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Timothy J. Ness - One of the best experts on this subject based on the ideXlab platform.

  • Bladder Distension increases blood flow in pain related brain structures in subjects with interstitial cystitis
    The Journal of Urology, 2016
    Co-Authors: Georg Deutsch, Hrishikesh Deshpande, Michael A Frolich, Henry H Lai, Timothy J. Ness
    Abstract:

    Purpose: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of Bladder Distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis.Materials and Methods: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full Bladder, 2) with an empty Bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution cha...

  • pd7 06 pudendal nerve stimulation inhibits the visceromotor responses to urinary Bladder Distension in a non opioid dependent manner
    The Journal of Urology, 2015
    Co-Authors: Timothy J. Ness, Alan Randich, Julie Hill, Jamie Mcnaught, Dwight E Nelson
    Abstract:

    INTRODUCTION AND OBJECTIVES: Pudendal nerve stimulation (PNS) reduces pain in humans with interstitial cystitis/Bladder pain syndrome (IC/BPS) and the visceromotor response (VMR) to urinary Bladder Distension (UBD) in a rat model of Bladder hypersensitivity. The effectiveness of PNSmay be impacted by pre-exposure of opioids which are commonly used in practice. To address co-administration concerns, the aim of this rat study was to evaluate if endogenous opioid system is involved in the neural control of Bladder nociceptive reflex by PNS. METHODS: Bladder hypersensitivity was produced by neonatal Bladder inflammation in female rat pups coupled with a second insult as an adult. Under urethane anaesthesia, wire electrodes were placed into the abdominal musculature to measure myoelectrical activity (VMR) to phasic UBD. Two pairs of hook electrodes were placed under each pudendal nerve bilaterally. The effects of PNS (10 Hz, pulse-width 0.1 ms) were assessed on VMR responses before and after the i.p. administration of saline or an opioid receptor antagonist naloxone hydrochloride (1 mg/kg). The effects of PNS were measured as percent change in VRMs ( SEM) compared to Area-under-the-Curve (AUC) of 0 Hz trial for VMRs evoked by 10, 20, 40 and 60 mmHg, 20 s UBD. RESULTS: PNS at 1xmotor threshold (Tmot) or 3xTmot produced statistically significant inhibition on VMRs to UBD. Such effects were frequency-dependent; maximal inhibitory effects produced by electrical stimulation of 5 Hz or greater (up to 100 Hz). Low frequencies of stimulation (0.1 and 1 Hz) did not produce decreases in VMR to UBD. Neither naloxone nor saline produced any statistically significant alternations on inhibitory effects of PNS (3xTmot, 10 Hz). The VMRs to PNS were decreased 26.9 4.0% and 30.9 7.9%, respectively before and after naloxone (p<0.05, repeated measure ANOVA). Similarly before and after saline injection, the VMRs to PNS were significantly decreased 31.9 8.4% and 25.2 8.3%, respectively (p<0.05). CONCLUSIONS: PNS inhibited the nociceptive response in a rat model of Bladder hypersensitivity. The inhibitory effects of PNS could not be blocked by pretreatment of naloxone. Data from this study suggest the potential for clinical utility of PNS in reducing the symptoms of IC/BPS. Though the mechanism of this effect was not determined, the insensitivity to naloxone shows that non-opioid actions are involved in the pudendal neuromodulation on pain control and suggests potential utility of PNS in treating painful Bladder syndromes like IC/BPS even when concomitant opioids are being utilized.

  • early in life Bladder inflammation alters u50 488h but not morphine induced inhibition of visceromotor responses to urinary Bladder Distension
    Neuroscience Letters, 2013
    Co-Authors: Amber D Shaffer, Timothy J. Ness, Alan Randich
    Abstract:

    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.

  • footshock stress differentially affects responses of two subpopulations of spinal dorsal horn neurons to urinary Bladder Distension in rats
    Brain Research, 2011
    Co-Authors: Meredith T Robbins, Alan Randich, Jennifer J. Deberry, Timothy J. Ness
    Abstract:

    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.

