.

Online survey of university students' perception, awareness and adherence to COVID-19 prevention measures.

BACKGROUND: Determining factors correlated with protective measures against COVID-19 is important to improve public health response. This study describes student opinions related to university COVID-19 preventive measures. METHODS: In fall 2020, 643 US university students completed an online survey on perception, awareness, and adherence to COVID-19 preventive measures. Outcomes included protocol effectiveness (self or others), protocol adherence (self or others), consequences of protocol violation, knowledge of violations, and level of concern for COVID-19. Multiple linear regression models determined correlates of outcome variables. Covariates included gender, race, residence, area of study, class, and knowledge of someone with a positive COVID-19 test. RESULTS: Overall, students agreed with protective measures (equivalent to higher scores). In adjusted linear models, females (versus males) had significantly higher scores for protocol effectiveness (self) (p < 0.001), consequences of protocol violation (p = 0.005), and concern about COVID-19 (p < 0.001). Asian/Pacific Islander (versus white) had significantly higher scores for protocol effectiveness (self) (p < 0.001), consequences of protocol violation (p = 0.008), and concern about COVID-19 (p = 0.001). Graduate students (versus freshman) had higher scores for protocol effectiveness (self) (p < 0.001), protocol adherence (self) (p = 0.004) and concern about COVID-19 (p < 0.001). In contrast, participants who had a positive COVID-19 test had significantly lower scores for protocol effectiveness (self) (p = 0.02), protocol adherence (self) (p = 0.004), and consequences of protocol violation (p = 0.008). CONCLUSION: Overall, females, Asian/Pacific Islanders, and graduate students were more likely to agree with or adhere to COVID-19 prevention guidelines but those who tested positive for COVID-19 were less likely to do so. These results may inform future prevention efforts.

Neonatal cystitis alters mechanisms of stress-induced visceral hypersensitivity in rats.

In rodent models, conditioning with acute footshock (AFS) has been demonstrated to produce bladder hypersensitivity which is more robust when rats, tested as adults, had also been pretreated with neonatal bladder inflammation (NBI). The spinal neurochemical mechanisms of pro-nociceptive processes in rats pretreated with NBI are not fully known and so the present study administered intrathecal (IT) opioid (naloxone) and NMDA receptor (MK-801) antagonists to determine whether these receptors' actions had been altered by NBI. Female Sprague-Dawley rat pups were intravesically pretreated on postnatal days P14-P16 with a 1% zymosan solution or with control procedures and then raised to adulthood (12-15 weeks of age). Bladder hypersensitivity was induced through use of an AFS paradigm. Visceromotor responses (VMRs; abdominal muscle contractions) to graded, air pressure-controlled urinary bladder distension were used as nociceptive endpoints. Immediately following AFS pretreatments, rats were anesthetized and surgically prepared. Pharmacological antagonists were administered via an IT catheter onto the lumbosacral spinal cord and VMRs determined 15 min later. Administration of IT naloxone hydrochloride (10 µg) to rats which had been pretreated only with AFS resulted in VMRs that were more robust than VMRs in similarly pretreated rats that received IT normal saline. In contrast, IT naloxone had no significant effect on rats that had been pretreated with both NBI&AFS, although MK-801 was inhibitory. These effects of IT naloxone suggest the presence of inhibitory influences in normal rats that are absent in rats pretreated with NBI. Absence of inhibitory influences produced by AFS was also demonstrated in rats pretreated with NBI&AFS using measures of thermal paw withdrawal latency (PWL): rats pretreated with only AFS had longer PWLs than rats pretreated with both NBI&AFS. Together, a reduction in anti-nociceptive mechanisms coupled with pro-nociceptive NMDA-linked mechanisms results in more robust nociceptive responses to distension in rats which had experienced NBI.

Prevalence and predictors of mask use on a large US university campus during the COVID-19 pandemic: A brief report.

This observational study was conducted to determine the prevalence and correlates of wearing masks at a large Midwestern US university during the COVID-19 pandemic. A total of 7,237 individuals were observed over 24 hours. Overall mask use prevalence was 90.6% (95% confidence interval: 89.9, 91.2); mask use was significantly associated with being indoors (vs outdoors), female (vs male), and at the athletic center (vs the student union).

Lesions of the central amygdala and ventromedial medulla reduce bladder hypersensitivity produced by acute but not chronic foot shock.

