RESUMEN
BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.
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Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Nocicepción/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiología , Animales , Baclofeno/administración & dosificación , Femenino , Agonistas de Receptores GABA-B/administración & dosificación , Inyecciones Espinales , Ratas , Ratas Sprague-DawleyRESUMEN
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.
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Cistitis/fisiopatología , Péptidos Opioides/análisis , Médula Espinal/química , Vejiga Urinaria/química , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Ratas , Ratas Sprague-DawleyRESUMEN
The spinal mechanisms of visceral hypersensitivity are poorly understood, particularly when there is an interaction with somatic systems. Recently we demonstrated that rats which were pretreated with neonatal bladder inflammation (NBI) and subsequently pretreated as adults with bladder re-inflammation had augmented reflex and neuronal responses to urinary bladder distension via a corticotropin-releasing factor receptor type II (CRFR2) mechanism. Another insult producing similar augmented responses is somatic inflammation induced by Complete Freund's Adjuvant (CFA) in the hindlimb. Using neurochemical measures and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2-related mechanisms in bladder hyperalgesia secondary to NBI and CFA-induced hindlimb inflammation. ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR2 protein following pretreatment with NBI+CFA. Intrathecal CRFR2 antagonists blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI+CFA. Lumbosacral dorsal horn neuronal responses to bladder distension in rats pretreated with NBI+CFA were attenuated by the spinal topical administration of a CRFR2 antagonist. These findings are the first demonstration of a somatovisceral interaction working via CRFR2 receptors and support the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events. (Word Count 199). PERSPECTIVE: Bladder hypersensitivity occurs following neonatal cystitis and an adult insult such as somatic inflammation. This paper demonstrates that CRFR2-related mechanisms are associated with this hypersensitivity. This supports the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events.
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Cistitis , Hipersensibilidad , Receptores de Hormona Liberadora de Corticotropina , Animales , Femenino , Ratas , Hormona Liberadora de Corticotropina , Cistitis/inducido químicamente , Cistitis/complicaciones , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Inflamación , Dolor Pélvico , Ratas Sprague-Dawley , Vejiga Urinaria/metabolismoRESUMEN
Spinal mechanisms associated with visceral hypersensitivity are poorly understood. One model of bladder hypersensitivity with phenotypic features similar to the disorder interstitial cystitis/bladder pain syndrome is the neonatal bladder inflammation (NBI) model. In this model, rat pup bladders are infused with zymosan solutions on post-partum days 14-16 and then rats are retested as adults. Studies of other sites of deep tissue hypersensitivity have suggested a role for corticotropin-releasing factor (CRF) receptors type 1 and 2 (CRFR1 and CRFR2). Using neurochemical measures, pharmacological manipulations and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2s in bladder hyperalgesia secondary to NBI and acute bladder re-inflammation as an adult (ABI). ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR1s and CRFR2s following pretreatment with both NBI + ABI as well as NBI-related increases in the CRFR2 agonist urocortin 2. Intrathecal CRFR2 antagonists, but not a CRFR1 antagonist, blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI + ABI. Lumbosacral dorsal horn neuronal responses to distension in rats pretreated with NBI + ABI were attenuated by the spinal topical administration of a CRFR2 antagonist. These studies suggest therapeutic value of CRFR2 antagonists in the treatment of painful bladder disorders.
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Cistitis , Receptores de Hormona Liberadora de Corticotropina , Animales , Hormona Liberadora de Corticotropina/metabolismo , Cistitis/metabolismo , Cistitis/patología , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Vejiga Urinaria/metabolismoRESUMEN
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.
