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1.  Neonatal Bladder Inflammation Alters Activity of Adult Rat Spinal Visceral Nociceptive Neurons 
Neuroscience letters  2010;472(3):210-214.
This investigation examined the effect of inflammation produced by intravesical zymosan during the neonatal period on spinal dorsal horn neuronal responses to urinary bladder distension (UBD) as adults.
Female rat pups (P14-P16) were treated with intravesical zymosan or with anesthesia-only. These groups of rats were subdivided forming four groups: half received intravesical zymosan as adults and half received anesthesia-only. One day later, rats were anesthetized, the spinal cord transected at a cervical level and extracellular single-unit recordings of L6-S1 dorsal horn neurons obtained. Neurons were classified as Type I - inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II - not inhibited by HNCS - and were characterized for spontaneous activity and responses to graded UBD (20–60 mm Hg).
227 spinal dorsal horn neurons excited by UBD were characterized. In rats treated as neonates with anesthesia-only, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following adult intravesical zymosan treatment whereas Type I neurons demonstrated decreased spontaneous and UBD-evoked activity relative to controls. In rats treated as neonates with intravesical zymosan, the spontaneous and UBD-evoked activity of both Type I and Type II neurons increased following adult intravesical zymosan treatment relative to controls.
Neonatal bladder inflammation alters subsequent effects of acute bladder inflammation on spinal dorsal horn neurons excited by UBD such that overall there is greater sensory neuron activation. This may explain the visceral hypersensitivity noted in this model system and suggest that impaired inhibitory systems may be responsible.
PMCID: PMC2842906  PMID: 20149841
visceral; urinary bladder; cystitis; zymosan; spinal
2.  Acute Bladder Inflammation Differentially Affects Rat Spinal Visceral Nociceptive Neurons 
Neuroscience letters  2009;467(2):150-154.
The present investigation examined the effect of inflammation produced by intravesical zymosan on spinal dorsal horn neuronal responses to urinary bladder distension (UBD).
Extracellular single-unit recordings of neurons excited by UBD were obtained in spinalized female Sprague-Dawley rats. Neurons were classified as Type I - inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II - not inhibited by a HNCS. In Experiment 1 - following neuronal characterization, 1% zymosan was infused into the bladder and after two hours spinal units were recharacterized. Control rats received intravesical saline or subcutaneous zymosan. In Experiment 2 – rats were pretreated with intravesical zymosan 24 hours prior to surgical preparation. Control rats only received anesthesia.
137 spinal dorsal horn neurons excited by UBD were characterized. In comparison with controls, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following intravesical zymosan treatment (both Experiments 1 & 2) whereas Type I neurons demonstrated either no change (Experiment 1) or decreased activity (Experiment 2) following bladder inflammation. No significant changes were noted in neuronal activity in control experiments.
Inflammation differentially affects subpopulations of spinal dorsal horn neurons excited by UBD that can be differentiated according to the effect of HNCS. This results in an altered pattern of spinal sensory transmission that may serve as the mechanism for the generation of visceral nociception.
PMCID: PMC2783714  PMID: 19822190
visceral; urinary bladder; cystitis; zymosan; spinal
3.  Footshock-Induced Urinary Bladder Hypersensitivity: Role of Spinal Corticotropin-Releasing Factor Receptors 
Stress-induced hyperalgesia (SIH), a common clinical observation associated with multiple painful diseases including functional urinary disorders, presently has no mechanistic explanation. Using a Footshock treatment, a classical stressor, to magnify physiological responses in a model of urinary bladder pain, we examined one potential group of mediators of SIH, the corticotropin-releasing factor (CRF)-related neuropeptides. Exposure to a Footshock treatment produced bladder hypersensitivity in female Sprague Dawley rats, manifested as significantly more vigorous visceromotor responses (VMRs) to urinary bladder distension (UBD) compared to rats that were exposed to a Non-footshock treatment. This bladder hypersensitivity was significantly attenuated by blocking spinal CRF2 receptors but not CRF1 receptors. Furthermore, spinal administration of urocortin 2, a CRF2 receptor agonist, augmented UBD-evoked VMRs in a way similar to what was observed following exposure to Footshock, an effect significantly attenuated by pretreatment with spinal aSVG30, a CRF2 receptor antagonist. Surprisingly, neither spinal administration of CRF nor the CRF1 receptor antagonist, antalarmin, had an effect on bladder nociceptive responses. The results of the present study not only provide further support for a role of stress in the exacerbation of bladder pain, but also implicate spinal urocortins and their endogenous receptor, the CRF2 receptor, as potential mediators of this effect.