Both acute and chronic stress has been shown to exacerbate symptoms of chronic visceral pain conditions such as interstitial cystitis. Studies using animal models support these findings in that both acute and chronic exposure to foot shock-induced stress (FS) augment nociceptive reflex responses to urinary bladder distension (UBD). Only a few studies have examined the neural substrates mediating these phenomena and it is not clear whether acute and chronic stress engage the same or different substrates to produce bladder hypersensitivity. The present studies examined the role of two important central nervous system structures - the amygdala (AMG) and the ventromedial medulla (VMM) - in mediating/modulating hypersensitivity evoked by acute versus chronic FS using responses to graded UBD in adult, female Sprague-Dawley rats. Bladder hypersensitivity produced by acute FS was significantly reduced by either bilateral central AMG or VMM lesions using measures generated by graded UBD, but these lesions had no significant effects using the same measures on bladder hyperalgesia produced by chronic FS. Our findings provide evidence that neural substrates underlying bladder hypersensitivity produced by chronic stress differ from those produced by acute stress. These findings suggest that while the AMG and VMM participate in pain processing during periods of limited exposure to stress, prolonged stress may recruit a new set of neural substrates not initially activated by acute exposure to stress.

The Association Between Progesterone, Estradiol, and Oxytocin and Heat Pain Measures in Pregnancy: An Observational Cohort Study.

BACKGROUND: Hormonal action has been implicated as a possible mechanism for pregnancy-induced analgesia. Previous investigators have reported an increase in heat pain tolerance during labor compared with nonpregnant controls and postulated it was because of the hormonal changes during pregnancy. However, these previous reports did not include measurement of hormonal values. The purpose of our study was to quantitatively test if changes in pregnancy hormone concentrations correlated with changes in temperature ratings. METHODS: This was a prospective cohort study consisting of 32 women scheduled for elective cesarean delivery at term between July 2010 and January 2013. Heat pain threshold and tolerance, estrogen, progesterone, and oxytocin levels were measured twice in each patient at term and again 4 to 8 weeks postpartum. RESULTS: All hormone levels decreased significantly between term pregnancy and the postpartum visit (all P values < 0.029). However, there were no statistically significant differences between term and postpartum heat pain measurements. The mean baseline heat pain threshold was 40.9°C at term compared with 40.3°C °postpartum (P = 0.47; mean change, -0.6°C; 95% confidence interval of change, -1.8°C to +0.7°C). The mean baseline heat pain tolerance was 46.1°C at term and 46.0°C postpartum (P = 0.59; mean change, -0.1°C; 95% confidence interval of change, -0.8°C° to +0.6°C). CONCLUSIONS: Our findings show that amounts of estradiol and progesterone changed significantly between the term and the postpartum visit; however, the thermal pain tolerance did not significantly change. In summary, we did not observe an association between hormonal changes and changes in pain threshold measures. This finding argues against the concept of simple progesterone- or estrogen-induced analgesia in humans.

Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism.

Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors.

Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition.

It has been suggested that increased pain sensitivity and disruption of endogenous pain inhibitory processes may account, at least in part, for the greater prevalence and severity of chronic pain in women compared to men. However, previous studies addressing this topic have produced mixed findings. This study examined sex differences in pain sensitivity and inhibition using quantitative sensory testing (QST), while also considering the influence of other important factors such as depressive symptoms and sleep quality. Healthy men (n=24) and women (n=24) each completed a QST battery. This battery included an ischemic pain task (IPT) that used a submaximal effort tourniquet procedure as well as a conditioned pain modulation (CPM) procedure for the assessment of endogenous pain inhibition. Prior to QST, participants completed the Center for Epidemiologic Studies Depression Scale and the Pittsburgh Sleep Quality Index. Analyses revealed significant sex differences for the ischemic pain task and the conditioned pain modulation procedure, such that women tolerated the ischemic pain for a shorter amount of time and demonstrated less pain inhibition compared with men. This remained true even when accounting for sex differences in depressive symptoms and sleep quality. The results of this study suggest that women may be more pain sensitive and possess less-efficient endogenous pain inhibitory capacity compared with men. Whether interventions that decrease pain sensitivity and enhance pain inhibition in women ultimately improve their clinical pain outcomes is an area of research that deserves additional attention in the future.

The amygdala central nucleus is required for acute stress-induced bladder hyperalgesia in a rat visceral pain model.