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Péptido Relacionado con Gen de Calcitonina/análisis , Péptido Relacionado con Gen de Calcitonina/biosíntesis , Cistitis/metabolismo , Sustancia P/análisis , Sustancia P/biosíntesis , Vejiga Urinaria/química , Enfermedad Aguda , Factores de Edad , Animales , Ciclo Estral , Femenino , Ratas , Ratas Sprague-DawleyRESUMEN
This report describes methodological and exploratory investigations of the zymosan-induced neonatal bladder inflammation (NBI) model of interstitial cystitis/bladder pain syndrome (IC/BPS) in female rats. These results validate and extend the currently employed model by evaluating critical timepoints for obtaining treatment effects and identified that a second insult as an adult including repeat intravesical zymosan, intravesical lipopolysaccharide, acute footshock stress, neuropathic nociception (facial) or somatic inflammation (hindpaw) all resulted in magnified visceromotor responses to urinary bladder distension (UBD) in rats which had experienced NBI when compared with their controls. NBI also resulted in increased tone and reactivity of pelvic floor musculature to UBD, as well as increased responsiveness to intravesical potassium chloride solutions, abnormal anxiety measures (elevated plus maze) and an increased number of submucosal petechial hemorrhages following 30 min of hydrodistension of the bladder. These phenotypic findings have correlates to the clinical features of IC/BPS in humans and so support use of this model system to examine mechanisms of and treatments for IC/BPS.
RESUMEN
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.
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Ciclo Estral/fisiología , Péptidos Opioides/fisiología , Reflejo Abdominal/fisiología , Vejiga Urinaria/fisiología , Animales , Femenino , Inflamación , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Visceral pain is the most common reason for doctor visits in the US. Like somatic pain, virtually all visceral pain sensations begin with the activation of primary sensory neurons innervating the viscera and/or the blood vessels associated with these structures. Visceral afferents also play a central role in tissue homeostasis. Recent studies show that in addition to monitoring the state of the viscera, they perform efferent functions through the release of small molecules (e.g. peptides like CGRP) that can drive inflammation, thereby contributing to the development of visceral pathologies (e.g. diabetes Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M., 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, Cell 127 1123-1135). Visceral afferents are heterogeneous with respect to their anatomy, neurochemistry and function. They are also highly plastic in that their cellular environment continuously influences their response properties. This plasticity makes them susceptible to long-term changes that may contribute significantly to the development of persistent pain states such as those associated with irritable bowel syndrome, pancreatitis, and visceral cancers. This review examines recent insights into visceral afferent anatomy and neurochemistry and how neonatal insults can affect the function of these neurons in the adult. New approaches to the treatment of visceral pain, which focus on primary afferents, will also be discussed.
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Nociceptores/metabolismo , Dolor/fisiopatología , Células Receptoras Sensoriales/metabolismo , Vísceras/inervación , Aferentes Viscerales/fisiopatología , Animales , Humanos , Inflamación/metabolismo , Inflamación/fisiopatología , Plasticidad Neuronal/fisiología , Neuropéptidos/metabolismo , Dolor/etiología , Canales Catiónicos TRPV/metabolismo , Vísceras/fisiopatología , Aferentes Viscerales/crecimiento & desarrolloRESUMEN
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.
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Cistitis Intersticial/fisiopatología , Cistitis/fisiopatología , Electromiografía , Hipersensibilidad/diagnóstico , Hielo , Administración Intravesical , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Mentol/farmacología , Contracción Muscular/fisiología , Umbral del Dolor , Probabilidad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Sensibilidad y Especificidad , AguaRESUMEN
Bladder inflammation resulting from intravesical administration of zymosan significantly enhances the visceromotor reflex (VMR) evoked by urinary bladder distension (UBD). The present study examined whether intrathecal (i.t.) administration of receptor antagonists to either norepinephrine (NE) or serotonin (5-HT) altered this enhancement effect. I.t. administration of the non-specific 5-HT receptor antagonist methysergide (30 microg), the 5-HT(3) receptor antagonist ondansetron, or the 5-HT(1A) receptor antagonist WAY 100635 eliminated the enhancement effect produced by intravesical zymosan and also tended to reduce electromyographic (EMG) responses to UBD in non-inflamed rats. I.t. administration of either the non-specific NE receptor antagonist phentolamine (30 microg) or the alpha(1) antagonist WB 4101 also eliminated the enhancement effect, whereas i.t. administration of the alpha(2) antagonist yohimbine failed to significantly affect the enhancement effect. The effects of phentolamine and methysergide were not mediated by changes in bladder compliance. This is the first study to demonstrate that bladder hypersensitivity resulting from bladder inflammation is partly mediated by 5-HT and NE facilitatory effects. Based on these and previous findings we conclude that the net nociceptive response to bladder distension under conditions of bladder inflammation represents a complex interaction of facilitatory influences of spinal 5-HT and NE, and inhibitory influences of spinal opioids.