  • rostral ventral medulla modulation of the visceromotor reflex evoked by urinary Bladder Distension in female rats
    The Journal of Pain, 2008
    Co-Authors: Alan Randich, Jennifer J. Deberry, Hannah Mebane, Timothy J. Ness
    Abstract:

    Abstract 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 because 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. Perspective Stimulation of the RVM resulted in inhibitory, facilitatory, and biphasic modulation of the visceromotor reflex to urinary Bladder Distension. Inhibitory effects of stimulation were attenuated by naloxone, and lesions of the RVM enhanced the VMR in rats with inflamed Bladders. These data indicate an important role of the RVM in modulating Bladder pain.

William C. De Groat - One of the best experts on this subject based on the ideXlab platform.

  • mp11 04 sympathetic afferents in the hypogastric nerve facilitate nociceptive Bladder activity in cats
    The Journal of Urology, 2019
    Co-Authors: Yan Zheng, Jicheng Wang, James R. Roppolo, William C. De Groat, Todd Yecies, Tara Nikonow, Haotian Cai, Bing Shen, Nathalie Pace, Changfeng Tai
    Abstract:

    INTRODUCTION AND OBJECTIVES:The normal micturition reflex in cats is mediated by Aδ-afferents in the pelvic nerve, while pelvic C-fiber afferents do not respond to Bladder Distension in normal phys...

  • voiding reflex in chronic spinal cord injured cats induced by stimulating and blocking pudendal nerves
    Neurourology and Urodynamics, 2007
    Co-Authors: Changfeng Tai, Jicheng Wang, James R. Roppolo, Xianchun Wang, William C. De Groat
    Abstract:

    Aims To induce efficient voiding in chronic spinal cord injured (SCI) cats. Methods Voiding reflexes induced by Bladder Distension or by electrical stimulation and block of pudendal nerves were investigated in chronic SCI cats under α-chloralose anesthesia. Results The voiding efficiency in chronic SCI cats induced by Bladder Distension was very poor compared to that in spinal intact cats (7.3 ± 0.9% vs. 93.6 ± 2.0%, P < 0.05). In chronic SCI cats continuous stimulation of the pudendal nerve on one side at 20 Hz induced large amplitude Bladder contractions, but failed to induce voiding. However, continuous pudendal nerve stimulation (20 Hz) combined with high-frequency (10 kHz) distal blockade of the ipsilateral pudendal nerve elicited efficient (73.2 ± 10.7%) voiding. Blocking the pudendal nerves bilaterally produced voiding efficiency (82.5 ± 4.8%) comparable to the efficiency during voidings induced by Bladder Distension in spinal intact cats, indicating that the external urethral sphincter (EUS) contraction was caused not only by direct activation of the pudendal efferent fibers, but also by spinal reflex activation of the EUS through the contralateral pudendal nerve. The maximal Bladder pressure and average flow rate induced by stimulation and bilateral pudendal nerve block in chronic SCI cats were also comparable to those in spinal intact cats. Conclusions This study shows that after the spinal cord is chronically isolated from the pontine micturition center, Bladder Distension evokes a transient, inefficient voiding reflex, whereas stimulation of somatic afferent fibers evokes a strong, long duration, spinal Bladder reflex that elicits efficient voiding when combined with blockade of somatic efferent fibers in the pudendal nerves. Neurourol. Urodynam. 26:879–886, 2007. © 2007 Wiley-Liss, Inc.

