Visceral Perception Research Articles

Corticotropin‐releasing hormone receptor 1 antagonist blocks colonic hypersensitivity induced by a combination of inflammation and repetitive colorectal distension

Gastroenteritis is one of the risk factors for developing irritable bowel syndrome (IBS). However, the precise mechanism of postinfectious IBS is still unknown. We tested the hypothesis that a combination of previous inflammation and repetitive colorectal distention (CRD) makes the colon hypersensitive and that treatment with a corticotropin-releasing hormone receptor 1 (CRH-R1) antagonist blocks this colonic hypersensitivity. Rats were pretreated with vehicle or 2,4,6-trinitrobenzene sulphonic acid (TNBS) 6 weeks before CRD. For the CRD experiment, the colorectum was distended once a day for six consecutive days. The CRH-R1 antagonist (CP-154,526, 20 mg kg(-1)) or vehicle was injected subcutaneously 30 min before CRD. Visceral perception was quantified as visceromotor response (VMR) using an electromyograph. For histological examination, the rats were killed on the last day of CRD experiment, and haematoxylin and eosin-staining of colon segments was performed. Although from the first to the third day of CRD, VMRs increased in both the vehicle-treated rats and TNBS-treated rats, they were significantly higher in TNBS-treated rats than those in vehicle-treated controls. On the fifth day of CRD, however, VMRs in the vehicle-treated rats were significantly greater than those in TNBS-treated rats. Pretreatment of rats with CP-154,526 significantly attenuated the increase in VMR induced by repetitive CRD with previous inflammation. Finally, we found that repetitive CRD and repetitive CRD after colitis induced visceral inflammation. These results indicate that a combination of previous inflammation and repetitive CRD induces visceral hypersensitivity and that a CRH-R1 antagonist attenuates this response in rats.

Novel techniques to study visceral hypersensitivity in irritable bowel syndrome

Visceral hypersensitivity has emerged as a key hypothesis in explaining the painful symptoms of irritable bowel syndrome (IBS), and it has been proposed as a "biologic marker" for the condition. Visceral hypersensitivity can be influenced by peripheral and central mechanisms affecting pain perception. The optimal method for its assessment in humans has not been determined. Current techniques include stimulation via the computerized barostat and electrical stimulation, response measures including the lower limb reflex, and brain imaging modalities such as functional MRI and positron emission tomography. It has been shown that IBS patients have decreased sensory thresholds to colonic and rectal balloon distention by barostat. Studies using electrical stimulation and the RIII lower limb reflex have further confirmed enhanced visceral perception in IBS. Evidence from more recent neuro-imaging studies suggests that IBS patients have abnormal activation of brain circuits involved in emotional and cognitive modulation of sensory information, resulting in ineffective pain modulation; these circuits may have a pathophysiologic role in enhancing visceral perception. There are few effective pharmacologic treatments that relieve IBS symptoms, and improved understanding of brain-gut interactions and factors relating to enhanced visceral perception may guide us in developing more efficacious treatments.

The d‐alanine content of lipoteichoic acid is crucial for Lactobacillus plantarum‐mediated protection from visceral pain perception in a rat colorectal distension model

The mechanisms leading to positive effects of probiotics in irritable bowel syndrome and inflammatory bowel disease have not been clarified, but the possible involvement of cell wall components is widely discussed. Reduction of the D-alanine content of lipoteichoic acid (LTA) in Lactobacillus plantarum (Dlt(-) mutant) enhanced its anti-inflammatory properties in a mouse colitis model. Another lactobacillus species inhibited visceral pain perception in response to colorectal distension (CRD) in rats. Therefore, we investigated if LTA modification influences the constitutive intestinal pain perception in addition to modulation of cytokine release. Male Sprague-Dawley rats were gavaged with L. plantarum, L. plantarum Dlt(-) mutant or buffer control, respectively and the responses to CRD were tested in this non-inflammatory model. Tumour necrosis factor (TNF), interferon (IFN)-gamma and interleukin (IL)-10 release were measured in colon tissue homogenates and upon anti-CD3/CD28 activation of isolated splenocytes and mesenteric lymphocytes. Control animals showed significant bradycardia following noxious CRD, whereas only the L. plantarum Dlt(-) mutant inhibited the response. The mutant also decreased the activation-induced release of TNF and IFN-gamma from mesenteric T cells and the IL-10 concentration in colonic tissue, while increasing the activation-induced secretion of IL-10 in splenocytes and mesenteric lymphocytes and the baseline IL-10 release of splenocytes. In conclusion, d-alanine depletion of LTA in L. plantarum inhibited visceral pain perception in healthy, non-inflamed rats. Regardless of the non-inflammatory nature of the model decreased visceral pain perception was seen in parallel with anti-inflammatory properties.

