Psychophysiology of visceral pain in IBS and health

The psychophysiology of visceral pain as it relates to gastrointestinal motility, visceral sensitivity, and putative mechanisms of the processing of visceral stimuli by the central and peripheral nervous systems are discussed. Peripheral mechanisms may include low-grade mucosal inflammation, and it is likely that central nervous mechanisms such as neuronal plasticity at the level of the spinal cord and attentional bias at the cortical level are relevant for the chronification of visceral pain. From a psychophysiological perspective, visceral pain therefore remains a complex symptom because behavioral variables, such as the way an individual deals with stress, may be as important for the etiology of visceral pain as, for example, a history of inflammation.     

Postinflammatory visceral sensitivity and pain mechanisms

Abstract  The inflammatory reaction is normally tightly regulated, and as soon as the original insult has been cleared, a resolution phase starts that aims at leading the tissues back to a normal physiological state. However, after intestinal inflammation, a number of patients develop postinflammatory hypersensitivity symptoms, which can be defined as an excessive sensitivity to gut nociceptive stimulation. The pain experienced by those patients has been largely studied in the context of postinfectious intestinal diseases. The mechanisms of postinflammatory persistent visceral pain involve peripheral and central neuroplastic changes, low-grade chronic inflammation that sensitizes visceral afferent pathways and sensitization of non-neuronal resident cells of the gut. Several molecular determinants such as neurokinins, serotonin, proteases and voltage-gated ion channels seem to play a significant role in the control of postinflammatory visceral sensation. This review tries to give insights into the mechanisms of persistent visceral pain following the resolution of intestinal inflammation and tries to identify what needs to be done to further advance the field of postinflammatory hypersensitivity clinical management.     

Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

Visceral adipose tissue is accumulated with aging. An increase in visceral fat accompanied by low-grade inflammation is associated with several adult-onset diseases. However, the effects of visceral adipose tissue inflammation on the normal and ischemic brains of aged are not clearly defined. To examine the role of visceral adipose tissue inflammation, we evaluated inflammatory cytokines in the serum, visceral adipose tissue, and brain as well as blood–brain barrier (BBB) permeability in aged male mice (20 months) underwent sham or visceral fat removal surgery compared with the young mice (2.5 months). Additionally, ischemic brain injury was compared in young and aged mice with sham and visceral fat removal surgery. Interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in examined organs were increased in aged mice compared with the young mice, and these levels were reduced in the mice with visceral fat removal. Increased BBB permeability with reduced expression of tight junction proteins in aged sham mice were also decreased in mice with visceral fat removal. After focal ischemic injury, aged mice with visceral fat removal showed a reduction in infarct volumes, BBB permeability, and levels of proinflammatory cytokines in the ischemic brain compared with sham mice, although the neurological outcomes were not significantly improved. In addition, further upregulated visceral adipose tissue inflammation in response to ischemic brain injury was attenuated in mice with visceral fat removal. These results suggest that visceral adipose tissue inflammation is associated with age-related changes in the brain and contributes to the ischemic brain damage in the aged mice. We suggest that visceral adiposity should be considered as a factor affecting brain health and ischemic brain damage in the aged population.     

The cannabinoid CB2 receptor: a good friend in the gut

Mammalian tissues express the cannabinoid 1 (CB(1)) receptor and the cannabinoid 2 (CB(2)) receptor, the latter being involved in inflammation and pain. In somatic nerve pathways, the analgesic effects of CB(2) agonism are well documented. Two papers published in the Journal have provided evidence that CB(2) receptor activation inhibits visceral afferent nerve activity in rodents. These exciting findings are discussed in the context of recent data highlighting the emerging role of CB(2) receptor as a critical target able to counteract hypermotility in pathophysiological states, gut inflammation and possibly colon cancer.     