This study presents evidence that spinal urocortins and CRF2 receptors are involved in stress-induced hypersensitivity related to the urinary bladder. This provides a basis for investigating how urocortins mediate SIH, ultimately leading to more effective treatment options for patients suffering from painful bladder syndromes as well as stress-exacerbated chronic pain.
PMCID: PMC2579943  PMID: 18632307
Urinary bladder; hypersensitivity; visceral; urocortin; corticotropin-releasing factor
4.  Effects of Oxytocin and Prolactin on Stress-Induced Bladder Hypersensitivity in Female Rats 
Anecdotal evidence suggests that chronic bladder pain improves while breastfeeding. The present study sought to identify potential mechanisms for such a phenomenon by investigating the effects of the lactogenic hormones prolactin (PL) and oxytocin (OXY) in a rat model of bladder nociception. Lactating rats were less sensitive to urinary bladder distension (UBD) than controls. In investigating potential antinociceptive and anxiolytic roles for these hormones, we found exposure to a footshock paradigm (STRESS groups) produced bladder hypersensitivity in saline-treated rats, manifested as significantly higher electromyographical (EMG) responses to UBD, compared to rats exposed to a non-footshock paradigm (SHAM groups). This hypersensitivity was attenuated by the intraperitoneal administration of OXY prior to footshock in the STRESS-OXY group. The administration of PL augmented EMG responses in the SHAM-PL group but had no effect on the responses of the STRESS-PL group. In the absence of behavioral pretreatment, OXY attenuated UBD-evoked responses while PL had no effect. Moreover, OXY-treated rats spent more time in the open arm of an elevated plus maze compared to saline-treated rats suggesting anxiolysis. These studies suggest the potential for systemic OXY, but not PL, as an analgesic and anxiolytic treatment for painful bladder disorders such as interstitial cystitis.
PMCID: PMC2757490  PMID: 19595642
oxytocin; prolactin; nociception; pain; stress; anxiety; bladder
5.  Intrathecal Oxytocin Inhibits Visceromotor Reflex and Spinal Neuronal Responses to Noxious Distention of the Rat Urinary Bladder 
Background and Objectives
Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation.
Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 s; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings.
OXY doses of 0.15 μg or 1.5 μg inhibited VMRs to UBD by 37 ± 8% and 68 ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76 ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes.
These results argue that intrathecal OXY produces an OXY receptor specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.
PMCID: PMC3426637  PMID: 22878524
6.  A Peripheral Adrenoceptor-mediated Sympathetic Mechanism Can Transform Stress-induced Analgesia into Hyperalgesia 
Anesthesiology  2011;114(6):1403-1416.
Stress has paradoxical effects on pain, causing stress-induced analgesia, but also exacerbating pain via poorly understood mechanisms. Adrenergic neurotransmission is integral in pathways that regulate the response to both pain and stress. Hyperalgesia is often associated with enhanced adrenergic sensitivity of primary afferents, but sympathetic nervous system outflow has not been demonstrated to exacerbate pain perception following stress.
Rats or C57/BL6 wild type mice treated with α-2 receptor antagonists or α-2A receptor knockout mice were exposed to ultrasonic noise stress or footshock stress and subsequently tested for hotplate paw withdrawal latencies. The sensory sensitivity of α-2A knockout mice to electrical and chemical stimuli was tested neurophysiologically and behaviorally. The effects of sympatholytic treatments were investigated.
Noise and footshock stressors induced thermal hyperalgesia in rats pretreated systemically with α-2 antagonists. Wild type mice pretreated with α-2 antagonists and α-2A knockout mice also exhibited noise stress-induced thermal hyperalgesia. Local spinal or intraplantar injection of an α-2 antagonist counteracted stress-induced analgesia without causing hyperalgesia. α-2A knockout mice had decreased thresholds for peripheral sensitization with sulprostone and for windup of the dorsal horn neuronal response to repetitive electrical stimuli. Stress-induced hyperalgesia was abolished and the sensitization was attenuated by sympathectomy or systemic administration of an α-1-adrenergic antagonist.
Sympathetic postganglionic nerves can enhance pain sensation via a peripheral α-1-adrenoceptor mechanism when sympathetic outflow is disinhibited. The net effect of stress on pain sensation reflects a balance between descending spinal inhibition and sympathetic outflow that can shift towards pain facilitation when central and peripheral α-2-adrenoceptor inhibitory mechanisms are attenuated.