Intraganglionic laminar endings and esophageal visceral perception

Abnormal visceral perception participates in the occurrence of gastroesophageal reflux and is considered to be one important mechanisms in non-erosive reflux disease, functional heartburn and noncardiac chest pain. Generally, it is believed that vagal nerves take part in the regulation of esophageal physiology. Intraganglionic laminar ending (IGLE) is a special type of vagal afferent mechanoreceptors. This article reviews the characteristics of the IGLEs, including morphology, structure, distribution, and the mechanisms of esophageal visceral perception regulation.

The Effect of Auditory Stress on Perception of Intraesophageal Acid in Patients With Gastroesophageal Reflux Disease

Most patients with gastroesophageal reflux disease (GERD) report that stress exacerbates their symptoms, yet mechanisms underlying this association remain unknown. We sought to determine the effect of an acute laboratory stressor on perceptual and emotional responses to intraesophageal acid perfusion in healthy controls and patients with GERD. Forty-six patients with heartburn and 10 healthy controls underwent upper endoscopy and, if negative, pH monitoring. Assessment of psychologic factors and health-related quality of life was done by a questionnaire. Perceptual and emotional responses to intraesophageal acid at baseline, during auditory stress, and during an auditory control condition were determined using a randomized crossover design. Plasma levels of norepinephrine, adrenocorticotropic hormone, and cortisol were assessed. Twenty-nine subjects were identified as nonerosive reflux disease and 17 as erosive esophagitis. Quality of life, psychologic profile, and personality assessment variables were similar among the 2 patient groups and the controls. There was a significant reduction in mean lag time to initial symptom perception and an increase in mean intensity rating and mean acid perfusion sensitivity score in the 2 patient groups during the stress period, which was not seen during the control condition. Healthy controls demonstrated lack of a significant change in all parameters of stimulus response functions to acid, regardless of condition. Acute auditory stress can exacerbate heartburn symptoms in GERD patients by enhancing perceptual response to intraesophageal acid exposure. This greater perceptual response is associated with greater emotional responses to the stressor.

Translating symptoms into mechanisms: functional GI disorders

Functional gastrointestinal disorders are the most common problem in gastroenterological practice. They are defined by chronic abdominal symptom complexes that occur in the absence of underlying structural abnormalities. The pathogenesis of these disorders is heterogeneous and involves behavioral, infective, and inflammatory components. Common symptoms are abdominal pain, diarrhea, constipation, and bloating. Mechanisms underlying these symptoms include alterations in gastrointestinal motility, visceral perception, altered epithelial function, and disturbances in fermentation activity by gut commensal bacteria.