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Cistitis/fisiopatología , Norepinefrina/metabolismo , Reflejo/fisiología , Serotonina/metabolismo , Vejiga Urinaria/fisiopatología , Antagonistas Adrenérgicos alfa/administración & dosificación , Animales , Dilatación Patológica , Femenino , Inyecciones Espinales , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Antagonistas de la Serotonina/administración & dosificación , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inervaciónRESUMEN
There is increasing evidence that chronic pain may be associated with events that occur during critical periods of development. Recent studies have identified behavioral, spinal neurophysiological and spinal/peripheral neurochemical differences in rats that have experienced neonatal bladder inflammation (NBI): a putative model of the chronically painful bladder disorder, interstitial cystitis. Stress has been shown to exacerbate symptoms of interstitial cystitis and produces bladder hypersensitivity in animal models. We recently reported that Acute Footshock-induced bladder hypersensitivity was eliminated in otherwise normal rats by prior bilateral lesions of the central nucleus of the amygdala. Since the spinal and peripheral nervous systems of NBI-treated rats are known to differ from normal rats, the present experiments sought to determine whether a supraspinal nervous system structure, the central amygdala, is still necessary for the induction of Acute Footshock-induced hypersensitivity. The effect of bilateral amygdala electrolytic lesions on Acute Footshock-induced bladder hypersensitivity in adult female rats was tested in Control rats which underwent a control protocol as neonates and in experimental rats which experienced NBI. Consistent with our previous report, in Control rats, Acute Footshock-induced bladder hypersensitivity was eliminated by bilateral Amygdala Lesions. In contrast, Acute Footshock-induced bladder hypersensitivity in NBI-treated rats was unaffected by bilateral Amygdala Lesions. These findings provide evidence that NBI results in the recruitment of substrates of bladder hypersensitivity that may differ from those of normal rats. This, in turn, suggests that unique therapeutics may be needed for painful bladder disorders like interstitial cystitis.
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Núcleo Amigdalino Central/fisiopatología , Cistitis/fisiopatología , Hipersensibilidad/fisiopatología , Estrés Fisiológico/fisiología , Vejiga Urinaria/fisiopatología , Animales , Animales Recién Nacidos , Núcleo Amigdalino Central/metabolismo , Modelos Animales de Enfermedad , Electrochoque/métodos , Femenino , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/efectos de los fármacosRESUMEN
UNLABELLED: Abdominal electromyographic (EMG) responses to noxious intensities of urinary bladder distention (UBD) are significantly enhanced 24 hours after zymosan-induced bladder inflammation in adult female rats. This inflammation-induced hypersensitivity is concomitantly inhibited by endogenous opioids because intraperitoneal (i.p.) naloxone administration before testing significantly increases EMG response magnitude to UBD. This inhibitory mechanism is not tonically active because naloxone does not alter EMG response magnitude to UBD in rats without inflammation. At the dose tested, naloxone does not affect bladder compliance in rats with or without inflammation. The effects of i.p. naloxone probably result from blockade of a spinal mechanism because intrathecal naloxone also significantly enhances EMG responses to UBD in rats with inflammation. Rats exposed to bladder inflammation from P90-P92 before reinflammation at P120 show similar hypersensitivity and concomitant opioid inhibition, with response magnitudes being no different from that produced by inflammation at P120 alone. In contrast, rats exposed to bladder inflammation from P14-P16 before reinflammation at P120 show markedly enhanced hypersensitivity and no evidence of concomitant opioid inhibition. These data indicate that bladder inflammation in adult rats induces bladder hypersensitivity that is inhibited by an endogenous opioidergic mechanism. This mechanism can be disrupted by neonatal bladder inflammation. PERSPECTIVE: The present study observed that bladder hypersensitivity resulting from acute bladder inflammation is suppressed by an opioid-inhibitory mechanism. Experiencing bladder inflammation during the neonatal period can impair the expression of this opioid inhibitory mechanism in adulthood. This suggests that bladder insults during development may permanently alter visceral sensory systems and may represent 1 cause of painful bladder disorders.