PMCID: PMC3143476  PMID: 21540738
7.  Chronic Psychological Stress Enhances Nociceptive Processing in the Urinary Bladder in High-Anxiety Rats 
Physiology & behavior  2007;91(5):544-550.
This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).
PMCID: PMC2084207  PMID: 17521683
Bladder; Stress; Hyperalgesia; Visceral
8.  Footshock-induced responses in ventral subiculum neurons are mediated by locus coeruleus noradrenergic afferents 
The ventral subiculum (vSub) of the hippocampus is critically involved in mediating the forebrain’s response to stress, particularly with regard to psychogenic stressors. Stress, in turn, is known to aggravate many psychiatric conditions including schizophrenia, depression, anxiety, and drug abuse. Pathological alterations in hippocampal function have been identified in all these disorders; thus, it is of interest to understand how stress affects this brain region. The vSub receives dense projections from the stress-related locus coeruleus (LC); however, it is not known what role this input plays in signaling stressful stimuli. In this study, the direct LC innervation of the vSub was investigated as a potential mediator of stress responses in this region. To examine responses to an acute stressor, the effect of footshock on single vSub neurons was tested in rats. Footshock inhibited 13%, and activated 48% of neurons in this region. Importantly, responses to footshock were correlated with LC stimulation-evoked responses in single neurons, and LC inactivation blocked these responses. Furthermore, prazosin, an alpha-1 antagonist, reversed footshock-evoked inhibition, revealing an underlying activation. Inactivation of the basolateral amygdala (BLA) did not block phasic footshock-evoked activation; however, it reduced tonic activity in the vSub. These results suggest that the LC NE system plays an important role in mediating stress responses in the vSub. Footshock evokes both inhibition and excitation in the vSub, by activating noradrenergic inputs from the LC. These responses may contribute to stress adaptation; while an imbalance of this system may lead to pathological stress responses in mental disorders.
PMCID: PMC3718869  PMID: 23394871
stress; norepinephrine; footshock; ventral subiculum; locus coeruleus; rat
Neuroscience letters  2012;534:150-154.
Previous research has suggested that early-in-life (EIL) exposure to bladder inflammation impairs the function of endogenous opioid inhibitory system(s) and may contribute to the development of chronic bladder pain. This study examined how acute adult and/or prior EIL exposure to bladder inflammation altered the inhibitory effects of systemic κ- and μ-opioid agonists on the visceromotor reflex (VMR) to urinary bladder distension (UBD). Female rats were exposed intravesically EIL (P14–P16) to either the inflammatory agent zymosan or anesthesia-alone, and then rechallenged as adults (12–17 weeks) with either anesthesia-alone or zymosan. The VMR to 60 mmHg UBD was measured after cumulative intravenous (i.v.) administration of 1 mg/kg and 4 mg/kg of either the κ-opioid agonist U50,488H or the μ-opioid agonist morphine. Morphine produced dose-dependent inhibition of the VMR to UBD in all groups, and U50,488H produced dose-dependent inhibition of the VMR to UBD in all but one group. Animals that received bladder inflammation both EIL and as adults showed significantly augmented VMRs to UBD (>100% baseline values) following 1 mg/kg of U50,488H and diminished inhibition of VMRs following 4 mg/kg of U50,488H when compared with other groups. In contrast, neither EIL nor adult bladder inflammation markedly altered the inhibition of the VMR to UBD produced by either 1 or 4 mg/kg of i.v. morphine. These data suggest EIL and adult exposure to bladder inflammation selectively decreases the inhibitory effects of κ-opioids and thereby may enhance bladder hypersensitivity in patients with painful bladder syndromes.
PMCID: PMC3558537  PMID: 23201636
Opioid; Visceral Pain; Inflammation; Painful Bladder Syndrome; Animals; Newborn
10.  Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon–bladder cross-sensitization 
Brain research  2012;1491:213-224.
