Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers.

BACKGROUND: Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm. METHODS: The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate. RESULTS: LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all pFWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all pFWE < 0.05). CONCLUSIONS: Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.

Gut enterochromaffin cells drive visceral pain and anxiety.

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

Greater interruption of visual processing and memory encoding by visceral than somatic pain in healthy volunteers - An fMRI study.

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

When gut feelings teach the brain to fear pain: Context-dependent activation of the central fear network in a novel interoceptive conditioning paradigm.

The relevance of contextual factors in shaping neural mechanisms underlying visceral pain-related fear learning remains elusive. However, benign interoceptive sensations, which shape patients' clinical reality, may context-dependently become conditioned predictors of impending visceral pain. In a novel context-dependent interoceptive conditioning paradigm, we elucidated the putative role of the central fear network in the acquisition and extinction of pain-related fear induced by interoceptive cues and pain-predictive contexts. In this fMRI study involving rectal distensions as a clinically-relevant model of visceroception, N = 27 healthy men and women underwent differential conditioning. During acquisition training, visceral sensations of low intensity as conditioned stimuli (CS) predicted visceral pain as unconditioned stimulus (US) in one context (Con+), or safety from pain in another context (Con-). During extinction training, interoceptive CS remained unpaired in both contexts, which were operationalized as images of different rooms presented in the MRI scanner. Successful contextual conditioning was supported by increased negative valence of Con+ compared to Con- after acquisition training, which resolved after extinction training. Although interoceptive CS were perceived as comparatively pleasant, they induced significantly greater neural activation of the amygdala, ventromedial PFC, and hippocampus when presented in Con+, while contexts alone did not elicit differential responses. During extinction training, a shift from CS to context differentiation was observed, with enhanced responses in the amygdala, ventromedial, and ventrolateral PFC to Con+ relative to Con-, whereas no CS-induced differential activation emerged. Context-dependent interoceptive conditioning can turn benign interoceptive cues into predictors of visceral pain that recruit key regions of the fear network. This first evidence expands knowledge about learning and memory mechanisms underlying interoceptive hypervigilance and maladaptive avoidance behavior, with implications for disorders of the gut-brain axis.

A novel visceral pain model of uterine cervix inflammation in rat.

Treatment of visceral pain originating from the uterine cervix is a substantial clinical problem. The underlying mechanisms of such visceral pain remain unclear mainly due to a lack of reliable model. This study aimed to develop and evaluate the performance of a rat model of pain induced by uterine cervix inflammation. Rats were randomized to six groups according to the solution injected into the uterine cervix: normal saline, vehicle, capsaicin (0.3 mg, 0.6 mg, 0.9 mg), capsaicin 0.9 mg + morphine (n = 15 in each group). Spontaneous behaviors after cervical injection were recorded by a computerized video system and analyzed offline. An equation for calculating a novel pain score was derived from particular behaviors, based on Pearson's correlation analysis and regression analysis. c-Fos expression in the spinal cord was detected. The pain score and c-fos expression in the spinal cord were highest in the 0.9 mg capsaicin group and lowest in the normal saline and vehicle groups (P < 0.05). Intrathecal morphine significantly decreased the pain score (P < 0.05) and c-fos expression in the spinal cord (P < 0.05). Injection of capsaicin into the uterine cervix in rats could be a practical model of inflammatory cervical pain, which can be evaluated using our novel pain score. This model will provide further insight into the mechanism underlying visceral pain originating from the uterine cervix.

Dependency on sex and stimulus quality of nociceptive behavior in a conscious visceral pain rat model.

Visceral pain may be influenced by many factors. The aim of this study was to analyze the impact of sex and quality of intracolonic mechanical stimulus on the behavioral manifestations of visceral pain in a preclinical model. Male and female young adult Wistar rats were sedated, and a 5 cm long latex balloon was inserted into the colon. Sedation was reverted and behavior was recorded. The pressure of the intracolonic balloon was gradually increased using a sphygmomanometer. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation. Two different types of stimulation were used: tonic and phasic. Phasic stimulation consisted of repeating several times (3x) the same short stimulus (20 s) within a 5 min interval allowing a 1 min break between individual stimuli. For tonic stimulation the stimulus was maintained throughout the whole 5 min interval. Both phasic and tonic stimulation produced a pressure-dependent increase of abdominal contractions. The abdominal response was more intense under phasic than under tonic stimulation, but with differences depending on the sex of the animals: females exhibited more contractions than males and of similar duration at all pressures, whereas duration of contractions pressure-dependently increased in males. The duration of tonically stimulated contractions was lower and not sex- or pressure-dependent. In the rat, responses to colonic distension depend on the quality of the stimulus, which also produces sex-dependent differences that must be taken into account in the development of models of pathology and visceral pain treatments.