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Analgésicos Opioides/metabolismo , Inflamación/fisiopatología , Reflejo/fisiología , Enfermedades de la Vejiga Urinaria/fisiopatología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Dilatación Patológica , Modelos Animales de Enfermedad , Electromiografía/métodos , Femenino , Inflamación/inducido químicamente , Contracción Muscular/fisiología , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Vísceras/fisiopatología , ZimosanRESUMEN
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.
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Núcleo Amigdalino Central/cirugía , Electrochoque/efectos adversos , Bulbo Raquídeo/cirugía , Estrés Psicológico/complicaciones , Enfermedades de la Vejiga Urinaria/etiología , Enfermedades de la Vejiga Urinaria/prevención & control , Enfermedad Aguda , Animales , Núcleo Amigdalino Central/patología , Enfermedad Crónica , Electrochoque/psicología , Femenino , Pie , Bulbo Raquídeo/patología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/patología , Estrés Psicológico/psicología , Vejiga Urinaria/patología , Enfermedades de la Vejiga Urinaria/psicologíaRESUMEN
UNLABELLED: Inflammatory events experienced during early development may permanently alter sensory processing. Because urinary tract infections frequently occur during early development in females and painful bladder disorders have a high female prevalence, the present studies were undertaken to determine whether inflammation of the bladder in female rats could lead to altered sensory processing later in life. Female rat pups were anesthetized and treated as neonates (14th-16th days of life) or as adolescents (28th-30th days of life) with either intravesical zymosan (yeast cell wall component that produces robust inflammation), intravesical normal saline, or only with anesthesia. As adults, rats that had their bladders inflamed as neonates exhibited increased spontaneous micturition frequency and, after reinflammation of the bladder, increased cardiovascular and abdominal muscle contractile responses to urinary bladder distension when compared with controls. Similar effects were not observed in rats which did not experience inflammation of the bladder until adolescence. Evan's blue extravasation, a measure of the magnitude of inflammatory changes, was also greater in rats treated as neonates with intravesical zymosan. Thermal and mechanical hindpaw sensitivity was not altered by bladder inflammation. Altogether, this suggests that neonatal bladder inflammation increases bladder sensitivity and may be a cause of the hypersensitivity of painful bladder syndromes. PERSPECTIVE: The present study observed that bladder inflammation experienced in a neonatal rat led to accentuated responses to urinary bladder distension when tested as adults. This suggests that events experienced during development may permanently sensitize visceral sensory systems and so represent one of the causes of painful bladder disorders.