Cross-sensitization in the pelvis may contribute to etiology of functional pelvic pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increasing evidence suggests the involvement of transient receptor potential vanilloid 1 (TRPV1) receptors in the development of neurogenic inflammation in the pelvis and pelvic organ cross-sensitization. The objective of this study was to test the hypothesis that desensitization of TRPV1 receptors in the urinary bladder can minimize the effects of cross-sensitization induced by experimental colitis on excitability of bladder spinal neurons. Extracellular activity of bladder neurons was recorded in response to graded urinary bladder distension (UBD) in rats pretreated with intravesical resiniferatoxin (RTX, 10−7 M). Colonic inflammation was induced by intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The duration of excitatory responses to noxious UBD during acute colonic inflammation (3 days post-TNBS) was significantly shortened in the group with RTX pretreatment (25.37±.5 s, n=49) when compared to the control group (35.1±4.2 s, n=43, p≤0.05). The duration of long-lasting excitatory responses, but not short-lasting responses of bladder spinal neurons during acute colitis was significantly reduced by RTX from 52.9±6.6 s (n=21, vehicle group) to 34.4±2.1 s (RTX group, n=21, p≤0.05). However, activation of TRPV1 receptors in the urinary bladder prior to acute colitis increased the number of bladder neurons receiving input from large somatic fields from 22.7% to 58.2% (p≤0.01). The results of our study provide evidence that intravesical RTX reduces the effects of viscerovisceral cross-talk induced by colonic inflammation on bladder spinal neurons. However, RTX enhances the responses of bladder neurons to somatic stimulation, thereby limiting its therapeutic potential.
PMCID: PMC3607291  PMID: 23146715
Spinal neurons; Chronic pelvic pain; Intravesical vanilloids; Bladder pain syndrome
11.  Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic-pituitary-adrenal response to stress 
Journal of neurochemistry  2010;113(4):919-929.
The Mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self-administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress.
PMCID: PMC2912162  PMID: 20202080
nicotine self-administration; adrenocorticotropic hormone; corticosterone; footshock stress; homeostatic plasticity; rat
12.  Effects of acupuncture on stress-induced relapse to cocaine-seeking in rats 
Psychopharmacology  2012;222(2):303-311.
Cocaine addiction is associated with high rates of relapse, and stress has been identified as a major risk factor. We have previously demonstrated that acupuncture reduces drug self-administration and dopamine release in the nucleus accumbens (NAc), a brain structure implicated in stress-induced reinstatement of drug-seeking behavior.
This study was conducted to investigate the effects of acupuncture on footshock-induced reinstatement of cocaine-seeking and the expression of c-Fos and the transcription factor cAMP response element-binding protein (CREB) in the NAc, used as markers of neuronal activation in conditions of stress-induced reinstatement to cocaine.
Male Sprague–Dawley rats were trained to self-administer cocaine (1.0 mg/kg) for 14 days, followed by extinction and then footshock stress. Acupuncture was applied at bilateral Shenmen (HT7) points for 1 min after footshock stress.
Results and conclusions
Acute footshock stress reinstated cocaine-seeking behavior and enhanced c-Fos expression and phosphorylated CREB (pCREB) activation in the NAc shell in cocaine pre-exposed rats. On the other hand, acupuncture at HT7, but not at control point (LI5), markedly reduced reinstatement of cocaine-seeking (86.5 % inhibition vs. control value), c-Fos expression (81.7% inhibition), and pCREB activation (79.3% inhibition) in the NAc shell. These results suggest that acupuncture attenuates stress-induced relapse by regulating neuronal activation in the NAc shell.
PMCID: PMC4056594  PMID: 22453546
Cocaine reinstatement; Footshock; Stress; Acupuncture; Nucleus accumbens; c-Fos; pCREB
13.  Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia 
Neuropharmacology  2007;54(1):161-171.
Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB1 antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Δ9-tetrahydrocannabinol (Δ9-THC). The converse was also true; acute Δ9-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Δ9-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.
PMCID: PMC2771679  PMID: 17714742
cannabinoid; sensitization; stress antinociception; rimonabant; tolerance; footshock; anxiety; THC; endocannabinoid; sensitization; stress antinociception; rimonabant; tolerance; footshock; anxiety
14.  Nicotine self-administration diminishes stress-induced norepinephrine secretion but augments adrenergic-responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release 
Journal of neurochemistry  2009;112(5):1327-1337.
Chronic nicotine self-administration augments the thalamo-pituitary-adrenal (HPA) responses to stress. Altered neuropeptide expression within corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) contributes to this enhanced HPA response to stress. Herein, we determined the role of norepinephrine, a primary regulator of CRF neurons, in the responses to footshock during nicotine self-administration. On day 12-15 of self-administration, microdialysis showed nicotine reduced PVN norepinephrine release by footshock (<50% of saline). Yet, the reduction in footshock-induced adrenocorticotropic hormone (ACTH) and corticosterone secretion due to intra-PVN prazosin (α1 adrenergic antagonist) was significantly greater in rats self-administering nicotine (2-fold) than saline. Additionally, PVN phenylephrine (α1 agonist) stimulated ACTH and corticosterone release to a similar extent in unstressed rats self-administering nicotine or saline. Nicotine self-administration also decreased footshock-induced c-Fos expression in the nucleus of the solitary tract (NTS)-A2/C2 catecholaminergic neurons that project to the PVN. Therefore, footshock-induced NTS activation and PVN norepinephrine input are both attenuated by nicotine self-administration, yet PVN CRF neurons are more responsive to α1 stimulation, but only during stress. This plasticity in noradrenergic regulation of PVN CRF neurons provides a new mechanism contributing to the HPA sensitization to stress by nicotine self-administration and smoking.