Effect of water extracts from Cynanchum thesioides (Freyn) K. Schum. on visceral hypersensitivity and gut microbiota profile in maternally separated rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Irritable bowel syndrome (IBS) is a chronic, stress-related, functional gastrointestinal disorder characterized by abdominal discomfort and altered bowel habits; the manipulation of the microbiota is emerging as a promising therapeutic option for IBS. Cynanchum thesioides (CT) is an herb of traditional Mongolian medicine that has been employed in treating abdominal pain and diarrhea for hundreds of years. Phytochemical studies of this plant showed the presence of various flavonoids with antibacterial and anti-inflammatory activities. We hypothesized that Cynanchum thesioides manipulates the gut mycobiome and reverses visceral hypersensitivity in IBS rat model. PURPOSE OF THE STUDY: The aims of this study were to prove the in vivo efficacy of Cynanchum thesioides on improving visceral hypersensitivity in IBS rat model and to examine its effect on gut bacterial communities, focusing on the potential interrelationships among microbiota and visceral hypersensitivity. MATERIALS AND METHODS: We induced visceral hypersensitivity rat models by maternal separation (MS) of Sprague-Dawley rats, and administered CT water extracts to MS rats for 10 consecutive days. The abdominal withdrawal reflex score and threshold of colorectal distention were employed to assess visceral sensitivity. We then used the Illumina HiSeq platform to analyze bacterial 16S rRNA gene. RESULTS: Treatment with CT improved visceral hypersensitivity in MS rats, and this was accompanied by alterations in the structure and composition of the gut microbiota. The extent of the stability of the gut microbiota was improved after treatment with CT. The genera Pseudomonas, Lachnospiracea_incertae_sedis, and Clostridium XlVa (which were more prevalent in MS rats) were significantly decreased, whereas the abundance of some genera were less prevalent in MS rats-for example, Clostridium IV, Elusimicrobium, Clostridium_sensu_stricto, and Acetatifactor were significantly enriched after treatment with CT. CONCLUSION: Water-extracted CT was beneficial against visceral hypersensitivity in IBS and favorably affected the structure, composition, and functionality of gut microbiota. CT is therefore a promising agent in therapy of IBS.

Histone H3K9 methylation regulates chronic stress and IL-6-induced colon epithelial permeability and visceral pain.

BACKGROUND: Chronic stress is associated with activation of the HPA axis, elevation in pro-inflammatory cytokines, decrease in intestinal epithelial cell tight junction (TJ) proteins, and enhanced visceral pain. It is unknown whether epigenetic regulatory pathways play a role in chronic stress-induced intestinal barrier dysfunction and visceral hyperalgesia. METHODS: Young adult male rats were subjected to water avoidance stress ± H3K9 methylation inhibitors or siRNAs. Visceral pain response was assessed. Differentiated Caco-2/BBE cells and human colonoids were treated with cortisol or IL-6 ± antagonists. Expression of TJ, IL-6, and H3K9 methylation status at gene promoters was measured. Transepithelial electrical resistance and FITC-dextran permeability were evaluated. KEY RESULTS: Chronic stress induced IL-6 up-regulation prior to a decrease in TJ proteins in the rat colon. The IL-6 level inversely correlated with occludin expression. Treatment with IL-6 decreased occludin and induced visceral hyperalgesia. Chronic stress and IL-6 increased H3K9 methylation and decreased transcriptional GR binding to the occludin gene promoter, leading to down-regulation of protein expression and increase in paracellular permeability. Intrarectal administration of a H3K9 methylation antagonist prevented chronic stress-induced visceral hyperalgesia in the rat. In a human colonoid model, cortisol decreased occludin expression, which was prevented by the GR antagonist RU486, and IL-6 increased H3K9 methylation and decreased TJ protein levels, which were prevented by inhibitors of H3K9 methylation. CONCLUSIONS & INFERENCES: Our findings support a novel role for methylation of the repressive histone H3K9 to regulate chronic stress, pro-inflammatory cytokine-mediated reduction in colon TJ protein levels, and increase in paracellular permeability and visceral hyperalgesia.