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Cistitis/fisiopatología , Hiperalgesia/fisiopatología , Dolor Pélvico/fisiopatología , Vejiga Urinaria Neurogénica/fisiopatología , Vejiga Urinaria/fisiopatología , Músculos Abdominales/fisiopatología , Factores de Edad , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Cistitis/complicaciones , Cistitis/microbiología , Modelos Animales de Enfermedad , Electromiografía , Azul de Evans , Femenino , Hiperalgesia/etiología , Mediadores de Inflamación/farmacología , Contracción Muscular/fisiología , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo/fisiología , Vejiga Urinaria/crecimiento & desarrollo , Vejiga Urinaria/inervación , Vejiga Urinaria Neurogénica/etiología , Trastornos Urinarios/etiología , Trastornos Urinarios/fisiopatología , Aferentes Viscerales/fisiopatologíaRESUMEN
BACKGROUND: 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 administered into the urinary bladder in order to characterize this form of bladder sensitization. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Cistitis/fisiopatología , Dolor/fisiopatología , Vejiga Urinaria/fisiopatología , Zimosan/toxicidad , Administración Intravesical , Animales , Presión Sanguínea , Colorantes/farmacocinética , Cistitis/inducido químicamente , Cistitis/complicaciones , Electromiografía , Azul de Evans/farmacocinética , Femenino , Dolor/etiología , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/química , Zimosan/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: Intravenous lidocaine (IVL) produces analgesia in multiple painful disorders. The neurophysiological effects of IVL are not well defined, but studies in visceral nociceptive systems have shown that IVL has differential effects on subgroups of spinal neurons. The present study determined whether a similar differential effect of IVL occurs in spinal neurons excited by noxious cutaneous stimuli. METHODS: In decerebrate, cervical spinal cord-transected rats, the lumbosacral spinal cord was exposed by a laminectomy. Single-unit recordings were made of dorsal horn neurons excited by noxious cutaneous stimuli. Each neuron's response to noxious (pinch) and nonnoxious (brush) cutaneous stimuli were determined and the effect of a counterirritation stimulus (noxious skin pinch presented in the upper body) on spontaneous activity quantified. In a subset of neurons, sequential doses of IVL were administered, and responses of each neuron to repeated 50 degrees C heating of the hindpaw/tail were determined. RESULTS: IVL dose-dependently inhibited neurons excited by heating of the hindpaw/tail. IVL produced significantly greater inhibition of both spontaneous and heat-evoked activity in neurons that did not show counterirritation effects when compared with those neurons that did show counterirritation effects. Standard classification of neurons as wide-dynamic range or nociceptive-specific was less predictive of the IVL effect. CONCLUSIONS: IVL had differential inhibitory effects on 2 spinal cutaneous nociceptive neuron populations. Other drugs could also have differential effects on sensory pathways, suggesting a mechanism whereby certain drugs differentially affect different types of pain.
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Anestésicos Locales/farmacología , Lidocaína/farmacología , Inhibición Neural , Nociceptores/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Animales , Estado de Descerebración , Relación Dosis-Respuesta a Droga , Calor , Inyecciones Intravenosas , Lidocaína/administración & dosificación , Masculino , Nociceptores/metabolismo , Dolor/metabolismo , Dolor/prevención & control , Dimensión del Dolor , Células del Asta Posterior/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND OBJECTIVES: Neuromodulation has been reported to reliably improve symptoms of bladder overactivity and sometimes pain. The effect of electrical stimulation of several nerve pathways demonstrated to alter cystometric responses to bladder distension was examined on nociceptive responses in models of bladder hypersensitivity. METHODS: Bladder hypersensitivity was produced by several published methods including neonatal inflammation, acute inflammation, and chronic stress. Effects of different sites of stimulation (L6 and T13 nerve roots, proximal and distal pudendal nerves [PNs]) on nociceptive reflex responses to urinary bladder distension in urethane-anesthetized female rats were assessed and a parametric analysis of parameters of stimulation was performed. RESULTS: Bilateral biphasic stimulation of the proximal PNs resulted in statistically significant inhibition of visceromotor and cardiovascular responses to bladder distension in rats made hypersensitive by neonatal bladder inflammation. We found a range of optimal stimulation frequencies (5-10 Hz) which produced robust inhibitory effects when using short pulse widths (100-240 µs). Onset of inhibition was within minutes and persisted for several minutes after the stimulus was discontinued. Use of bilateral PN stimulation in acute inflammation and stress-induced hypersensitivity models as well as unilateral stimulation, very distal PN cutaneous branch stimulation, and stimulation of the T13 and L6 nerve roots all proved ineffective with the parameters used. CONCLUSIONS: This study suggests that inhibitory effects of bilateral PN stimulation can be evoked in a rodent hypersensitivity model at relatively low frequencies with short pulse widths. The onset of effect is rapid, which suggests the potential for treating episodic pain in painful bladder disorders.