PMCID: PMC2819601  PMID: 20028457
nicotine; hypothalamic paraventricular nucleus; corticotrophin-releasing factor; norepinephrine; adrenocorticotropic hormone; stress
15.  Pelvic nerve input mediates descending modulation of homovisceral processing in the thoracolumbar spinal cord of the rat 
Gastroenterology  2007;133(5):1544-1553.
Background and aims
Colonic afferents project to the lumbosacral and thoracolumbar spinal cord via the pelvic and hypogastric/lumbar colonic nerves, respectively. Both spinal regions process inflammatory colonic stimuli. The role of thoracolumbar segments in processing acute colorectal pain is questionable, however, since the lumbosacral spinal cord appears sufficient to process reflex responses to acute pain. Here we demonstrate that activity in pelvic nerve colonic afferents actively modulates thoracolumbar dorsal horn neuron processing of the same colonic stimulus via a supraspinal loop: homovisceral descending modulation.
Dorsal horn neurons were recorded in the rat thoracolumbar spinal cord following acute or chronic pelvic neurectomy and cervical cold block.
Acute pelvic neurectomy or lidocaine inhibition of lumbosacral dorsal roots facilitated the excitatory response of thoracolumbar dorsal horn neurons to colorectal distention (CRD) and decreased the percentage of neurons inhibited by CRD, suggesting colonic input over the pelvic nerve inhibits thoracolumbar processing of the same stimulus. Ectopic activity developed in the proximal pelvic nerve following chronic neurectomy reactivating the inhibitory circuit, inhibiting thoracolumbar neurons. Cervical cold block alleviated the inhibition in intact or chronic neurectomized rats. However, the facilitated response following acute pelvic neurectomy was inhibited by cervical cold block exposing an underlying descending facilitation. Inhibiting pelvic nerve input following cervical cold block had minimal effect.
These data demonstrate that input over the pelvic nerve modulates the response of thoracolumbar spinal neurons to CRD via a supraspinal loop, and that increasing thoracolumbar processing increases visceral hyperalgesia.
PMCID: PMC2094005  PMID: 17916357
visceral pain; descending modulation; brainstem; inhibition; facilitation; spinal cord; colorectal distention; electrophysiology
16.  Inflammation-Induced Enhancement of the Visceromotor Reflex to Urinary Bladder Distention: Modulation by Endogenous Opioids and the Effects of Early-In-Life Experience with Bladder Inflammation 
Abdominal electromyographic (EMG) responses to noxious intensities of urinary bladder distention (UBD) are significantly enhanced 24 hrs following 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 since 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 likely result from blockade of a spinal mechanism, because intrathecal (i.t.) naloxone also significantly enhances EMG responses to UBD in rats with inflammation. Rats exposed to bladder inflammation from P90-P92 prior to re-inflammation 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 prior to re-inflammation 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.
PMCID: PMC4012257  PMID: 17704007
bladder; opioids; inflammation; neonatal; visceromotor reflex; pain
17.  Neonatal Cystitis-Induced Colonic Hypersensitivity in Adult Rats: A Model of Viscero-Visceral Convergence 
The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms.
Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days (postnatal days 14th–16th). The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissue. CRD or urinary bladder distension (UBD)-sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N-methyl-D-aspartic acid (NMDA) NR1 subunit in the L6-S1 spinal cord was examined using Western blot.
The VMR to CRD (≥10mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD-sensitive PNAs from the zymosan rats was significantly higher than the control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (p > 0.05). The expression of spinal NR1 subunit was significantly higher in zymosan-treated rats compared to saline treated rats (p <0.05).
Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD-sensitive PNAs. Neonatal cystitis does results in overexpression of spinal NR1 subunit in adult rats.
PMCID: PMC3117950  PMID: 21592255
cystitis; visceral hyperalgesia; neonatal; viscero-visceral convergence
18.  Lesions of the Fasciculus Retroflexus Alter Footshock-Induced cFos Expression in the Mesopontine Rostromedial Tegmental Area of Rats 
PLoS ONE  2013;8(4):e60678.
