Visceral Hyperalgesia Research Articles

TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis

Urinary bladder pain is a primary symptom associated with interstitial cystitis/painful bladder syndrome. We used systemic injections of cyclophosphamide (CYP), an alkylating antineoplastic agent, to induce cystitis and examine the roles of 2 channels previously demonstrated to be required for inflammatory visceral hyperalgesia: transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1). Injection of CYP (100mg/kg, i.p.) every other day for 5days was accompanied by bladder edema and urothelial ulceration, but without significant plasma extravasation or infiltration of neutrophils. Toluidine blue staining showed a significant increase in the number of degranulated bladder mast cells after CYP treatment. Despite this mild pathology, CYP-treated mice exhibited bladder hyperalgesia 1 day after the final injection that persisted 7days later. Although many previous studies of visceral hyperalgesia have reported changes in dorsal root ganglion neuron TRPV1 expression and/or function, we found no change in bladder afferent TRPV1 expression or sensitivity on the basis of the percentage of bladder afferents responsive to capsaicin, including at submaximal concentrations. In contrast, the percentage of bladder afferents expressing functional TRPA1 protein (ie, those responsive to mustard oil) increased ∼2.5-fold 1day after CYP treatment, and remained significantly elevated 7days later. Moreover, bladder hyperalgesia was reversed by acute treatment with the TRPA1 antagonist HC-030031 (300mg/kg, i.p.). Our results indicate that CYP-induced bladder hyperalgesia can be induced without robust inflammation or changes in primary afferent TRPV1. However, significant changes were observed in TRPA1 expression, and blockade of TRPA1 alleviated CYP-induced bladder hyperalgesia.

Neuron-glial communication mediated by TNF-α and glial activation in dorsal root ganglia in visceral inflammatory hypersensitivity

Communication between neurons and glia in the dorsal root ganglia (DRG) and the central nervous system is critical for nociception. Both glial activation and proinflammatory cytokine induction underlie this communication. We investigated whether satellite glial cell (SGC) and tumor necrosis factor-α (TNF-α) activation in DRG participates in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat model of visceral hyperalgesia. In TNBS-treated rats, TNF-α expression increased in DRG and was colocalized to SGCs enveloping a given neuron. These SGCs were activated as visualized under electron microscopy: they had more elongated processes projecting into the connective tissue space and more gap junctions. When nerves attached to DRG (L6-S1) were stimulated with a series of electrical stimulations, TNF-α were released from DRG in TNBS-treated animals compared with controls. Using a current clamp, we noted that exogenous TNF-α (2.5 ng/ml) increased DRG neuron activity, and visceral pain behavioral responses were reversed by intrathecal administration of anti-TNF-α (10 μg·kg(-1)·day(-1)). Based on our findings, TNF-α and SGC activation in neuron-glial communication are critical in inflammatory visceral hyperalgesia.

Analgesic effect of minocycline in rat model of inflammation-induced visceral pain

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5min of administration, systemic injection of the drug produced a delayed effect (60min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia.

Changes in responses of neurons in spinal and medullary subnucleus reticularis dorsalis to acupoint stimulation in rats with visceral hyperalgesia.

The purpose of this study was to explore the mechanism of acupoints sensitization phenomenon at the spinal and medulla levels. Experiments were performed on adult male Sprague-Dawley rats and visceral noxious stimuli was generated by colorectal distension (CRD). The activities of wide dynamic range (WDR) and subnucleus reticularis dorsalis (SRD) neurons were recorded. The changes of the reactions of WDR and SRD neurons to electroacupuncture (EA) on acupoints of “Zusanli-Shangjuxu” before and after CRD stimulation were observed. The results showed that visceral nociception could facilitate the response of neurons to acupoints stimulation. In spinal dorsal horn, EA-induced activation of WDR neurons further increased to 106.84 ± 17.33% (1.5 mA) (P < 0.001) and 42.27 ± 13.10% (6 mA) (P < 0.01) compared to the neuronal responses before CRD. In medulla oblongata, EA-induced activation of SRD neurons further increased to 63.28 ± 15.96% (1.5 mA) (P < 0.001) and 25.02 ± 7.47% (6 mA) (P < 0.01) compared to that before CRD. Taken together, these data suggest that the viscerosomatic convergence-facilitation effect of WDR and SRD neurons may underlie the mechanism of acupoints sensitization. But the sensitizing effect of visceral nociception on WDR neurons is stronger than that on SRD neurons.