Acute stress induces visceral hypersensitivity via glucocorticoid receptor-mediated membrane insertion of TRPM8: Involvement of a non-receptor tyrosine kinase Pyk2.

BACKGROUND: Psychological stress is an important factor for the development and recurrence of irritable bowel syndrome (IBS). The mechanisms underlying stress-induced visceral hypersensitivity (VH), a key pathophysiological component in IBS, are still incompletely understood. We aimed to test whether transient receptor potential melastatin 8 (TRPM8) participates in acute stress-induced VH. METHODS: Rats were subjected to 1-hour water avoidance stress (WAS). Visceral sensitivity was measured with visceromotor response to colorectal distension. Western blot and immunofluorescence were applied to evaluate the expression of GR and TRPM8 and activation of PKA, Akt, and PKC pathways. RESULTS: WAS-caused VH depended on glucocorticoid receptors (GRs) and TRPM8 channels. In a dorsal root ganglion (DRG)-derived cell line, corticosterone rapidly (within 30 minutes) induced membrane expression of TRPM8. This effect was inhibited by GR antagonism and was mimicked by membrane-impermeable corticosterone. PKA, PI3K/Akt, and PKC pathways, which lied downstream of GR and acted in parallel to promote membrane expression of TRPM8, contributed to WAS-induced VH. The non-receptor tyrosine kinase Pyk2, which may serve as a convergence point for PKA, PI3K/Akt, and PKC pathways, facilitated membrane insertion of TRPM8 via tyrosine-phosphorylating TRPM8 in L6-S2 DRGs and participated in WAS-induced VH. CONCLUSIONS: Collectively, acute stress-induced VH could involve membrane-bound GR-dependent enhancement of TRPM8 function in nociceptive DRG neurons. Mechanistically, Pyk2 could act as a key mediator that coordinates multiple protein kinase signaling and triggers phosphorylation and membrane insertion of TRPM8.

Cortisol affects pain sensitivity and pain-related emotional learning in experimental visceral but not somatic pain: a randomized controlled study in healthy men and women.

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

Are there sex differences in visceral sensitivity in young healthy men and women?

BACKGROUND: Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women. METHODS: In 280 young healthy volunteers (50% female), visceral sensory and pain thresholds were determined using rectal balloon distensions. Gastrointestinal (GI) symptoms, chronic stress, and trait anxiety as IBS-related risk factors were assessed with questionnaires. Men and women were compared regarding visceral sensitivity and multiple regression analyses were conducted to evaluate the predictive value of sex and risk factors for visceral sensitivity. Subgroups with high, intermediate, and low sensitivity were compared regarding psychological and biological characteristics. KEY RESULTS: Men and women did not differ in sensory or pain thresholds or in IBS-related risk factors. In multiple regression analyses, no predictor of visceral sensitivity could be identified. While sensitivity subgroups differed in sensory and pain thresholds, the proportions of men and women were comparable, and groups did not differ in IBS-related risk factors. CONCLUSIONS AND INFERENCES: Despite the large sample size, we found no evidence supporting sex differences in visceral sensitivity. At least in healthy young volunteers, our findings suggest that sex, GI symptoms, anxiety, or chronic stress do not contribute to altered visceral sensitivity.

Naloxone prolongs abdominal constriction writhing-like behavior in a zebrafish-based pain model.

The ability to detect noxious stimuli is essential to survival. However, pathological pain is maladaptive and severely debilitating. Endogenous and exogenous opioids modulate pain responses via opioid receptors, reducing pain sensibility. Due to the high genetic and physiological similarities to rodents and humans, the zebrafish is a valuable tool to assess pain responses and the underlying mechanisms involved in nociception. Although morphine attenuates pain-like responses of zebrafish, there are no data showing if the antagonism of opioid receptors prolongs pain duration in the absence of an exogenous opioid. Here, we investigated whether a common opioid antagonist naloxone affects the abdominal constriction writhing-like response, recently characterized as a zebrafish-based pain behavior. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg/kg; 2.5 mg/kg; 5.0 mg/kg) or acetic acid with naloxone to investigate the changes in their body curvature for 1 h. Acetic acid elicited a robust pain-like response in zebrafish, as assessed by aberrant abdominal body curvature, while no effects were observed following PBS injection. Although naloxone alone did not alter the frequency and duration of this behavior, it dose-dependently prolonged acetic acid-induced abdominal curvature response. Besides reinforcing the use of the abdominal writhing-like phenotype as a behavioral endpoint to measure acute pain responses in zebrafish models, our novel data suggest a putative role of endogenous opioids in modulating the recovery from pain stimulation in zebrafish.