Midbrain dopamine neurons are an essential part of the circuitry underlying motivation and reinforcement. They are activated by rewards or reward-predicting cues and inhibited by reward omission. The lateral habenula (lHb), an epithalamic structure that forms reciprocal connections with midbrain dopamine neurons, shows the opposite response being activated by reward omission or aversive stimuli and inhibited by reward-predicting cues. It has been hypothesized that habenular input to midbrain dopamine neurons is conveyed via a feedforward inhibitory pathway involving the GABAergic mesopontine rostromedial tegmental area. Here, we show that exposing rats to low-intensity footshock (four, 0.5 mA shocks over 20 min) induces cFos expression in the rostromedial tegmental area and that this effect is prevented by lesions of the fasciculus retroflexus, the principal output pathway of the habenula. cFos expression is also observed in the medial portion of the lateral habenula, an area that receives dense DA innervation via the fr and the paraventricular nucleus of the thalamus, a stress sensitive area that also receives dopaminergic input. High-intensity footshock (120, 0.8 mA shocks over 40 min) also elevates cFos expression in the rostromedial tegmental area, medial and lateral aspects of the lateral habenula and the paraventricular thalamus. In contrast to low-intensity footshock, increases in cFos expression within the rostromedial tegmental area are not altered by fr lesions suggesting a role for non-habenular inputs during exposure to highly aversive stimuli. These data confirm the involvement of the lateral habenula in modulating the activity of rostromedial tegmental area neurons in response to mild aversive stimuli and suggest that dopamine input may contribute to footshock- induced activation of cFos expression in the lateral habenula.
PMCID: PMC3625179  PMID: 23593280
19.  Optimization of a Pain Model: Effects of Body Temperature and Anesthesia on Bladder Nociception in Mice 
PLoS ONE  2013;8(11):e79617.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urological condition that is resistant to treatment and poorly understood. To determine novel molecular treatment targets and to elucidate the contribution of the nervous system to IC/BPS, many rodent bladder pain models have been developed. In this study we evaluated the effects of anesthesia induction and temperature variation in a mouse model of bladder pain known as urinary bladder distension (UBD). In this model compressed air is used to distend the bladder to distinct pressures while electrodes record the reflexive visceromotor response (VMR) from the overlying abdominal muscle. Two isoflurane induction models are commonly used before UBD: a short method lasting approximately 30 minutes and a long method lasting approximately 90 minutes. Animals were anesthetized with one of the methods then put through three sets of graded bladder distensions. Distensions performed following the short anesthesia protocol were significantly different from one another despite identical testing parameters; this same effect was not observed when the long anesthesia protocol was used. In order to determine the effect of temperature on VMRs, animals were put through three graded distension sets at 37.5 (normal mouse body temperature), 35.5, and 33.5°C. Distensions performed at 33.5 and 35.5°C were significantly lower than those performed at 37.5°C. Additionally, Western blot analysis revealed significantly smaller increases in spinal levels of phosphorylated extracellular-signal regulated kinase 2 (pERK2) following bladder distension in animals whose body temperature was maintained at 33.5°C as opposed to 37.5°C. These results highlight the significance of the dynamic effects of anesthesia on pain-like changes and the importance of close monitoring of temperature while performing UBD. For successful interpretation of VMRs and translation to human disease, body temperature should be maintained at 37.5°C and isoflurane induction should gradually decrease over the course of 90 minutes.
PMCID: PMC3818235  PMID: 24223980
20.  Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice 
Alcohol (Fayetteville, N.Y.)  2008;42(6):469-476.
Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans.
PMCID: PMC2575102  PMID: 18599253
Ethanol self-administration; Mice; Footshock stress; Corticosterone
21.  Rostral Ventral Medulla Modulation of the Visceromotor Reflex Evoked by Urinary Bladder Distension in Female Rats 
The present studies examined the involvement of the rostral ventral medulla (RVM) in modulating the visceromotor response (VMR) evoked by urinary bladder distension (UBD) in adult female rats. The VMR was indexed by electromyographic (EMG) responses of the abdominal external oblique muscle to UBD. Experiment 1 showed that the predominant effect of electrical stimulation of the RVM in normal rats was to produce intensity-dependent inhibition of the VMR (54% of sites sampled). Facilitatory, biphasic, or no effects were obtained at the remaining sites. Experiment 2 showed that RVM-induced inhibition of the VMR was significantly attenuated by intraperitoneal (i.p.) administration of naloxone, but not saline vehicle. In Experiment 3, we examined the effect of lesions of the RVM in rats with inflamed bladders since previous research has shown that an endogenous opioid inhibitory system is engaged by bladder inflammation. Electrolytic lesions of the RVM, but not sham-lesions of the RVM, significantly increased the VMR to graded UBD in rats with augmented VMRs induced by prior inflammation of the bladder. The present data suggest that the RVM can inhibit the VMR to UBD acting in part via an opioid inhibitory system and that bladder inflammation can recruit the RVM to produce a net inhibitory effect on the VMR to UBD.