Nonorganic pain and visceral hyperalgesia in childhood

Visceral pain is different from the somatic one: visceral receptors have different functional engagement, the nociception degree differ from one organ to another, the few visceral afferent fibers are predominantly unmyelinated and have an extensive divergence in the central nervous system; the responses involve autonomic activation. The matrix of abdominal visceral pain, functional at birth, is overburdened by mechanical, chemical, osmotic impulses; overlapping infections or inflammation, by the released mediators create the conditions for acquiring the peripheral and central “sensibility” and the “pain memory”; behavioral and emotional factors can aggravate the visceral pain matrix hyperreactivity. In this pathogenic context it defines nonorganic pain and its severe form, visceral hyperalgesia. Genetic peculiarities influence the pain sensitivity. Based on the biopsychosocial model of functional disorders, Rome III criteria tagged the abdominal functional pain and the irritable bowel syndrome as a positive diagnosis and not a diagnosis of exclusion. Nonorganic pain, often associated with recurrent abdominal pain is among the most common medical problems encountered in pediatrics. Most patients with mild pain have a good evolution over time; a small percentage present serious and sometimes disabling symptoms. Pediatricians frequently have difficulties in delineation the diagnosis of nonorganic pain and that, sometimes, involves treatment failure. The authors present the epidemiological data, the pathophysiological mechanisms involved, the clinical approach and the therapeutic options on nonorganic pain and visceral hyperalgesia in children.

Rifaximin Alters Intestinal Bacteria and Prevents Stress-Induced Gut Inflammation and Visceral Hyperalgesia in Rats

Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress.

The inhibitory effect of tongxieyaofang on rats with post infectious irritable bowel syndrome through regulating colonic par-2 receptor

BackgroundThe aims of this study were to evaluate the effect and mechanism of a traditional Chinese medicine formula: Tongxieyaofang (TXYF) on Rats with Post Infectious Irritable Bowel Syndrome (PI-IBS).MethodsSD male rats in adult were used to model PI-IBS and treated with TXYF at three dosage for 14 consecutive days, and then visceral sensation and the frequency of stool in PI-IBS rats were investigated. In addition, the contents of SP, TNF- α and IL-6 in colonic mucosal were analyzed by ELISA. Moreover faecal serine protease activity and PAR-2 mRNA expression were measured by ultraviolet spectrophotometry and RT-PCR, respectively.ResultsOur study showed that TXYF attenuated visceral hyperalgesia and inhibited stool frequency in Campylobacter-stimulated Post Infectious Irritable Bowel Syndrome (PI-IBS) rats. Furthermore, TXYF decreased the colonic SP, TNF- α and IL-6 content in PI-IBS rats. In addition, the up-regulated colonic mucosa PAR-2 mRNA expression in PI-IBS rats was significantly suppressed by orally TXYF.ConclusionsTXYF attenuated PI-IBS symptom by attenuating behavioral hyperalgesia and anti-diarrhea, the underlying mechanism was mediated by inhibiting PAR-2 receptor expression, reducing the levels of SP, TNF- α and IL-6 in colonic mucosa and decreasing faecal serine protease activity.