Chronic stress has been implicated in the pathogenesis of chronic visceral pain conditions, such as interstitial cystitis (IC), and bouts of acute stress exacerbate clinical urological pain. Studies using animal models have shown that exposure to chronic footshock stress augments reflex responses to urinary bladder distension (UBD) in animal models, however acute effects in animal models are largely unknown, as are the central nervous system mechanisms of stress-related increases in nociception. The amygdala is a salient structure for integration of sensory and cognitive/emotional factors. The present study determined the role of the central nucleus of the amygdala (CeA) in stress-related bladder hypersensitivity. We examined the effects of CeA manipulations (lesions and chemical stimulation) on visceromotor responses (abdominal muscle contractions) to UBD in adult, female Sprague-Dawley rats. We report that acute footshock stress produces bladder hyperalgesia that can be prevented by bilateral CeA lesions, despite no effect of lesions on baseline somatic sensation, as indicated by flinch/jump thresholds to electrical shock. Further, acute glucocorticoid stimulation of the CeA recapitulated stress-induced hyperalgesia. Of note is that CeA lesions, but not chemical stimulation, significantly affected HPA axis activation, as indicated by measurements of circulating corticosterone. Our findings conclusively show that the CeA is necessary for the generation of bladder hyperalgesia in response to acute stress. The CeA may play multiple stress-related roles in nociceptive modulation, i.e., via direct facilitation of the HPA axis during acute stress, or via modulation of other systems that augment acute stress responsiveness.

Oxytocin - a multifunctional analgesic for chronic deep tissue pain.

The treatment of chronic pain arising from deep tissues is currently inadequate and there is need for new pharmacological agents to provide analgesia. The endogenous paracrine hormone/neurotransmitter oxytocin is intimately involved in the modulation of multiple physiological and psychological functions. Recent experiments have given clear evidence for a role of oxytocin in the modulation of nociception. The present article reviews the existent human and basic science data related to the direct and indirect effects of oxytocin on pain. Due to its analgesic, anxiolytic, antidepressant and other central nervous system effects, there is strong evidence that oxytocin and other drugs acting through the oxytocin receptor could act as multifunctional analgesics with unique therapeutic value.

Intranasal Oxytocin Administration is Associated With Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States.

OBJECTIVES: This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. MATERIALS AND METHODS: A total of 30 pain-free, young adults each completed 3 laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States. CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; nondominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory and then self-administered a single (40 IU/1 mL) dose of intranasal oxytocin or placebo in a randomized counterbalanced order. Thirty minutes postadministration, participants again completed the State-Trait Anxiety Inventory and repeated assessments of ischemic pain sensitivity and CPM followed by the Profile of Mood States. RESULTS: Findings demonstrated that ischemic pain sensitivity did not significantly differ across the 3 study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. DISCUSSION: This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety.

Early in life bladder inflammation alters opioid peptide content in the spinal cord and bladder of adult female rats.

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 ß-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.

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. METHODS: 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 seconds; 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. RESULTS: Oxytocin doses of 0.15 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. CONCLUSIONS: 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.

Effects of acute adult and early-in-life bladder inflammation on bladder neuropeptides in adult female rats.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Footshock stress differentially affects responses of two subpopulations of spinal dorsal horn neurons to urinary bladder distension in rats.

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 at the spinal level while the acute stress effects are dependent on a supraspinal substrate.

Effect of estrogen on bladder nociception in rats.

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.

Neonatal bladder inflammation produces functional changes and alters neuropeptide content in bladders of adult female rats.

UNLABELLED: 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 to 16 with intravesical zymosan or anesthesia alone. At 12 to 16 weeks of age, micturition frequency and cystometrograms were measured. Similarly treated rats had their bladders removed for measurement of plasma extravasation after intravesical mustard oil, for neuropeptide analysis (calcitonin gene-related peptide or Substance P) or for detailed histological examination. Rats treated with zymosan as neonates exhibited increased micturition frequency, reduced micturition volume thresholds, greater extravasation of Evans blue after intravesical mustard oil administration, and greater total bladder content of calcitonin gene-related peptide and Substance P. 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. PERSPECTIVE: 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.

Effects of oxytocin and prolactin on stress-induced bladder hypersensitivity in female rats.

UNLABELLED: 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 nonfootshock 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. PERSPECTIVE: This study presents evidence that systemic oxytocin has both analgesic and anxiolytic properties which may make it a potentially useful agent for patients with stress-exacerbated chronic-pain syndromes such as interstitial cystitis. These studies do not suggest a similar role for prolactin.

Footshock-induced urinary bladder hypersensitivity: role of spinal corticotropin-releasing factor receptors.

UNLABELLED: 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 classic 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 with rats that were exposed to a non-footshock treatment. This bladder hypersensitivity was significantly attenuated by blocking spinal CRF(2) receptors but not CRF(1) receptors. Furthermore, spinal administration of urocortin 2, a CRF(2) receptor agonist, augmented UBD-evoked VMRs in a way similar to what was observed after exposure to Footshock, an effect significantly attenuated by pretreatment with spinal aSVG30, a CRF(2) receptor antagonist. Surprisingly, neither spinal administration of CRF nor the CRF(1) 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 CRF(2) receptor, as potential mediators of this effect. PERSPECTIVE: This study presents evidence that spinal urocortins and CRF(2) 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 with painful bladder syndromes as well as stress-exacerbated chronic pain.