  • Bladder inhibition or voiding induced by pudendal nerve stimulation in chronic spinal cord injured cats
    Neurourology and Urodynamics, 2007
    Co-Authors: Jicheng Wang, William C. De Groat, Xianchun Wang, James R. Roppolo
    Abstract:

    Aims To investigate pudendal-to-Bladder spinal reflexes in chronic spinal cord injured (SCI) cats induced by electrical stimulation of the pudendal nerve. Methods Bladder inhibition or voiding induced by pudendal nerve stimulation at different frequencies (3 or 20 Hz) was studied in three female, chronic SCI cats under α-chloralose anesthesia. Results Voiding induced by a slow infusion (2–4 ml/min) of saline into the Bladder was very inefficient (voiding efficiency = 7.3% ± 0.9%). Pudendal nerve stimulation at 3 Hz applied during the slow infusion inhibited reflex Bladder activity, and significantly increased Bladder capacity to 147.2 ± 6.1% of its control capacity. When the 3-Hz stimulation was terminated, voiding rapidly occurred and the voiding efficiency was increased to 25.4 ± 6.1%, but residual Bladder volume was not reduced. Pudendal nerve stimulation at 20 Hz induced large Bladder contractions, but failed to induce voiding during the stimulation due to the direct activation of the motor pathway to the external urethral sphincter. However, intermittent pudendal nerve stimulation at 20 Hz induced post-stimulus voiding with 78.3 ± 12.1% voiding efficiency. The voiding pressures (39.3 ± 6.2 cmH2O) induced by the intermittent pudendal nerve stimulation were higher than the voiding pressures (23.1 ± 1.7 cmH2O) induced by Bladder Distension. The flow rate during post-stimulus voiding induced by the intermittent pudendal nerve stimulation was significantly higher (0.93 ± 0.04 ml/sec) than during voiding induced by Bladder Distension (0.23 ± 0.07 ml/sec). Conclusions This study indicates that a neural prosthetic device based on pudendal nerve stimulation might be developed to restore micturition function for people with SCI. Neurourol. Urodynam. 26:570–577, 2007. © 2007 Wiley-Liss, Inc.

James R. Roppolo - One of the best experts on this subject based on the ideXlab platform.

  • mp11 04 sympathetic afferents in the hypogastric nerve facilitate nociceptive Bladder activity in cats
    The Journal of Urology, 2019
    Co-Authors: Yan Zheng, Jicheng Wang, James R. Roppolo, William C. De Groat, Todd Yecies, Tara Nikonow, Haotian Cai, Bing Shen, Nathalie Pace, Changfeng Tai
    Abstract:

    INTRODUCTION AND OBJECTIVES:The normal micturition reflex in cats is mediated by Aδ-afferents in the pelvic nerve, while pelvic C-fiber afferents do not respond to Bladder Distension in normal phys...

  • voiding reflex in chronic spinal cord injured cats induced by stimulating and blocking pudendal nerves
    Neurourology and Urodynamics, 2007
    Co-Authors: Changfeng Tai, Jicheng Wang, James R. Roppolo, Xianchun Wang, William C. De Groat
    Abstract:

    Aims To induce efficient voiding in chronic spinal cord injured (SCI) cats. Methods Voiding reflexes induced by Bladder Distension or by electrical stimulation and block of pudendal nerves were investigated in chronic SCI cats under α-chloralose anesthesia. Results The voiding efficiency in chronic SCI cats induced by Bladder Distension was very poor compared to that in spinal intact cats (7.3 ± 0.9% vs. 93.6 ± 2.0%, P < 0.05). In chronic SCI cats continuous stimulation of the pudendal nerve on one side at 20 Hz induced large amplitude Bladder contractions, but failed to induce voiding. However, continuous pudendal nerve stimulation (20 Hz) combined with high-frequency (10 kHz) distal blockade of the ipsilateral pudendal nerve elicited efficient (73.2 ± 10.7%) voiding. Blocking the pudendal nerves bilaterally produced voiding efficiency (82.5 ± 4.8%) comparable to the efficiency during voidings induced by Bladder Distension in spinal intact cats, indicating that the external urethral sphincter (EUS) contraction was caused not only by direct activation of the pudendal efferent fibers, but also by spinal reflex activation of the EUS through the contralateral pudendal nerve. The maximal Bladder pressure and average flow rate induced by stimulation and bilateral pudendal nerve block in chronic SCI cats were also comparable to those in spinal intact cats. Conclusions This study shows that after the spinal cord is chronically isolated from the pontine micturition center, Bladder Distension evokes a transient, inefficient voiding reflex, whereas stimulation of somatic afferent fibers evokes a strong, long duration, spinal Bladder reflex that elicits efficient voiding when combined with blockade of somatic efferent fibers in the pudendal nerves. Neurourol. Urodynam. 26:879–886, 2007. © 2007 Wiley-Liss, Inc.