Abnormal dendritic cells mediated immune response in a rat model of visceral hypersensitivity

To explore the role of altered characteristics of intestinal dendritic cell (DC) in the induction of visceral hyperalgesia through the activation of mast cells in a rat model of irritable bowel syndrome (IBS). A total of 20 Sprague-Dawley rats were divided into modeling and control groups (n = 10 each). The IBS rat model was established by combining colorectal distention with restraint stress. Abdominal withdrawal reflex (AWR) was employed to evaluate visceral sensitivity. The surface marker of intestinal DC was analyzed by immunohistochemistry. Toluidine blue staining was used to determine the number of mast cells (MC). The expressions of interleukin (IL) -4 and IL-9 in colonic mucosa were measured by enzyme-linked immunosorbent assay (ELISA) and the level of proteinase-activated receptor-2 (PAR-2) was measured by Western blot. Mesenteric lymph node (MLN) DC and splenic CD4(+)/CD8(+)T cells were isolated and purified by magnetic label-based technique. Cytokine production of MLN DC co-culturing with CD4(+) or CD8(+)T cells was determined. The number of colonic MC in modeling group was more than that in control group ((2.73 ± 0.21) vs (1.13 ± 0.10), P = 0.000). The expressions of PAR-2, IL-4 and IL-9 in colonic mucosa were all higher than those in control group (2.13 ± 0.81 vs 0.42 ± 0.29, (7.2 ± 1.2) vs (3.3 ± 1.0) pg/ml, (7.3 ± 1.3) vs (5.2 ± 0.6) pg/ml, P = 0.026, 0.000, 0.001). Co-cultured MLN DC with CD4(+) T cells showed a predominant IL-4 secretion in the modeling group ((1.22 ± 0.33) vs (0.80 ± 0.48) pg/ml, P = 0.000). Increased colonic DC may stimulate CD4(+) T cells to secrete a high level of IL-4 to cause the degranulation of mast cells and the generation of visceral hypersensitivity in IBS rats.

59. Afferent immune-to-brain communication in human pain: A brain imaging study on experimental endotoxemia in a visceral pain model

We previously showed that experimentally-induced endotoxemia leads to visceral hyperalgesia in healthy males (Benson et al., Pain 2012;153(4):794–9). However, it remains unclear whether and to what extent these effects are mirrored by altered pain processing within the brain. Hence, we designed a follow-up study to analyze behavioral and neural responses to visceral stimuli using functional magnetic resonance imaging (fMRI) and present preliminary analyses herein. Implementing a randomized, placebo-controlled design, healthy males received an intravenous injection of either lipopolysaccharide (LPS group; 0.4 ng/kg) or saline (control group). Visceral sensory and pain thresholds were assessed using pressure-controlled rectal distensions at baseline (prior to injection) and 3 h post injection. Additionally, subjective painfulness of rectal stimuli delivered during scanning was evaluated online using visual analogue scales. Blood samples were collected before and up to 6 h post injection to characterize changes in relevant immune parameters. LPS administration expectedly led to increases in circulating TNF-alpha, IL-6, and body temperature (all p

Exercise-mediated improvements in painful neuropathy associated with prediabetes in mice

Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. Exercise reduced but did not restore these metabolic abnormalities to normal levels. In addition, mice fed a high-fat diet developed significant cutaneous and visceral hyperalgesia, similar to mice that develop neuropathy associated with diabetes. Finally, a high-fat diet significantly modulated neurotrophin protein expression in peripheral tissues and altered the composition of epidermal innervation. Over time, mice that exercised normalized with regards to their behavioral hypersensitivity, neurotrophin levels, and epidermal innervation. These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients who will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification.

Curcumin acts via transient receptor potential vanilloid‐1 receptors to inhibit gut nociception and reverses visceral hyperalgesia

An antinociceptive effect has been reported for curcumin in animal models and in humans, but the molecular mechanisms of curcumin's effect remain undefined. In this study, we explored the possibility that curcumin inhibit visceral nociception via antagonizing the transient receptor potential vanilloid-1 (TRPV1) receptor. The effects of curcumin were explored using two experimental models: viscero-motor response (VMR) to colorectal distension (CRD) in rats and jejunal afferent firing in the ex vivo mouse jejunum preparations [TRPV1 knockout (KO) and wild-type mice, naive and trinitrobenzene sulfonic acid (TNBS)-treated Kunming mice]. In addition, capsaicin-induced calcium transients and whole-cell currents were examined in acutely dissociated dorsal root ganglia (DRG) neurons. In the anesthetized rat, curcumin (4mgkg(-1) min(-1) for 3min) caused a marked and rapidly reversible inhibition of CRD-induced VMRs. In the mouse jejunum, the mesenteric afferent nerve response to ramp distension was attenuated by curcumin (3, 10μmolL(-1) ), an effect that was significantly reduced in TRPV1 KO mice compared with wild-type (WT) controls. Moreover, in WT mice, curcumin (1-30μmolL(-1) ) was found to inhibit the afferent responses to capsaicin in a concentration-dependent manner. Trinitrobenzene sulfonic acid-induced hypersensitivity of jejunal afferents was also attenuated by curcumin. Curcumin potently inhibited capsaicin-induced rise in intracellular calcium and inward currents in mouse or rat DRG neurons. Our results provide strong evidence that curcumin inhibit visceral nociception via antagonizing TRPV1 and may be a promising lead for the treatment of functional gastrointestinal diseases.