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Estimulación Eléctrica , Nervio Pudendo , Vejiga Urinaria/inervación , Animales , Femenino , Nervios Periféricos , Ratas , Reflejo , Enfermedades de la Vejiga Urinaria/complicaciones , Enfermedades de la Vejiga Urinaria/terapiaRESUMEN
In experiment 1, quantitative regional comparisons of the antinociceptive and cardiovascular responses produced by electrical stimulation in the caudal medulla, including regions such as the nucleus tractus solitarius (NTS), nucleus reticularis ventralis (NRV), nucleus reticularis gigantocellularis (NRGC), nucleus reticularis paragigantocellularis (NRPGC), nucleus raphe obscurus (NRO), and medial portions of the lateral reticular nucleus (LRN), were made in the rat. Electrical stimulation in all of these regions resulted in inhibition of the nociceptive tail-flick reflex, although the threshold intensity for inhibition was greater for sites in NTS compared to many sites ventral to the NTS. Antinociception was generally accompanied by an increase in mean arterial blood pressure, with the exception of sites in the NRO, where depressor responses were evoked by stimulation. Detailed comparisons between the NTS and NRV revealed that greater intensities of electrical stimulation were required to produce antinociception for sites in the NTS as compared to the NRV. There were no significant differences in threshold intensities for antinociception as a function of rostrocaudal subdivisions of the NTS, but the lateral subdivision of the NTS was significantly more efficacious than the medial subdivision. This mediolateral difference within NTS was primarily due to stimulation in medial sites producing overt movements in some animals, probably due to stimulation of adjacent midline nuclei or pathways. Within the NRV, thresholds for inhibition of the tail-flick reflex were greater for sites in the dorsal subdivision as compared to the ventral subdivision, which contains spinopetal projections from the NRM. The slopes of the lines of recruitment for inhibition of the tail-flick reflex at stimulation sites in either the NTS or NRV were both very steep, similar to other forms of antinociception. In experiment 2, the pulse duration of electrical stimulation was varied for sites of stimulation in the lateral NTS and NRV to generate strength-duration curves. This experiment confirmed that stimulation sites in the lateral NTS required greater current intensities to inhibit the tail-flick reflex than sites in the NRV. However, the chronaxies derived from the strength-duration functions for the NTS or NRV were both approximately 170 microseconds, indicating that the antinociceptive effects in these regions may not be exclusively due to the stimulation of fibers of passage. These results are discussed in terms of the role of the NTS, NRV, and caudal medulla in the modulation of nociceptive responses and cardiovascular function.
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Presión Sanguínea/fisiología , Bulbo Raquídeo/fisiología , Dolor/fisiopatología , Vías Aferentes/fisiología , Animales , Estimulación Eléctrica , Calor , Masculino , Bulbo Raquídeo/anatomía & histología , Dimensión del Dolor , Ratas , Ratas Endogámicas , Reclutamiento Neurofisiológico , Reflejo/fisiología , Umbral Sensorial/fisiología , Cola (estructura animal)/inervaciónRESUMEN
Physiological, chemical or electrical activation of vagal afferents produces antinociception in rats. The present study examined the effects of electrical stimulation of the subdiaphragmatic vagus (SDV) on the nociceptive tail-flick reflex, arterial blood pressure, and heart rate in rats lightly anesthetized with pentobarbital sodium. The intensity of SDV stimulation (20 Hz, 2 msec) necessary to inhibit the tail-flick reflex to a 10 sec cut-off latency for 3 consecutive trials was defined as the threshold to produce antinociception. Electrical stimulation of the SDV suppressed the tail-flick reflex in a linear, intensity-dependent manner. In addition, the threshold varied as a function of either the frequency or the pulse width of SDV stimulation, such that decreases in either frequency or pulse width, from 20 Hz and 2 msec, respectively, systematically increased the threshold current necessary to