Role of histaminergic neurons in hypnotic modulation of brain processing of visceral perception

Modulating visceral sensation of the body is important to the understanding of emotion formation. Molecules that act during hypnosis and modify visceral pain perception are not known. We tested our hypothesis that hypnotic suggestion changes electrophysiological processing of visceroafferent signals in the human brain and that these conditions are in part dependent on histaminergic neurons. Twelve healthy male subjects were studied on two separate days: a day of treatment with histamine H1 receptor antagonist (d-chlorpheniramine 100 microg kg(-1), intravenously) and another day of that with placebo (saline, the same amount) in a randomized order. We recorded cortical evoked potentials to 100 rectal electrical stimuli after neutral, hyperalgesic or analgesic hypnotic suggestions as given to modulate the visceral perception. Analgesic suggestion reduced the amplitude of the deepest positive peak of viscerosensory evoked potential. Administration of histamine H1 antagonist diminished the attenuation of viscerosensory evoked potential by analgesic suggestion. Our results suggest that central pain modulatory system in the brain is activated by hypnotic suggestion and that brain histamine is a mediator in the hypnotic modulation of visceral sensory pathway as well as in the control of consciousness level. These findings lead us to possible new treatment for control of visceral perception.

Neurochemical bases of visceral nociception: Mathematical model

A mathematical model of visceral perception was constructed, comprising primary sensory, motor, intestinofugal and principal neurons, interstitial cells of Cajal and smooth muscle elements that are arranged in a functional circuit through chemical synapses. The mathematical description of constructive elements was based on detailed morphological, anatomical, electrophysiological and neuropharmacological characteristics of cells and chemical processes of electrochemical coupling. Emphasis was given to signal transduction mechanisms that involved multiple neurotransmitters and receptor polymodality. The role of co-transmission by acetylcholine (ACh), serotonin (5-HT), noradrenalin (NA), N-methyl- d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and their corresponding receptors—muscarinic and nicotinic type ACh receptors, β-adrenoceptors, 5-HT 3/4 type serotonergic receptors, NMDA and AMPA receptors in pathogenesis of nociception was studied numerically. Results of computer simulations reproduced patterns of electrical activity of neurons and mechanical responses of the smooth muscle similar to those observed in in vivo and in vitro experiments when ACh, 5-HT, NA, NMDA and AMPA were acting either alone or co-jointly. The results provide neurochemical bases for explanation of pathophysiological mechanisms of visceral nociception, which cannot be elucidated by existing experimental methods. Care should be taken though when extrapolating the numerical results onto the actual system because of limiting assumptions of the model.

Increased visceral sensitivity to capsaicin after DSS-induced colitis in mice: spinal cord c-Fos expression and behavior

During acute and chronic inflammation visceral pain perception is altered. Conflicting data exist, however, on visceral pain perception in the postinflammatory phase. The aim of the present study was to investigate whether visceral pain perception is altered after resolution of dextran sodium sulfate (DSS)-induced inflammation of the colon. Visceral sensory function in mice was assessed by monitoring behavioral responses to intracolonic capsaicin instillation. Two hours later the number of c-Fos-positive neurons in lamina I/II and X of spinal cord segments T(12/13)-S1 was determined as a measure of neuronal activation. DSS colitis was induced by adding 1% of DSS to the drinking water. The course of DSS-induced colitis was assessed by determining the disease activity index score. Animals developed a transient colitis and had recovered at day 49. At this time point, cytokine levels and colon length were similar to control animals. Importantly, after resolution of DSS-induced colitis the behavioral response to intracolonic capsaicin was increased compared with control mice. Moreover, capsaicin-induced spinal cord neuronal c-Fos expression was significantly increased. Interestingly, after colitis animals also exhibited referred somatic hyperalgesia as measured with von Frey hairs on the abdominal wall. We conclude that postinflammatory visceral hyperalgesia occurs after resolution of DSS-induced colitis and that capsaicin-induced behavioral responses and spinal cord neuronal c-Fos activation are effective readouts for determination of visceral pain perception.