Cumulative Effects of Psychologic Distress, Visceral Hypersensitivity, and Abnormal Transit on Patient-reported Outcomes in Irritable Bowel Syndrome.

BACKGROUND & AIMS: Little is known about the link between pathophysiologic factors and symptoms of irritable bowel syndrome (IBS), or whether these factors have cumulative effects on patient-reported outcomes (PROs). We investigated whether pathophysiologic alterations associated with IBS have cumulative or independent effects on PROs. METHODS: We performed a retrospective analysis of data from 3 cohorts of patients with IBS (n = 407; 74% female; mean age, 36 ± 12 years), based on Rome II or Rome III criteria, seen at a specialized unit for functional gastrointestinal disorders in Sweden from 2002 through 2014. All patients underwent assessments of colonic transit time (radiopaque markers); compliance, allodynia, and hyperalgesia (rectal barostat); anxiety and depression (Hospital Anxiety and Depression scale), as pathophysiologic factors. Dysfunction was defined by available normal values. PROs included IBS symptom severity, somatic symptom severity, and disease-specific quality of life. RESULTS: Allodynia was observed in 36% of patients, hyperalgesia in 22%, accelerated colonic transit in 18%, delayed transit in 7%, anxiety in 52%, and depression in 24%: each of these factors was associated with severity of at least 1 symptom of IBS. Rectal compliance was not associated with more severe symptoms of IBS. At least 3 pathophysiologic factors were present in 20% of patients, 2 in 30%, 1 in 31%, and none in 18%. With increasing number of pathophysiologic abnormalities, there was a gradual increase in IBS symptom severity (P < .0001) and somatic symptom severity (P < .0001), and a gradual reduction in quality of life (P < .0001). CONCLUSION: Visceral hypersensitivity, including allodynia and hyperalgesia, abnormal colonic transit, and psychologic factors are all associated with IBS symptoms. These factors have a cumulative effect on gastrointestinal and nongastrointestinal symptoms, as well as on quality of life, in patients with IBS and are therefore relevant treatment targets.

Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase.

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15-45 mg of TNBS) in 30 rats, whereas the control rats (n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity (P = 0.03), 2) an increased colon weight-to-length ratio (P = 0.01), 3) higher inflammatory and fibrosis scores (P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production (P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae. NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.

Behavioural and neural responses to aversive visceral stimuli in women with primary dysmenorrhoea.

BACKGROUND: Chronic pelvic pain, in particular dysmenorrhoea, is a significant yet unresolved healthcare problem in gynaecology. As interoceptive sensitivity and underlying neural mechanisms remain incompletely understood, this functional magnetic resonance imaging (fMRI) study assessed behavioural and neural responses to visceral stimuli in primary dysmenorrhoea (PMD). METHODS: Women with PMD (N = 19) without psychological comorbidity and healthy women (N = 20) were compared with respect to visceral sensory and pain thresholds, and to neural responses to individually calibrated mildly painful and painful rectal distensions implemented during scanning. Trial-by-trial ratings of perceived intensity were accomplished with visual analogue scales (VAS). RESULTS: Although women with dysmenorrhoea reported significantly higher chronic pain intensity and pain interference with daily life activities (p < 0.01, assessed with the West Haven-Yale Multidimensional Pain Inventory), there were no differences between groups in visceral sensitivity and mean trial-by-trial VAS ratings were virtually identical. Analysis of neural responses revealed activation in brain regions previously shown to be involved in the processing of visceral stimuli with differences between painful and mildly painful stimulation, but no group differences were found even when using a liberal statistical threshold. CONCLUSIONS: Dysmenorrhoea patients show unaltered perceptual and neural responses to experimental interoceptive stimuli. Despite limited sample size, these negative results argue against a generalized sensitization towards interoceptive stimuli in patients without psychological comorbidities. Future studies should clarify the role of psychosocial factors in central sensitization using more pain region-specific models in larger and clinically more heterogeneous samples. SIGNIFICANCE: Despite higher chronic pain and pain interference with daily life activities, women with primary dysmenorrhoea do not differ from healthy women with respect to visceral sensitivity or neural processing of aversive interoceptive stimuli induced by rectal distensions. Generalized sensitization may be present only in subgroups with pronounced psychosocial or psychiatric disturbances.