Effect of DSS-induced colitis on visceral sensitivity to colorectal distension in mice

The present study aimed at evaluating the effect of dextran sodium sulphate (DSS)-induced colitis on visceral sensitivity, measured as the visceromotor response (VMR) to colorectal distension (CRD) in BALB/c and C57Bl/6 male mice. Inflammation was induced by the addition of 4% DSS to the drinking water for 5 (C57Bl/6) or 6-7 days (BALB/c). Parallel groups were used to monitor histopathological changes and visceral sensitivity. Pseudo-affective visceral pain responses were evoked using an increasing phasic CRD paradigm (10-60 mmHg) in conscious mice on predetermined days (pretreatment controls, 12, 16, 20, 30, 40 and 51). In both mouse strains, significant histopathological changes developed between days 2 and 5 of DSS treatment, and persisted until day 12 (P < 0.05). On day 15, inflammatory scores were reduced by about 50%. Despite evidence of inflammation in DSS-treated mice, no differences could be shown in the VMR to CRD between DSS-treated mice and controls at any time point tested. In addition, no differences were seen before and after DSS treatment in the same group of mice. In conclusion, these data suggest that DSS-induced colonic inflammation does not affect the visceral sensitivity to CRD, neither at short or long term, in BALB/c or C57Bl/6 male mice.     

Dorsoventral hippocampus distinctly modulates visceral sensitivity and anxiety behaviors in male IBS-like rats

Accumulating evidences suggest dysfunctions in the hippocampus are associated with chronic pain. Nevertheless, the role of hippocampal circuitry in pain memories and emotional responses is not yet fully understood. In this study, we utilized a comprehensive approach that combined electromyography (EMG), photochemical genetic techniques, and anxiety-related behavioral paradigms to investigate the involvement of dorsal hippocampus (DH) and ventral hippocampus (VH) in visceral sensitivity and anxiety behaviors in male rats. Our results demonstrated that IBS-like rats exhibited comorbid visceral hypersensitivity and anxiety, along with the number of activated neurons in the VH was higher than that in the DH. Manipulation of glutamatergic neurons in the hippocampus was identified as a crucial mechanism underlying the mediation of both visceral sensitivity and anxiety behaviors. Specifically, optogenetic activation of the DH induced both visceral hypersensitivity and anxiety, while activation of the VH induced anxiety but did not affect visceral sensitivity. Conversely, chemogenetic inhibition of the DH reduced both visceral hypersensitivity and anxiety, whereas inhibition of the VH alleviated anxiety but did not alleviate visceral hypersensitivity in IBS-like rats. Our study highlights the important role of early life stress in inducing visceral hypersensitivity and anxiety, and further elucidates the distinct functional contributions of the DH and VH to these behavioral changes. These findings provide a theoretical basis for the diagnosis and treatment of IBS, and suggest that targeting specific hippocampal neuron subtypes may represent a promising therapeutic approach.     

Individual reactivity to the open-field predicts the expression of cardiovascular and behavioural sensitisation to novel stress

Posttraumatic stress disorder (PTSD) is the fourth most common psychiatric disorder. It is associated with cardiovascular disorders and irritable bowel syndrome (IBS). Besides stressful life-events, a prior history of gastrointestinal infection is a predisposing factor for the development of IBS. Only a proportion of persons exposed to traumatic events develop PTSD. Several factors, like genetic predisposition, stressor intensity, cognitive appraisal mechanisms and coping processes influence the likelihood of developing PTSD after exposure to a trauma. We used a single session of footshocks in rats, an animal model with a high degree of validity for PTSD, to study whether transient colonic inflammation alters local and distal visceral sensitivity, and whether reactivity to the open-field (low (LA) or high (HA) active) predicts long-term stress-induced behavioural and cardiovascular sensitisation and altered visceral pain sensitivity. A distention series and noise challenge were given 2 weeks after foot-shocks, followed by a transient colonic inflammation period and a second distention series and noise challenge 4 weeks after foot-shocks. During exposure to noise, both before and after inflammation, footshocked rats showed increased immobility compared to controls, which was significantly greater in LA rats than in HA rats. LA preshocked rats also showed a greater blood pressure response to the noise test, but this only became evident in the second noise-test. Neither footshocks nor colonic inflammation affected duodenal pain sensitivity. The results provide additional evidence for long-lasting cardiovascular hyperresponsivity after a stressful event and indicate that its degree is predicted by personality traits or coping style.     