PMCID: PMC2576287  PMID: 18619908
bladder; rostral ventromedial medulla; visceromotor reflex; pain; inhibition
22.  Chronic Intermittent Cold Stress Sensitizes Neuro-Immune Reactivity in the Rat Brain 
Psychoneuroendocrinology  2011;36(8):1164-1174.
Chronic stress contributes to many neuropsychiatric disorders in which the HPA axis, cognition and neuro-immune activity are dysregulated. Patients with major depression, or healthy individuals subjected to acute stress, present elevated levels of circulating pro-inflammatory markers. Acute stress also activates pro-inflammatory signals in the periphery and in the brain of rodents. However, despite the clear relevance of chronic stress to human psychopathology, the effects of prolonged stress exposure on central immune activity and reactivity have not been well characterized. Our laboratory has previously shown that, in rats, chronic intermittent cold stress (CIC stress, 4 °C, 6h/day, 14 days) sensitizes the HPA response to a subsequent novel stressor, and produces deficits in a test of cognitive flexibility that is dependent upon prefrontal cortical function. We have hypothesized that CIC stress could potentially exert some of these effects by altering the neuro-immune status of the brain, leading to neuronal dysfunction. In this study, we have begun to address this question by determining whether previous exposure to CIC stress could alter the subsequent neuro-immune response to an acute immunological challenge (lipopolysaccharide, LPS) or an acute heterologous stressor (footshock). We examined the response of the pro-inflammatory cytokines, IL1β and IL6, the enzyme cyclooxygenase 2, and the chemokines, CXCL1 and MCP-1 in plasma, hypothalamus and prefrontal cortex. There was no effect of CIC stress on basal expression of these markers 24h after the termination of stress. However, CIC stress enhanced the acute induction of the pro-inflammatory cytokines, IL1β and particularly IL6, and the chemokines, CXCL1 and MCP-1, in plasma, hypothalamus and prefrontal cortex in response to LPS, and also sensitized the hypothalamic IL1β response to acute footshock. Thus, sensitization of acute pro-inflammatory responses in the brain could potentially mediate some of the CIC-dependent changes in HPA and cognitive function.
PMCID: PMC3130087  PMID: 21411230
Chronic stress; lipopolysaccharide; footshock; cytokines; prefrontal cortex; hypothalamus
23.  Central infusion of interleukin-1 receptor antagonist blocks the reduction in social behavior produced by prior stressor exposure 
Physiology & behavior  2009;98(1-2):139-146.
ARAKAWA, H., P. BLANDINO Jr. AND T DEAK. Central infusion of interleukin-1 receptor antagonist blocks the reduction in social behavior produced by prior stressor exposure. PHYSIOL BEHAV **(*) 000-000, 2009.-Pro-inflammatory cytokines such as interleukin-1beta (IL-1β) in the brain modulate sickness behavior in rodents, in which animals show complex changes in behavior such as reduction of general activity, reduced social motivation, and fever response. The present studies examined the impact of lipopolysacharide (LPS) and stressor (footshock) exposure on the later expression of social behavior in Sprague-Dawley rats using two separate behavioral paradigms. In Experiment 1, a traditional test for social interaction in which animals were allowed to investigate a juvenile rat in their home cages was conducted at 4 different time points following LPS or foot shock treatment. In Experiment 2, social investigation task which allowed animals to sniff the hole connected to other chamber where a stimulus animal was placed, but prevented physical contact, was used to measure social investigation at several time points following LPS or footshock treatment. Both systemic infusion of LPS (100 μg/kg) and 2 hr footshock exposure (80 shocks, 1mA, 5 sec duration) elicited a time-dependent reduction of social interaction (Exp. 1) and investigation (Exp. 2); LPS-treated rats displayed a more profound reduction of social investigation from 2 hr to 6 hr after treatment, while rats exposed to footshock showed a reduction 6 hr after the footshock exposure. In Experiment 3, the footshock-induced reduction of social investigation was blocked by pretreatment with IL-1 receptor antagonist (IL-1Ra; 100 μg icv) infusion. Together, these findings support a growing body of literature showing that stress-dependent changes in brain cytokines play a key role in mediating behavioral consequences of stressor exposure.