Chronic stress and intestinal permeability: Lubiprostone regulates glucocorticoid receptor-mediated changes in colon epithelial tight junction proteins, barrier function, and visceral pain in the rodent and human.

BACKGROUND: Chronic psychological stress is associated with increased intestinal epithelial permeability and visceral hyperalgesia. Lubiprostone, an agonist for chloride channel-2, promotes secretion and accelerates restoration of injury-induced epithelial barrier dysfunction. The mechanisms underlying how lubiprostone regulates colon epithelial barrier function and visceral hyperalgesia in chronic stress remain unknown. METHODS: Male rats were subjected to water avoidance stress for 10 consecutive days. Lubiprostone was administered daily during the stress phase. Visceromotor response to colorectal distension was measured. Human colon crypts and cell lines were treated with cortisol and lubiprostone. The transepithelial electrical resistance and FITC-dextran permeability were assayed. Chromatin immunoprecipitation was conducted to assess glucocorticoid receptor binding at tight junction gene promoters. KEY RESULTS: Lubiprostone significantly decreased chronic stress-induced visceral hyperalgesia in the rat (P < 0.05; n = 6). WA stress decreased occludin and claudin-1 and increased claudin-2 in rat colon crypts, which was prevented by lubiprostone. Cortisol treatment induced similar alterations of tight junction protein expression in Caco-2/BBE cells (P < 0.05) and significantly changed paracellular permeability in monolayers (P < 0.01). These changes were blocked by lubiprostone. Glucocorticoid receptor and its binding at occludin promoter region were decreased in cortisol-treated cells and human colon crypts, which was largely reversed by lubiprostone. In rat colonic cells, glucocorticoid receptor and its co-chaperone proteins were down-regulated after corticosterone treatment and lubiprostone reversed these changes. CONCLUSIONS & INFERENCES: Lubiprostone preferentially prevents chronic stress-induced alterations of intestinal epithelial tight junctions, barrier function, and visceral hyperalgesia that was associated with modulation of glucocorticoid receptor expression and function.

The gut-brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation.

Over the past few years, scientific interest in the gut-brain axis (i.e., the bidirectional communication system between the gastrointestinal tract and the brain) has exploded, mostly due to the identification of the gut microbiota as a novel key player in this communication. However, important progress has also been made in other aspects of gut-brain axis research, which has been relatively underemphasized in the review literature. Therefore, in this review, we provide a comprehensive, although not exhaustive, overview of recent research on the functional neuroanatomy of the gut-brain axis and its relevance toward the multidisciplinary field of health neuroscience, excluding studies on the role of the gut microbiota. More specifically, we first focus on irritable bowel syndrome, after which we outline recent findings on the role of the gut-brain axis in appetite and feeding regulation, primarily focusing on the impact of subliminal nutrient-related gut-brain signals. We conclude by providing future perspectives to facilitate translation of the findings from gut-brain axis neuroscientific research to clinical applications in these domains.

Examining the mediational role of psychological flexibility, pain catastrophizing, and visceral sensitivity in the relationship between psychological distress, irritable bowel symptom frequency, and quality of life.

The aim of the current study was to use Structural Equation Modelling (SEM) to examine whether psychological flexibility (i.e. mindfulness, acceptance, valued-living) mediates the relationship between distress, irritable bowel syndrome (IBS) symptom frequency, and quality of life (QoL). Ninety-two individuals participated in the study (12 male, 80 female, Mage = 36.24) by completing an online survey including measures of visceral sensitivity, distress, IBS-related QoL, mindfulness, bowel symptoms, pain catastrophizing, acceptance, and valued-living. A final model with excellent fit was identified. Psychological distress significantly and directly predicted pain catastrophizing, valued-living, and IBS symptom frequency. Pain catastrophizing directly predicted visceral sensitivity and acceptance, while visceral sensitivity significantly and directly predicted IBS symptom frequency and QoL. Symptom frequency also had a direct and significant relationship with QoL. The current findings suggest that interventions designed to address unhelpful cognitive processes related to visceral sensitivity, pain catastrophizing, and psychological distress may be of most benefit to IBS-related QoL.