Altered Rectal Perception in Irritable Bowel Syndrome Is Associated With Symptom Severity

Diverging results exist regarding the connection between altered visceral perception and gastrointestinal (GI) symptoms, as well as the effects of psychological status on visceral sensitivity. We sought to investigate different aspects of rectal perception in irritable bowel syndrome (IBS) and the association with GI and psychological symptoms. We included 109 patients with IBS meeting Rome II criteria (77 women; age range, 20-71 years) and 29 healthy controls (21 women; age range, 20-68 years). They underwent rectal balloon distentions determining sensory thresholds for discomfort and pain, the perceived intensity of unpleasantness, and the viscerosomatic referral area. The fifth percentile (thresholds) and 95th percentile (unpleasantness and referral area) in controls were used to define altered perception. Questionnaires were used to assess severity of IBS-related GI symptoms and psychological symptoms. When combining the 3 aspects of perception, 67 patients (61%) had altered rectal perception. These patients, compared with normosensitive patients, more frequently reported moderate or severe pain (73% vs 44%; P < .01), bloating (73% vs 36%; P < .0001), diarrhea (47% vs 21%; P < .01), satiety (39% vs 13%; P < .01), and clinically significant anxiety (31% vs 12%; P < .05). In a multivariate analysis, only pain and bloating remained associated with altered rectal perception. Altered rectal perception is common in IBS and seems to be one important pathophysiologic factor associated with GI symptom severity in general and pain and bloating in particular. It is not just a reflection of the psychological state of the patient.

Effect of long‐term treatment with octreotide on rectal sensitivity in patients with non‐constipated irritable bowel syndrome

Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. Forty-six non-constipated irritable bowel syndrome patients (52% female, 19-63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms.

Corticotropin‐releasing factor receptor 1‐deficient mice show decreased anxiety and colonic sensitivity

Corticotropin releasing factor (CRF) is an important mediator in the stress response. Previous studies in rodent models demonstrated that stress-induced colonic hypersensitivity was inhibited by CRF1 receptor antagonism. As CRF(1)R-deficient mice have (+/+), CRF(1)R (+/-) and CRF(1)R (-/-) mice colonic sensitivity was assessed via a visceromotor behavioural response (VMR) induced by colorectal distension (CRD, 0-60 mmHg). In the CRF(1)R (+/+) mice there was a pressure-dependent increase in the VMR to CRD that was moderately attenuated in the CRF1R (+/-) mice. However in the CRF(1)R (-/-) mice a VMR to CRD was only observed at the highest distension pressure (60 mmHg). A CRF(1)R antagonist, NBI 30775 (30 mg kg(-1) i.p.) significantly decreased the VMR to CRD in CRF(1)R +/+ mice. An identical inhibitory effect of NBI 30775 was observed in 43% of the CRF(1)R +/- mice. This study provides pharmacological and genetic evidence for the importance of CRF(1)R in colonic sensitivity and suggests a link between stress and visceral perception.

Induction of mu opioid and cannabinoid receptors by probiotics: A new mechanism of regulation of visceral pain perception

Induction of mu opioid and cannabinoid receptors by probiotics: A new mechanism of regulation of visceral pain perception

Is it possible to generate cerebral evoked potentials with a mechanical stimulus from the duodenum in rats?

The study aim was to develop a model to generate cerebral evoked potentials (CEPs) by mechanical distention of the duodenum in rats. Twenty Sprague–Dawley rats were anaesthetized and the EEG recorded from the left and right somatosensory cortices (S1L, S1R). A balloon catheter was implanted into the duodenum. A pneumatic device, triggered by data acquisition software, inflated the balloon for 200ms every 3s to deliver a repeatable noxious stimulus. EEG was recorded for 100ms before and 500ms after onset of inflation and the response to 512 stimuli averaged to generate a CEP. Two CEPs were generated in each animal and data summed to calculate a single CEP for each channel.Data were excluded when the signal to noise ratio was <2, therefore data are presented from 11 animals. A repeatable CEP was identified in waveforms recorded from S1L. The mean (S.D.) CEP comprised a triphasic waveform (P1, N1, P2) with latencies of 246.0 (24.7), 289.3 (12.8) and 321.5 (13.2)ms, respectively. We are the first group to have generated and characterized a CEP following mechanical stimulation of the duodenum. This model can be applied to further elucidate the mechanisms leading to visceral pain perception.

Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation

Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress. We first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients. We then administered alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by alphahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing. Several studies have identified immunoreactive CRH and urocortin as well as CRH-R1 and CRH-R2 mRNAs in human colonic mucosa. In addition, reverse transcription-polymerase chain reaction has revealed the expression of CRH-R1 mRNA in both the myenteric and submucosal plexus in the guinea pig. Application of CRH has been shown to evoke depolarizing responses associated with elevated excitability in both myenteric and submucosal neurons. On the other hand, peripheral injection of CRH has been reported to induce discrete effects on colonic secretory and motor function, and permeability. There are functional differences between CRH-R1 and CRH-R2. For instance, activation of CRH-R1 causes a proinflammatory response, whereas stimulation of CRH-R2 provokes anti-inflammatory changes. In addition, there is evidence of the contrasting roles of CRH-R1 and CRH-R2 in visceral nociception. While CRH-R1 is involved in the pro-nociceptive effects of visceral pain, CRH-R2 mediates an anti-nociceptive response. These findings suggest the major role of CRH in stress-related pathophysiology of IBS and possibly in inflammation of the intestinal mucosa.

Introduction to the Proceedings of the 2nd International Symposium on Visceral Perception in Gastroenterology

Neurogastroenterology & MotilityVolume 19, Issue s1 p. iv-iv Introduction to the Proceedings of the 2nd International Symposium on Visceral Perception in Gastroenterology Michael Fried, Michael FriedSearch for more papers by this authorMichael Camilleri, Michael CamilleriSearch for more papers by this authorJan Tack, Jan TackSearch for more papers by this authorMonika A. Kwiatek, Monika A. KwiatekSearch for more papers by this author Michael Fried, Michael FriedSearch for more papers by this authorMichael Camilleri, Michael CamilleriSearch for more papers by this authorJan Tack, Jan TackSearch for more papers by this authorMonika A. Kwiatek, Monika A. KwiatekSearch for more papers by this author First published: 03 January 2007 https://doi.org/10.1111/j.1365-2982.2006.00897.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume19, Issues1January 2007Pages iv-iv RelatedInformation

For distinguished contributions to psychophysiology: Robert M. Stern

Robert “Bob” Stern received the Distinguished Scientific Contribution to Psychophysiology award in 2004 for his scientific achievements in psychophysiology of visceral, particularly gastrointestinal, psychophysiology. The Society for Psychophysiological Research honors a pioneer whose contributions paved the way for the development of Behavioral Medicine and Social Cognitive Psychophysiology. Robert Stern's textbooks educated and inspired countless students worldwide for psychophysiology and shaped a positive and critical attitude of the public toward our discipline. Bob was born and raised in the Bronx in the “shadow of the Yankee-Stadium.” He describes his childhood often as “unremarkable,” hiding the information on the warm and loving atmosphere of the family environment. In this caring and altruistic–empathic climate a person grew who, later in adult life, reciprocated that attitude to all around him. As Department Head and head of countless Minority Committees his tolerant and open personality won him the sympathy of all around. At Franklin & Marshall College in Lancaster, Pennsylvania, he earned a degree in philosophy, instigating his lifelong interest in the mind–body problem and social–ethical problems of science. After an “intermezzo” at Tufts University, he met his mentor, R.C. Davis, at Indiana University, whose work on the electrogastrogram left him “imprinted” on the psychophysiology of the gastrointestinal tract and its function and its pathology in nausea, eating disorders, and motion sickness. Most of his 100 publications from then on (the mid-1960s) were devoted to the topic of gastric motility and responsiveness. But in his early career as a young scientist at Penn State University, he wrote brilliant essays on “sociopsychophysiology,” detection of deception, and he conducted the first critical experiments on operant conditioning (“biofeedback”) of skin conductance. The mechanisms behind visceral perception and its implication for somatic and psychosomatic diseases then became a major focus of his research. This work remained one of the founding pillars of behavioral medicine. A lifelong mutual friendship with the European “father” of visceroception, Gyorgi Adam of the Hungarian Academy of Science in Budapest, brought Bob's ideas and writings to the old continent and had a lasting influence on the rapid growth of European psychophysiology. Several awards from European and U.S. funding agencies for scholarships abroad intensified Bob's international reputation. As a visiting professor at several German Universities (Mainz, Tübingen, Vienna), he contributed substantially to the amazing recovery of biological psychology in Germany after its destruction by Nazi rule. The book Psychophysiological Recording (first edition with W. Ray and R.C. Davis, second edition with Bill Ray and Karen Quigley) and his teaching at Penn State and abroad set the standards for scholarly education of psychophysiology until today. After decades of careful experimentation with electrogastrographic (EGG) recordings using—among other methods—a rotating drum developed by the famous perception researcher and friend at Penn State, Herschel Leibowitz, Bob came to the conclusion that motion sickness and sensitivity to nausea have a genetic and a learned component. He tested numerous treatment approaches for nausea induced by motion sickness. He favors a habituation–desensitization approach and thoroughly tested it in the controlled laboratory, a tantalizing task combining the huge rotating drum environment with the delicate measurement of gastric activity. Robert Stern has been an active member of our society for more than 40 years, serving on the board and several committees, and is a brilliant scientist and an adviser on ethical and social–political issues. Bob recently retired, but he maintains his office at Penn State, where, with two colleagues, he is writing a book on the mechanisms and management of nausea. He spends his winters as a visiting professor in the GI division of the Wake Forest University Medical School in Winston-Salem, North Carolina. Scientists of his stature and with a broad view of our place in society and culture constitute a model mentor for students and scholars of psychophysiology.