PMCID: PMC2752949  PMID: 19414023
Footshock; Pro-inflammatory cytokine; Sickness behavior; Social investigation; IL-1Ra; LPS; Rats; stress
24.  Fish oil consumption prevents glucose intolerance and hypercorticosteronemy in footshock-stressed rats 
Environmental stress plays an important role in the development of glucose intolerance influencing lipid and glucose metabolism through sympathetic nervous system, cytokines and hormones such as glucocorticoids, catecholamines and glucagon. Otherwise, fish oil prevents glucose intolerance and insulin resistance. Although the mechanisms involved are not fully understood, it is known that sympathetic and HPA responses are blunted and catecholamines and glucocorticoids concentrations can be modulated by fish consumption. The aim of the present study was to evaluate whether fish oil, on a normal lipidic diet: 1) could prevent the effect of footshock-stress on the development of glucose intolerance; 2) modified adiponectin receptor and serum concentration; and 3) also modified TNF-α, IL-6 and interleukin-10 (IL-10) levels in adipose tissue and liver. The study was performed in thirty day-old male Wistar randomly assigned into four groups: no stressed (C) and stressed (CS) rats fed with control diet, and no stressed (F) and stressed (FS) rats fed with a fish oil rich diet. The stress was performed as a three daily footshock stress sessions.
Body weight, carcass fat and protein content were not different among groups. FS presented a reduction on the relative weight of RET. Basal serum glucose levels were higher in CS and FS but 15 min after glucose load just CS remained with higher levels than other groups. Serum corticosterone concentration was increased in CS, this effect was inhibited in FS. However, 15 min after footshock-stress, corticosterone levels were similar among groups. IL-6 was increased in EPI of CS but fish oil consumption prevented IL-6 increase in FS. Similar levels of TNF-α and IL-10 in RET, EPI, and liver were observed among groups. Adipo R1 protein concentration was not different among groups. Footshock-stress did not modify AdipoR2 concentration, but fish oil diet increases AdipoR2 protein concentration.
Footshock-stress promotes glucose intolerance associated to corticosterone serum level and epididymal white adipose tissue IL-6 concentration increase. The fish oil consumption by stressed rats normalized the stress responses. These results suggested that fish oil intake could be useful to minimize or prevent the development of diseases associated to the stress.
PMCID: PMC3112421  PMID: 21569357
25.  Acute Stress Increases Depolarization-Evoked Glutamate Release in the Rat Prefrontal/Frontal Cortex: The Dampening Action of Antidepressants 
PLoS ONE  2010;5(1):e8566.
Behavioral stress is recognized as a main risk factor for neuropsychiatric diseases. Converging evidence suggested that acute stress is associated with increase of excitatory transmission in certain forebrain areas. Aim of this work was to investigate the mechanism whereby acute stress increases glutamate release, and if therapeutic drugs prevent the effect of stress on glutamate release.
Rats were chronically treated with vehicle or drugs employed for therapy of mood/anxiety disorders (fluoxetine, desipramine, venlafaxine, agomelatine) and then subjected to unpredictable footshock stress. Acute stress induced marked increase in depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex in superfusion, and the chronic drug treatments prevented the increase of glutamate release. Stress induced rapid increase in the circulating levels of corticosterone in all rats (both vehicle- and drug-treated), and glutamate release increase was blocked by previous administration of selective antagonist of glucocorticoid receptor (RU 486). On the molecular level, stress induced accumulation of presynaptic SNARE complexes in synaptic membranes (both in vehicle- and drug-treated rats). Patch-clamp recordings of pyramidal neurons in the prefrontal cortex revealed that stress increased glutamatergic transmission through both pre- and postsynaptic mechanisms, and that antidepressants may normalize it by reducing release probability.
Acute footshock stress up-regulated depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex. Stress-induced increase of glutamate release was dependent on stimulation of glucocorticoid receptor by corticosterone. Because all drugs employed did not block either elevation of corticosterone or accumulation of SNARE complexes, the dampening action of the drugs on glutamate release must be downstream of these processes. This novel effect of antidepressants on the response to stress, shown here for the first time, could be related to the therapeutic action of these drugs.
PMCID: PMC2797327  PMID: 20052403

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