Su2097 Conditioning and Extinction Learning of Visceral Pain in Healthy Subjects - An FMRI Study

Background: The mechanism(s) mediating the higher prevalence of chronic abdominal pain and IBS in women remain incompletely understood. Although the importance of central mechanisms is increasingly acknowledged, sex differences in associative learning andmemory processes have thus far not been studied in the context of visceral pain. Fear conditioning is an established experimental model to investigate learning and memory processes relevant for the pathophysiology and/or treatment of conditions including anxiety disorders, chronic back pain and fibromyalgia. Fear conditioning appears particularly well-suited also in the context of visceral hyperalgesia and IBS given the well-documented overlap between IBS (and other somatization disorders) with pre-clinical as well as clinical anxiety. We recently implemented the first fear conditioning study with painful rectal distensions as US in healthy subjects (Kattoor et al., PLOS ONE, in press). Herein, we present results from an extension of this study testing sex differences in the behavioral and neural processes mediating aversive visceral learning, extinction and the recovery of fear, i.e., reinstatement. Methods: In BMImatched healthy males and females (N = 15 males, 15 females), visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS-) were presented without US (differential delay conditioning). During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, males and females were compared with respect to conditioned anticipatory neural activation (CS+ . CS-) along with perceived CS-US contingency, CS unpleasantness and salivary cortisol. Results: Pain ratings and distension-induced neural activationwere comparable betweenmales and females. Similarly, no sex differences were observed in perceived CS-US contingency, CS+ valence ratings or cortisol. However, in the late acquisition phase, presentation of the CS+ led to significantly greater anticipatory activation of the insular cortex in women. During extinction, women demonstrated reduced anticipatory activation of the posterior cingulate cortex compared to males. During reinstatement, the CS+ led to significantly greater activation of the hippocampus, thalamus and cerebellum in women. Conclusions: This is the first study to support differences between males and females in the neural processes of aversive visceral learning and memory. Our finding of enhanced neural responses in key brain areas for memory, especially in hippocampus, suggest enhanced reactivation of the old fear memory trace in women. This could play a role in the female preponderance of chronic abdominal pain and irritable bowel syndrome.

Su2098 Positive and Negative Mood Modulate Esophageal Pain Perception in Health

Background: The mechanism(s) mediating the higher prevalence of chronic abdominal pain and IBS in women remain incompletely understood. Although the importance of central mechanisms is increasingly acknowledged, sex differences in associative learning andmemory processes have thus far not been studied in the context of visceral pain. Fear conditioning is an established experimental model to investigate learning and memory processes relevant for the pathophysiology and/or treatment of conditions including anxiety disorders, chronic back pain and fibromyalgia. Fear conditioning appears particularly well-suited also in the context of visceral hyperalgesia and IBS given the well-documented overlap between IBS (and other somatization disorders) with pre-clinical as well as clinical anxiety. We recently implemented the first fear conditioning study with painful rectal distensions as US in healthy subjects (Kattoor et al., PLOS ONE, in press). Herein, we present results from an extension of this study testing sex differences in the behavioral and neural processes mediating aversive visceral learning, extinction and the recovery of fear, i.e., reinstatement. Methods: In BMImatched healthy males and females (N = 15 males, 15 females), visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS-) were presented without US (differential delay conditioning). During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, males and females were compared with respect to conditioned anticipatory neural activation (CS+ . CS-) along with perceived CS-US contingency, CS unpleasantness and salivary cortisol. Results: Pain ratings and distension-induced neural activationwere comparable betweenmales and females. Similarly, no sex differences were observed in perceived CS-US contingency, CS+ valence ratings or cortisol. However, in the late acquisition phase, presentation of the CS+ led to significantly greater anticipatory activation of the insular cortex in women. During extinction, women demonstrated reduced anticipatory activation of the posterior cingulate cortex compared to males. During reinstatement, the CS+ led to significantly greater activation of the hippocampus, thalamus and cerebellum in women. Conclusions: This is the first study to support differences between males and females in the neural processes of aversive visceral learning and memory. Our finding of enhanced neural responses in key brain areas for memory, especially in hippocampus, suggest enhanced reactivation of the old fear memory trace in women. This could play a role in the female preponderance of chronic abdominal pain and irritable bowel syndrome.