Contribution of sensitivity, volume and tone to visceral perception in the upper gastrointestinal tract in man: emphasis on testing

Upper gastrointestinal (GI) symptoms occur frequently in the general population, making them among the most common indications responsible for patients consulting the healthcare system. Consequently, understanding and characterization of the upper GI symptoms is important for the diagnosis and assessment of organ dysfunction. In practice, assessment of clinical symptoms is difficult and it is still to a large extent unclear how sensitivity, volume and tone contribute to visceral perception in the upper GI tract. The goal of advanced research in upper GI symptoms is to obtain a better understanding of the mechanisms involved in transduction, transmission, and perception under normal and pathophysiological conditions. An important step towards this goal is understanding the information provided by and the inherent limitations of the currently available measuring techniques. This article focuses on the sensory testing of the oesophagus, and methods and concepts used to assess the relation between gastric volumes or tone and upper GI symptoms. It also summarizes the contributions of these techniques towards identifying the components responsible for the generation of upper GI symptoms.

Role of histaminergic neurons in cognitive control of hypersensitive visceral perception

Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer’s disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3β) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3β phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3β phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3β intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals.

Somatic Referral of Visceral Sensations and Rectal Sensory Threshold for Pain in Children with Functional Gastrointestinal Disorders

To test the hypothesis that abdominal pain related to functional gastrointestinal disorders is associated with visceral hypersensitivity and abnormal perception of visceral sensations. We examined 35 children (10-17.6 years old) fulfilling the Rome II criteria with irritable bowel syndrome (IBS; n = 21), functional abdominal pain (FAP; n = 8) or functional dyspepsia (FD; n = 6) compared with 10 control subjects (10.2-16.1 years). All underwent a rectal barostat examination. Painful sensations were reported on a human body diagram. The projections of sensations induced by rectal distension, the rectal sensory threshold for pain (RSTP) and the diagnostic value of RSTP measurements were measured. Rectal distension induced sensations that projected to the S3 dermatome in the control subjects and FD and to aberrant sites in children with IBS and FAP. The RSTP was decreased in children with IBS and FAP compared with control subjects (P <.002) and was not different in children with FD compared with control subjects. At 30.8 mm Hg, the 5th percentile for the control subjects, the RSTP had a sensitivity rate of 89% and a specificity rate of 83% for IBS and FAP diagnosis. Children with IBS and FAP are characterized by the association of rectal hypersensitivity and abnormal pain referral after rectal distension.