  • Bladder inhibition or voiding induced by pudendal nerve stimulation in chronic spinal cord injured cats
    Neurourology and Urodynamics, 2007
    Co-Authors: Jicheng Wang, William C. De Groat, Xianchun Wang, James R. Roppolo
    Abstract:

    Aims To investigate pudendal-to-Bladder spinal reflexes in chronic spinal cord injured (SCI) cats induced by electrical stimulation of the pudendal nerve. Methods Bladder inhibition or voiding induced by pudendal nerve stimulation at different frequencies (3 or 20 Hz) was studied in three female, chronic SCI cats under α-chloralose anesthesia. Results Voiding induced by a slow infusion (2–4 ml/min) of saline into the Bladder was very inefficient (voiding efficiency = 7.3% ± 0.9%). Pudendal nerve stimulation at 3 Hz applied during the slow infusion inhibited reflex Bladder activity, and significantly increased Bladder capacity to 147.2 ± 6.1% of its control capacity. When the 3-Hz stimulation was terminated, voiding rapidly occurred and the voiding efficiency was increased to 25.4 ± 6.1%, but residual Bladder volume was not reduced. Pudendal nerve stimulation at 20 Hz induced large Bladder contractions, but failed to induce voiding during the stimulation due to the direct activation of the motor pathway to the external urethral sphincter. However, intermittent pudendal nerve stimulation at 20 Hz induced post-stimulus voiding with 78.3 ± 12.1% voiding efficiency. The voiding pressures (39.3 ± 6.2 cmH2O) induced by the intermittent pudendal nerve stimulation were higher than the voiding pressures (23.1 ± 1.7 cmH2O) induced by Bladder Distension. The flow rate during post-stimulus voiding induced by the intermittent pudendal nerve stimulation was significantly higher (0.93 ± 0.04 ml/sec) than during voiding induced by Bladder Distension (0.23 ± 0.07 ml/sec). Conclusions This study indicates that a neural prosthetic device based on pudendal nerve stimulation might be developed to restore micturition function for people with SCI. Neurourol. Urodynam. 26:570–577, 2007. © 2007 Wiley-Liss, Inc.

Jicheng Wang - One of the best experts on this subject based on the ideXlab platform.

  • mp11 04 sympathetic afferents in the hypogastric nerve facilitate nociceptive Bladder activity in cats
    The Journal of Urology, 2019
    Co-Authors: Yan Zheng, Jicheng Wang, James R. Roppolo, William C. De Groat, Todd Yecies, Tara Nikonow, Haotian Cai, Bing Shen, Nathalie Pace, Changfeng Tai
    Abstract:

    INTRODUCTION AND OBJECTIVES:The normal micturition reflex in cats is mediated by Aδ-afferents in the pelvic nerve, while pelvic C-fiber afferents do not respond to Bladder Distension in normal phys...

  • voiding reflex in chronic spinal cord injured cats induced by stimulating and blocking pudendal nerves
    Neurourology and Urodynamics, 2007
    Co-Authors: Changfeng Tai, Jicheng Wang, James R. Roppolo, Xianchun Wang, William C. De Groat
    Abstract:

    Aims To induce efficient voiding in chronic spinal cord injured (SCI) cats. Methods Voiding reflexes induced by Bladder Distension or by electrical stimulation and block of pudendal nerves were investigated in chronic SCI cats under α-chloralose anesthesia. Results The voiding efficiency in chronic SCI cats induced by Bladder Distension was very poor compared to that in spinal intact cats (7.3 ± 0.9% vs. 93.6 ± 2.0%, P < 0.05). In chronic SCI cats continuous stimulation of the pudendal nerve on one side at 20 Hz induced large amplitude Bladder contractions, but failed to induce voiding. However, continuous pudendal nerve stimulation (20 Hz) combined with high-frequency (10 kHz) distal blockade of the ipsilateral pudendal nerve elicited efficient (73.2 ± 10.7%) voiding. Blocking the pudendal nerves bilaterally produced voiding efficiency (82.5 ± 4.8%) comparable to the efficiency during voidings induced by Bladder Distension in spinal intact cats, indicating that the external urethral sphincter (EUS) contraction was caused not only by direct activation of the pudendal efferent fibers, but also by spinal reflex activation of the EUS through the contralateral pudendal nerve. The maximal Bladder pressure and average flow rate induced by stimulation and bilateral pudendal nerve block in chronic SCI cats were also comparable to those in spinal intact cats. Conclusions This study shows that after the spinal cord is chronically isolated from the pontine micturition center, Bladder Distension evokes a transient, inefficient voiding reflex, whereas stimulation of somatic afferent fibers evokes a strong, long duration, spinal Bladder reflex that elicits efficient voiding when combined with blockade of somatic efferent fibers in the pudendal nerves. Neurourol. Urodynam. 26:879–886, 2007. © 2007 Wiley-Liss, Inc.

  • Bladder inhibition or voiding induced by pudendal nerve stimulation in chronic spinal cord injured cats
    Neurourology and Urodynamics, 2007
    Co-Authors: Jicheng Wang, William C. De Groat, Xianchun Wang, James R. Roppolo
    Abstract:

    Aims To investigate pudendal-to-Bladder spinal reflexes in chronic spinal cord injured (SCI) cats induced by electrical stimulation of the pudendal nerve. Methods Bladder inhibition or voiding induced by pudendal nerve stimulation at different frequencies (3 or 20 Hz) was studied in three female, chronic SCI cats under α-chloralose anesthesia. Results Voiding induced by a slow infusion (2–4 ml/min) of saline into the Bladder was very inefficient (voiding efficiency = 7.3% ± 0.9%). Pudendal nerve stimulation at 3 Hz applied during the slow infusion inhibited reflex Bladder activity, and significantly increased Bladder capacity to 147.2 ± 6.1% of its control capacity. When the 3-Hz stimulation was terminated, voiding rapidly occurred and the voiding efficiency was increased to 25.4 ± 6.1%, but residual Bladder volume was not reduced. Pudendal nerve stimulation at 20 Hz induced large Bladder contractions, but failed to induce voiding during the stimulation due to the direct activation of the motor pathway to the external urethral sphincter. However, intermittent pudendal nerve stimulation at 20 Hz induced post-stimulus voiding with 78.3 ± 12.1% voiding efficiency. The voiding pressures (39.3 ± 6.2 cmH2O) induced by the intermittent pudendal nerve stimulation were higher than the voiding pressures (23.1 ± 1.7 cmH2O) induced by Bladder Distension. The flow rate during post-stimulus voiding induced by the intermittent pudendal nerve stimulation was significantly higher (0.93 ± 0.04 ml/sec) than during voiding induced by Bladder Distension (0.23 ± 0.07 ml/sec). Conclusions This study indicates that a neural prosthetic device based on pudendal nerve stimulation might be developed to restore micturition function for people with SCI. Neurourol. Urodynam. 26:570–577, 2007. © 2007 Wiley-Liss, Inc.

Alan Randich - One of the best experts on this subject based on the ideXlab platform.