Su2096 Towards a Better Understanding of Learning and Memory Processes in Abdominal Pain: Evidence of Enhanced Reactivation of Classically-Conditioned Fear Memories in Healthy Women Compared to Males

Background: The mechanism(s) mediating the higher prevalence of chronic abdominal pain and IBS in women remain incompletely understood. Although the importance of central mechanisms is increasingly acknowledged, sex differences in associative learning andmemory processes have thus far not been studied in the context of visceral pain. Fear conditioning is an established experimental model to investigate learning and memory processes relevant for the pathophysiology and/or treatment of conditions including anxiety disorders, chronic back pain and fibromyalgia. Fear conditioning appears particularly well-suited also in the context of visceral hyperalgesia and IBS given the well-documented overlap between IBS (and other somatization disorders) with pre-clinical as well as clinical anxiety. We recently implemented the first fear conditioning study with painful rectal distensions as US in healthy subjects (Kattoor et al., PLOS ONE, in press). Herein, we present results from an extension of this study testing sex differences in the behavioral and neural processes mediating aversive visceral learning, extinction and the recovery of fear, i.e., reinstatement. Methods: In BMImatched healthy males and females (N = 15 males, 15 females), visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS-) were presented without US (differential delay conditioning). During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, males and females were compared with respect to conditioned anticipatory neural activation (CS+ . CS-) along with perceived CS-US contingency, CS unpleasantness and salivary cortisol. Results: Pain ratings and distension-induced neural activationwere comparable betweenmales and females. Similarly, no sex differences were observed in perceived CS-US contingency, CS+ valence ratings or cortisol. However, in the late acquisition phase, presentation of the CS+ led to significantly greater anticipatory activation of the insular cortex in women. During extinction, women demonstrated reduced anticipatory activation of the posterior cingulate cortex compared to males. During reinstatement, the CS+ led to significantly greater activation of the hippocampus, thalamus and cerebellum in women. Conclusions: This is the first study to support differences between males and females in the neural processes of aversive visceral learning and memory. Our finding of enhanced neural responses in key brain areas for memory, especially in hippocampus, suggest enhanced reactivation of the old fear memory trace in women. This could play a role in the female preponderance of chronic abdominal pain and irritable bowel syndrome.

742 Chronic Stress-Induced Visceral Hyperalgesia: Molecular Evidence for Corticosterone (CORT)-Mediated Reduction in Cannabinoid Receptor Type 1 (CB1) via Functional Glucocorticoid Response Element (Gre) on CB1 Promoter in an Epigenetic Manner

742 Chronic Stress-Induced Visceral Hyperalgesia: Molecular Evidence for Corticosterone (CORT)-Mediated Reduction in Cannabinoid Receptor Type 1 (CB1) via Functional Glucocorticoid Response Element (Gre) on CB1 Promoter in an Epigenetic Manner

Alterations in Prefrontal-Limbic Functional Activation and Connectivity in Chronic Stress-Induced Visceral Hyperalgesia

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([14C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH.