Cannabinoid Receptor Type 1 in the Brain Regulates the Affective Component of Visceral Pain in Mice.

Endocannabinoids acting through cannabinoid receptor type 1 (CB1) are major modulators of peripheral somatic and visceral nociception. Although only partially studied, some evidence suggests a particular role of CB1 within the brain in nociceptive processes. As the endocannabinoid system regulates affect and emotional behaviors, we hypothesized that cerebral CB1 influences affective processing of visceral pain-related behaviors in laboratory animals. To study nocifensive responses modulated by supraspinal CB1, we used conditional knock-out mice lacking CB1 either in cortical glutamatergic neurons (Glu-CB1-KO), or in forebrain GABAergic neurons (GABA-CB1-KO), or in principal neurons of the forebrain (CaMK-CB1-KO). These mutant mice and mice treated with the CB1 antagonist SR141716 were tested for different pain-related behaviors. In an acetic acid-induced abdominal constriction test, supraspinal CB1 deletions did not affect nocifensive responses. In the cerulein-model of acute pancreatitis, mechanical allodynia or hyperalgesia were not changed, but Glu-CB1- and CaMK-CB1-KO mice showed significantly increased facial grimacing scores indicating increased affective responses to this noxious visceral stimulus. Similarly, these brain-specific CB1 KO mice also showed significantly changed thermal nociception in a hot-plate test. These results reveal a novel, and important role of CB1 expressed by cortical glutamatergic neurons in the affective component of visceral nociception.

Cognitive behavioral therapy for irritable bowel syndrome: the effects on state and trait anxiety and the autonomic nervous system during induced rectal distensions - An uncontrolled trial.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS), is a common multifactorial gastrointestinal disorder linked to disturbances in the microbe gut-brain axis. Cognitive behavioral therapy (CBT), in face-to-face format has showed promising results on IBS and its associated psychological symptoms. The present study explored for the first time if CBT for IBS affects the autonomic nervous system (ANS) during experimentally induced visceral pain and cognitive stress, respectively. The levels of state and trait anxiety, current and perceived stress were also evaluated. METHODS: In this uncontrolled trial, individual CBT was performed in face-to-face format for 12 weeks in 18 subjects with IBS. Heart rate variability and skin conductance were measured during experimentally induced visceral pain and during a cognitive task (Stroop color-word test), before and after intervention. The levels of state and trait anxiety as well as self-rated current and perceived stress were also measured before and after the intervention. RESULTS: CBT did not affect ANS activity during experimentally induced visceral pain and cognitive stress. The sympathetic activity was high, typical for IBS and triggered during both visceral pain and cognitive stress. The levels of state and trait anxiety significantly decreased after the intervention. No significant changes in self-rated current or perceived stress were found. CONCLUSIONS: Results suggest that face-to-face CBT for IBS improved anxiety- a key psychological mechanism for the IBS pathophysiology, rather than the autonomic stress response to experimentally induced visceral pain and cognitive stress, respectively. IMPLICATIONS: This study indicates that IBS patients present high levels of stress and difficulties coping with anxiety and ANS activity during visceral pain and a cognitive stress test, respectively. These manifestations of IBS are however not targeted by CBT, and do not seem to be central for the study participants IBS symptoms according to the current and our previous study. Face-to-face CBT for IBS, it does not seem to affect modulation of ANS activity in response to induced visceral pain or cognitive stress. Instead, face-to-face CBT decreased levels of state and trait anxiety. Implications for further studies include that anxiety seems to be important in the IBS pathophysiology, and needs further scientific attention. This is in line with the fear-avoidance model which suggests that anxious responses to pain and discomfort drive hypervigilance to, and (behavioral) avoidance of, symptom provoking stimuli and vice versa. Catastrophic cognitions, hypervigilance and avoidant behavioral responses are proposed to produce vicious circles that withhold and exacerbate pain-related symptoms and disability, and lead to lower quality of life. Larger scale studies of potential autonomic changes are needed in order to elucidate which mechanisms elicit its effects in face-to-face CBT for IBS, and provide new avenues in understanding the pathophysiology of IBS.