PROP Taste Sensitivity is Related to Visceral but Not Moral Disgust

Taste perception and the emotion of disgust are both processed by the anterior insular cortex. A current debate in the emotion and disgust literature is whether visceral and moral disgust responses are fundamentally the same. The purpose of the present study was therefore to test whether visceral and moral disgust would be responded to similarly as a function of taste sensitivity. Several disgust questionnaires measuring different components of visceral disgust (core, pathogen, sexual) and moral disgust were administered along with a 6-n-propylthiouracil (PROP) taste sensitivity test. Individuals were categorized on the basis of their responses to PROP as super-tasters, tasters, and non-tasters. PROP taster status was used as an independent variable to assess responses on the various disgust questionnaires, and PROP scores were also correlated with the disgust-dependent measures. Results showed that super-tasters were more responsive to all visceral components of emotional disgust than tasters and non-tasters, and that taste sensitivity was positively correlated with disgust responsivity. However, taste sensitivity was not related to responses concerning moral disgust in any way. Results are discussed in terms of the proposed theoretical underpinnings of emotional disgust and the physiological and neuroanatomical foundations that may mediate different forms of it.     

Visceral hypersensitivity and intolerance symptoms in lactose malabsorption

Lactose malabsorption is not always associated with intolerance symptoms. The factors responsible for symptom onset are not yet completely known. As differences in visceral sensitivity may play a role in the pathogenesis of functional symptoms, we evaluated whether an alteration of visceral sensitivity is present in subjects with lactose intolerance. Thirty subjects, recruited regardless of whether they were aware of their capacity to absorb lactose, underwent an evaluation of intestinal hydrogen production capacity by lactulose breath test, followed by an evaluation of lactose absorption by hydrogen breath test after lactose administration and subsequently an evaluation of recto-sigmoid sensitivity threshold during fasting and after lactulose administration, to ascertain whether fermentation modifies intestinal sensitivity. The role of differences in gastrointestinal transit was excluded by gastric emptying and mouth-to-caecum transit time by (13)C-octanoic and lactulose breath tests. Lactulose administration induced a significant reduction of discomfort threshold in subjects with lactose intolerance but not in malabsorbers without intolerance symptoms or in subjects with normal lactose absorption. Perception threshold showed no changes after lactulose administration. Severity of symptoms in intolerant subjects was significantly correlated with the reduction of discomfort thresholds. Visceral hypersensitivity should be considered in the induction of intolerance symptoms in subjects with lactose malabsorption.     

Prevalence of irritable bowel syndrome among university students: the roles of worry, neuroticism, anxiety sensitivity and visceral anxiety

OBJECTIVE: Relationships between presence of irritable bowel syndrome (IBS) and generalized anxiety disorder (GAD), chronic worry, neuroticism, anxiety sensitivity and anxiety about visceral sensations were examined among university students. METHODS: College student participants were administered self-report diagnostic measures of IBS and GAD, the Penn State Worry Questionnaire (PSWQ), the Neuroticism subscale of the Eysenck Personality Questionnaire, the Anxiety Sensitivity Index (ASI) and five additional items designed to measure visceral anxiety. RESULTS: The prevalence of IBS and its associated characteristics among students were similar to previous community survey studies, with the exception of lower symptom severity in the university sample. IBS was associated with a higher frequency of GAD and greater worry, neuroticism, anxiety sensitivity and visceral anxiety. Logistic regression analyses further showed that the measure of anxiety specific to visceral sensations was the strongest predictor of IBS diagnostic status. CONCLUSIONS: While various aspects of anxiety appear related to IBS, specific anxiety about visceral sensations appears to be the most significant factor. Implications of the associations between anxiety-related variables, particularly anxiety about visceral sensations, are discussed.     