Introducing our Associates

We are writing to you with one calendar year under our belt as the editors of Neurogastroenterology and Motility, and we are pleased to report the journal is strong, and it is an increasingly popular target journal for investigators in our field. In 2012, we handled 439 manuscripts, which is a robust 17% increase over the 2011 submissions, and represents a 50% increase in manuscript submissions in just 5 years. The impact factor continues to trend upward. It is currently 3.414, up from 3.349 the year before. This is noteworthy development because the number of articles published in the journal was increased in 2010 at the risk of a negative effect on the impact factor. To maintain the quality of the publications while continuing to publish our articles with a short lag time, the rejection rate has increased from roughly 41% to 47% of the submitted manuscripts. The average time between submission and publication is 8 weeks with accelerated time lines for clinical trials. The successful operation of our journal is highly dependent on the magnanimous services of our peer reviewers. In 2012, 364 members of the Neurogastroenterology and Motility community donated their time and expertise by participating in the rigorous review process and suggesting areas of improvement for the authors to strengthen and revise the manuscript that we accepted for publication. We thank all of you who have provided these services, and we would like to call special attention to the following 12 individuals who reviewed the most manuscripts, and did so with an average turnaround time of 11.4 days: Pieter Janssen, Pere Clave, Mark Fox, Sabine Roman, Michael Camilleri, Albert Bredenoord, Shin Fukudo, Purna Kashyap, David Linden, Bridget Southwell, Yvette Taché, and Heather Young. In an effort to further increase the service we provide to authors and deal with the increased workload that has accompanied the increase in manuscript submissions, we have added two Associate Editor positions to the editorial board structure. We are pleased to announce that Drs. Sylvie Bradesi (Basic Science) and Arjan J. Bredenoord (Clinical) are the two new Associate Editors. Dr Bradesi received her PhD in Biological Sciences at the Paul Sabatier University in Toulouse, France and pursued her postdoctoral training in Gastroenterology and Physiopathology of Visceral Pain under the mentorship of Dr Emeran Mayer at the Center for Neurovisceral Sciences and Women's Health at UCLA, Los Angeles. She is now at the Center for Neurobiology of Stress at UCLA, School of Medicine, Division of Digestive Diseases. She has developed a research program with a strong interest in the development of animal models for functional bowel disorders, investigating the physiopathology of visceral hyperalgesia and the functional role of CNS glial cells in pain facilitation and increased stress responsiveness. Albert J. (Arjan) Bredenoord graduated in Medicine at Antwerp University, Medicine at Antwerp University, Belgium where he performed translational studies of gastrointestinal motility. He subsequently worked on several clinical research GI motility projects at the Mayo Clinic, Rochester, USA, and at the University of Utrecht, the Netherlands, for which he earned a PhD. His clinical training was performed in Nieuwegein, the Netherlands, and at the Royal London Hospital in London, UK. He currently works at the Amsterdam Medical Center where he is dedicated to patients care, scientific research, and education. His primary expertise is on gastrointestinal motility of the esophagus. Another important announcement is that the journal is going entirely electronic as of January, 2014. Reprints of individual articles will be available but hard copies will no longer be published. The percentage of authors who ask for their article to be published in the hard copy version of the journal has decreased significantly in the past 2 years making the article version no longer a true representation of what Neurogastrenterology and Motility has to offer. In preparation for this transition, we encourage anyone who has not done so to register to receive the electronic Table of Contents via email. To do so, you will have to register for the Wiley Online Library and indicate that you wish to receive the Table of Contents for our journal. You can do this from the journal website. In conclusion, we thank you for your societies' support of the journal and look forward to another banner year for the journal.