produce antinociception. SDV stimulation also produced modest decreases in heart rate (HR), but arterial blood pressure (ABP) responses were highly variable in both the magnitude and direction of change. Intrathecal administration of 30 micrograms of the serotonergic receptor antagonist methysergide significantly increased the threshold for antinociception produced by SDV stimulation from 80 to 938.8 microA, whereas 15 micrograms of methysergide had no significant effect. Intrathecal administration of saline, 30 micrograms of naloxone, or 30 micrograms of phentolamine had no significant effect on the threshold of SDV stimulation required to produce antinociception. Systemic administration of naloxone (4 mg/kg i.p. or i.v.) also had no effect on the antinociceptive threshold. Intrathecal administration of these receptor antagonists had no significant effect on the ABP and HR responses produced by electrical stimulation of the SDV at the threshold intensity producing antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)
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Nociceptores/fisiología , Médula Espinal/fisiología , Nervio Vago/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Diafragma/inervación , Estimulación Eléctrica , Frecuencia Cardíaca/fisiología , Inyecciones Espinales , Masculino , Metisergida/farmacología , Naloxona/farmacología , Dimensión del Dolor , Fentolamina/farmacología , Ratas , Ratas Endogámicas , Tiempo de Reacción/fisiología , Umbral Sensorial/efectos de los fármacos , Umbral Sensorial/fisiologíaRESUMEN
Background and noxious heat-evoked responses of wide-dynamic-range (WDR) and high-threshold (HT) lumbosacral spinal dorsal horn neurons were recorded in spontaneously hypertensive rats (SHRs), Wistar-Kyoto normotensive rats (WKYs), lifetime captopril-treated SHRs, SHRs with bilateral cervical vagotomy, SHRs with bilateral sino-aortic deafferentation (SAD), and SHRs with either a single or repeated administration of naloxone methobromide (NMB). Stimulus-response functions (SRFs) were generated for neurons using 15 sec of heating of the foot at temperatures ranging from 38 to 52 degrees C. Comparisons were made of neuronal response thresholds, slopes of the SRFs, mean discharge frequency during heat stimulation, arterial blood pressure (ABP), and heart rate (HR). The primary finding was that group mean SRFs for both WDR and HT neurons were shifted in a parallel, rightward fashion in SHRs compared to WKYs. Heat-evoked response thresholds were increased and asymptotic discharge frequencies were decreased in WDR and HT neurons of SHRs compared to WKYs. Analyses of group mean SRFs for WDR and HT neurons of SHRs receiving lifetime captopril treatment indicated they were normalized to the SRFs of WKYs, but detailed comparisons using discharge frequency during heat stimulation revealed that this was due to a statistical averaging effect. Specifically, lifetime captopril-treated SHRs not only showed enhanced neuronal responses to the onset of noxious heat but also enhanced adaptation of neuronal responses with continued heating compared to WKYs. Bilateral SAD in SHRs significantly increased the total discharge frequency of WDR neurons to heat stimuli between 44 and 52 degrees C, but produced no change in the response threshold for heat-evoked activation of these neurons. A similar effect of SAD was observed in HT neurons of SHRs, but the greater response thresholds of HT neurons precluded detection of any significant effect. Bilateral cervical vagotomy did not affect response thresholds, slopes, or total discharge frequencies of SHRs, although only WDR neurons were studied. SRFs of WDR and HT neurons in SHRs obtained pre- and post-administration of a single dose of NMB did not differ. However, repeated administration of NMB in SHRs resulted in a parallel, leftward shift in SRFs of both WDR and HT neurons. In all strains and treatments studied, there were no significant differences in background activities of these neurons that might contribute to the observed outcomes. In conclusion, the hypoalgesia reported in human essential hypertensives and animals with chronic hypertension may be due to a significant attenuation in spinal nociceptive transmission.(ABSTRACT TRUNCATED AT 400 WORDS)