Mechanisms of hypersensitivity in IBS and functional disorders

General introduction  The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.     

Novel insights in the role of peripheral corticotropin-releasing factor and mast cells in stress-induced visceral hypersensitivity

Visceral hypersensitivity is one of the hallmarks in irritable bowel syndrome (IBS) pathophysiology. Stress is well known to affect visceral sensitivity in humans and rodents, an effect which is associated in part with alterations of intestinal epithelial permeability in rodents. Although the pathophysiology of visceral hypersensitivity is still unclear, two key factors have been identified as playing a major role in its modulation, namely peripheral corticotropin-releasing factor (CRF) and mast cells. In a recent study in Neurogastroenterology and Motility, van den Wijngaard et al. demonstrate that the mast-cell dependent visceral hypersensitivity observed in maternally separated rats after an acute exposure to a psychological stress can be prevented but not reversed by the peripherally restricted CRF receptor antagonist, α-helical CRF(9-41). They further show that the preventive effect of the CRF receptor antagonist is linked to a stabilization of mast cells and maintenance of the epithelial barrier at the colonic level. These data suggest that post stress mast cell activation and subsequent visceral hypersensitivity are not targeted by peripheral CRF receptor antagonists. These novel insights in the role of peripheral CRF in the modulation of stress-induced visceral hypersensitivity add to our growing understanding of the mechanisms that may lie at the origin of visceral pain disturbances following stress and will contribute to enhance the development of drugs that may have potential therapeutic benefits for IBS patients.     

Assessment of visceral sensitivity using radio telemetry in a rat model of maternal separation

Stress plays an important role in the development of visceral hypersensitivity, a key mechanism underlying the pathophysiology of the irritable bowel syndrome. Visceral sensitivity in rats is generally assessed under restrain conditions. To avoid this potential stress factor, we developed a model using implanted radio telemetry for remote measurement of the visceromotor response (VMR) to colorectal distention (CRD). Ten days after implantation of a radio telemetry transmitter and EMG electrodes, visceral sensitivity was evaluated by applying a standardized distension protocol (1, 1.5 and 2 mL) on three different days. In a second series, visceral sensitivity was assessed in maternally separated rats before, directly after and at 6 and 24 h after water avoidance (WA) stress. CRD resulted in a reproducible VMR response on the three different study days. In separated but not in non-handled rats, WA significantly increased visceral sensitivity at 6 h (P=0.006) and 24 h (P=0.004) after WA. Our results show that radio telemetry is a reliable and well tolerated new tool for evaluating visceral sensitivity in rats. These data further confirm that maternal separation is a good model for evaluating the mechanisms underlying visceral hypersensitivity.     

Current data and ideas on digestive sensitivity.

Remarkable advances have recently been made in the study of visceral sensitivity. Both electrophysiological and histological data emphasize the richness and the complexity of information elicited in the visceral area including the digestive tract. In addition these afferents are largely involved in physiological mechanisms which are not only restricted to the visceral area. The current knowledge of visceral sensitivity leads us to reconsider the classical ideas and concepts previously accepted in this field and raises questions to help gain a better comprehension of sensory physiology in general.     

PAR4: A new role in the modulation of visceral nociception

Abstract  Protease-activated receptors (PARs) are a family of G-protein-coupled receptors with a widespread distribution that are involved in various physiological functions including inflammation and nociception. In a recent study in Neurogastroenterology and Motility, Augé et al. describe for the first time the presence of PAR4 on visceral primary afferent neurons and its role in modulating colonic nociceptive responses, colonic hypersensitivity and primary afferent responses to PAR2 and Transient Receptor Potential Vanilloid-4 (TRPV4). Using the model of visceromotor response (VMR) to colorectal distension (CRD), they show that a PAR4 agonist delivered into the colon lumen decreases basal visceral response to CRD and reduces the exacerbated VMR to CRD induced by treatment with PAR2 or TRPV4 agonists. In isolated sensory neurons, they show that a PAR4 agonist inhibits calcium mobilization induced by PAR2 or TRPV4 agonists. Finally, they describe increased pain behaviour evoked by luminal application of mustard oil in PAR4 deficient mice compared to wild type controls. The newly discovered role of PAR4 in modulating visceral pain adds to our growing understanding of the contribution of colonic proteases and PARs to the mechanisms involved in colonic hypersensitivity and their potential role as therapeutic targets for irritable bowel syndrome.     

Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation

Background Recurrent abdominal pain is reported by a third of patients with diverticulosis, particularly those with previous episodes of acute diverticulitis. The current understanding of the etiology of this pain is poor. Our aim was to assess visceral sensitivity in patients with diverticular disease and its association with markers of previous inflammation and neuropeptides. Methods Patients with asymptomatic and symptomatic diverticular disease underwent a flexible sigmoidoscopy and biopsy followed 5–10 days later by visceral sensitivity testing with barostat‐mediated rectal distension. Inflammation was assessed by staining of serotonin (5HT) and CD3 positive cells. mRNA levels of tumor necrosis factor alpha (TNF α) and interleukin‐6 (IL‐6) were quantitated using RT‐PCR. Neuropeptide expression was assessed from percentage area staining with substance P (SP) and mRNA levels of the neurokinin 1 & 2 receptors (NK1 & NK2), and galanin 1 receptor (GALR1). Key Results Thirteen asymptomatic and 12 symptomatic patients were recruited. The symptomatic patients had a lower first reported threshold to pain (28.4 mmHg i.q.r 25.0–36.0) than the asymptomatic patients (47 mmHg i.q.r 36.0–52.5, P < 0.001). Symptomatic patients had a higher median overall pain rating for the stimuli than the asymptomatic patients (P < 0.02). Symptomatic patients had greater median relative expression of NK1 and TNF alpha mRNA compared with asymptomatic patients. There was a significant correlation between barostat VAS pain scores and NK 1 expression (Figure 4, r² 0.54, P < 0.02). Conclusions & Inferences Patients with symptomatic diverticular disease exhibit visceral hypersensitivity, and this may be mediated by ongoing low grade inflammation and upregulation of tachykinins.     

Chemosensitivity of the human gastrointestinal tract in health and in disease

Although visceral sensitivity in man comprises chemosensitivity, thermosensitivity and mechanosensitivity, only the latter has been intensively studied. Studies in health have aimed at characterising the type of mechanoreceptors involved in visceral mechanosensitivity,. Several authors have studied the prevalence and relevance to the symptom pattern of hypersensitivity to visceral balloon distention in patients with functional gastrointestinal disorders. Chemosensitivity of the gastrointestinal tract in man has received much less attention. In this issue of Neurogastroenterology and Motility, intraluminal application of capsaicin is described as a tool to study chemosensitivity of the proximal gastrointestinal tract. The authors report how activation of chemosensitive pathways induces symptoms that differ from those induced by activation of mechanosensitive pathways, and propose to use capsaicin as a tool to study the prevalence and role of hypersensitivity to visceral chemosensitivity in patients with functional gastrointestinal disorders. Our current knowledge of visceral chemosensitivity of the human gastrointestinal tract in health and in disease is reviewed, with a specific focus on the interaction between mechano- and chemosensitive pathways.     

Importance of 5-hydroxytryptamine receptors on intestinal afferents in the regulation of visceral sensitivity

Abstract  Serotonin (5-HT) plays an important role as a signalling molecule in the gastrointestinal (GI) tract. The regulation of GI sensitivity via 5-HT is mediated by specific 5-HT receptor subytypes on intrinsic and extrinsic afferents. This review discusses visceral afferent hypersensitivity in irritable bowel syndrome (IBS) and the importance of 5HT₃, 5HT₄, and 5HT_2B receptor-mediated mechanisms in the regulation of visceral sensitivity.