Effect of food allergy early in life on visceral hyperalgesia in the developing rats and role of substance P abnormal expression in colon

To explore the effect of food allergy (FA) on the development of visceralgia sensibility and the substance P (SP) expression in colon of developing rats with FA. Three-week old female Sprague-Dawley (SD) rats were randomly divided into two groups (n = 10 in each). The rats in FA group were sensitized with ovalbumin (OVA) 40 µg and Al(OH)3 1 mg suspension solution (0.2 ml) intraperitoneal (i.p.) injection on day 0, only OVA 40 µg solution i.p. on day 2, 4, 7, 9, 11, respectively, and the rats were challenged by gavage with OVA solution 30 mg (2 ml) on day 20, 24, 28, 30. The rats in non-sensitized (NS) group were not challenged except handled in the same ways. The serum OVA-IgE were determined by enzyme-linked immuno sorbent assay (ELISA) on day 0, 30. Jejunum segments were used to observe morphological structure, the expression of eosinophils, and the density and the percentage of degranulation of mast cells (MC). The rats were appraised for the pain sensibility of intestinal tract under colorectal distension irritation by the electrophysiological method on external oblique in the 18-24 hr after the last challenge. Colons were used to analyze the expression of SP through immunohistochemical staining and computer image analyzing system. The serum OVA-IgE concentration and the eosinophils, mast cell, the percentage of mast cells degranulation in FA group were more than NS group (P < 0.01). The amplitudes of spike external oblique muscle of abdomen (EOMA, µV) of the FA group under the colorectal distension (CRD) pressures at 0, 15, 30, 45, 60, 75 mm Hg were (17.74 ± 0.72), (18.63 ± 1.72), (22.55 ± 1.70), (28.63 ± 7.00), (33.97 ± 7.34), (37.26 ± 8.40), and (17.43 ± 1.18), (17.27 ± 1.16), (17.73 ± 1.42), (19.55 ± 3.54), (23.29 ± 5.46), (25.20 ± 4.75) in NS group. With the CRD pressure increased, the amplitudes of spike EOMA increased significantly. There were significant differences between groups under the CRD pressures at 30, 45, 60, 75 mm Hg (F = 47.470, 13.367, 13.317, 15.390, P < 0.01). The expressions of colons SP in FA group and NS group are 247.12 ± 90.83 and 103.90 ± 58.94, respectively (t = 4.183, P < 0.01). Sensitization through i.p. pathway and challenge by gavage with OVA in early life could result in FA in young SD rats. FA in early life enabled the amplitudes of spike EOMA and the expression of colons SP increase significantly. It may be related to increase in amount and degranulation of MC and SP abnormal expression in colon, which could lead to the development of visceralgia sensibility.

Neonatal colonic inflammation sensitizes voltage-gated Na+channels via upregulation of cystathionine β-synthetase expression in rat primary sensory neurons

The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood, and treatment remains difficult. We have previously reported that colon-specific dorsal root ganglion (DRG) neurons were hyperactive in a rat model of IBS induced by neonatal colonic inflammation (NCI). This study was designed to examine plasticity of voltage-gated Na(+) channel activities and roles for the endogenous hydrogen sulfide-producing enzyme cystathionine β-synthetase (CBS) in chronic visceral hyperalgesia. Abdominal withdrawal reflex (AWR) scores were recorded in response to graded colorectal distention in adult male rats as a measure of visceral hypersensitivity. Colon-specific DRG neurons were labeled with 1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate and acutely dissociated for measuring Na(+) channel currents. Western blot analysis was employed to detect changes in expressions of voltage-gated Na(+) (Na(V)) channel subtype 1.7, Na(V)1.8, and CBS. NCI significantly increased AWR scores when compared with age-matched controls. NCI also led to an ~2.5-fold increase in Na(+) current density in colon-specific DRG neurons. Furthermore, NCI dramatically enhanced expression of Na(V)1.7, Na(V)1.8, and CBS in colon-related DRGs. CBS was colocalized with Na(V)1.7 or -1.8 in colon-specific DRG neurons. Administration of O-(carboxymethyl)hydroxylamine hemihydrochloride (AOAA), an inhibitor for CBS, remarkably suppressed Na(+) current density and reduced expression of Na(V)1.7 and Na(V)1.8. More importantly, intraperitoneal or intrathecal application of AOAA attenuated AWR scores in NCI rats in a dose-dependent manner. These data suggest that NCI enhances Na(+) channel activity of colon DRG neurons, which is most likely mediated by upregulation of CBS expression, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.

Visceral pain: the importance of pain management services.

Visceral pain: the importance of pain management services.