  • pd7 06 pudendal nerve stimulation inhibits the visceromotor responses to urinary Bladder Distension in a non opioid dependent manner
    The Journal of Urology, 2015
    Co-Authors: Timothy J. Ness, Alan Randich, Julie Hill, Jamie Mcnaught, Dwight E Nelson
    Abstract:

    INTRODUCTION AND OBJECTIVES: Pudendal nerve stimulation (PNS) reduces pain in humans with interstitial cystitis/Bladder pain syndrome (IC/BPS) and the visceromotor response (VMR) to urinary Bladder Distension (UBD) in a rat model of Bladder hypersensitivity. The effectiveness of PNSmay be impacted by pre-exposure of opioids which are commonly used in practice. To address co-administration concerns, the aim of this rat study was to evaluate if endogenous opioid system is involved in the neural control of Bladder nociceptive reflex by PNS. METHODS: Bladder hypersensitivity was produced by neonatal Bladder inflammation in female rat pups coupled with a second insult as an adult. Under urethane anaesthesia, wire electrodes were placed into the abdominal musculature to measure myoelectrical activity (VMR) to phasic UBD. Two pairs of hook electrodes were placed under each pudendal nerve bilaterally. The effects of PNS (10 Hz, pulse-width 0.1 ms) were assessed on VMR responses before and after the i.p. administration of saline or an opioid receptor antagonist naloxone hydrochloride (1 mg/kg). The effects of PNS were measured as percent change in VRMs ( SEM) compared to Area-under-the-Curve (AUC) of 0 Hz trial for VMRs evoked by 10, 20, 40 and 60 mmHg, 20 s UBD. RESULTS: PNS at 1xmotor threshold (Tmot) or 3xTmot produced statistically significant inhibition on VMRs to UBD. Such effects were frequency-dependent; maximal inhibitory effects produced by electrical stimulation of 5 Hz or greater (up to 100 Hz). Low frequencies of stimulation (0.1 and 1 Hz) did not produce decreases in VMR to UBD. Neither naloxone nor saline produced any statistically significant alternations on inhibitory effects of PNS (3xTmot, 10 Hz). The VMRs to PNS were decreased 26.9 4.0% and 30.9 7.9%, respectively before and after naloxone (p<0.05, repeated measure ANOVA). Similarly before and after saline injection, the VMRs to PNS were significantly decreased 31.9 8.4% and 25.2 8.3%, respectively (p<0.05). CONCLUSIONS: PNS inhibited the nociceptive response in a rat model of Bladder hypersensitivity. The inhibitory effects of PNS could not be blocked by pretreatment of naloxone. Data from this study suggest the potential for clinical utility of PNS in reducing the symptoms of IC/BPS. Though the mechanism of this effect was not determined, the insensitivity to naloxone shows that non-opioid actions are involved in the pudendal neuromodulation on pain control and suggests potential utility of PNS in treating painful Bladder syndromes like IC/BPS even when concomitant opioids are being utilized.

  • early in life Bladder inflammation alters u50 488h but not morphine induced inhibition of visceromotor responses to urinary Bladder Distension
    Neuroscience Letters, 2013
    Co-Authors: Amber D Shaffer, Timothy J. Ness, Alan Randich
    Abstract:

    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.

  • footshock stress differentially affects responses of two subpopulations of spinal dorsal horn neurons to urinary Bladder Distension in rats
    Brain Research, 2011
    Co-Authors: Meredith T Robbins, Alan Randich, Jennifer J. Deberry, Timothy J. Ness
    Abstract:

    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.

  • rostral ventral medulla modulation of the visceromotor reflex evoked by urinary Bladder Distension in female rats
    The Journal of Pain, 2008
    Co-Authors: Alan Randich, Jennifer J. Deberry, Hannah Mebane, Timothy J. Ness
    Abstract:

    Abstract 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 because 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. Perspective Stimulation of the RVM resulted in inhibitory, facilitatory, and biphasic modulation of the visceromotor reflex to urinary Bladder Distension. Inhibitory effects of stimulation were attenuated by naloxone, and lesions of the RVM enhanced the VMR in rats with inflamed Bladders. These data indicate an important role of the RVM in modulating Bladder pain.

  • serotonergic and noradrenergic facilitation of the visceromotor reflex evoked by urinary Bladder Distension in rats with inflamed Bladders
    Neuroscience Letters, 2008
    Co-Authors: Alan Randich, Amber D Shaffer, Chelsea L Ball, Hannah Mebane
    Abstract:

    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.