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BACKGROUND AND AIMS: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF1) agonist, cortagine. METHODS: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine. KEY RESULTS: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p

Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC—visceral pain—could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Consistent with its marked expression in colonic nociceptors, GPR35 agonists inhibit transient receptor potential ankyrin 1–mediated colonic nociception highlighting their utility for the treatment of visceral pain. The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn (CS), and phosphodiesterase inhibitor, zaprinast, are agonists at mouse GPR35, promoting the activation of different Gi/o subunits. Pretreatment with either CS or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects were lost in tissue from GPR35−/− mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlights the pronociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and sensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show substantial efficacy in regulating blood glucose levels and lipid metabolism, initially as an effective treatment for diabetes mellitus. In recent years, GLP-1RAs have become a focal point in the medical community due to their innovative treatment mechanisms, robust therapeutic efficacy, and expansive development prospects. Notably, GLP-1RAs benefit pain management through their neuroprotective and metabolic regulatory properties, such as inhibiting inflammation responses and oxidative stress, promoting β-endorphin release and modulating several other crucial biological pathways. Hence GLP-1RAs hold promise for repurposing as treatments for pain disorders. In this narrative review, we thoroughly trace the current preclinical and clinical evidence of seven pain modalities, including inflammatory pain, osteoarthritis, visceral pain, neuropathic pain, diabetic neuropathy, cancer pain and headache, to support the efficacy and underlying biological mechanisms of GLP-1RAs as therapeutic agents for pain suffering. Despite these promising findings, further research is necessary to establish their long-term efficacy, optimal dosing strategies, and potential synergistic interactions of GLP-1RAs with existing pain management therapies. Future clinical trials should aim to distinguish the direct analgesic effects of GLP-1RAs from their metabolic benefits and explore their broader applications in pain conditions. The ongoing exploration of new indications for GLP-1RAs further highlights their transformative potential in advancing medical treatments across diverse clinical fields. [ABSTRACT FROM AUTHOR]

Pain relief following bariatric surgery (BS) can be difficult because many patients have obstructive sleep apnea and are more prone to breathing problems caused by excessive opioid use post-surgery. Using nerve blocks is an effective alternative since they enhance patient comfort and decrease the side effects of opioids. In our review, we comprehensively reviewed present methods to alleviate pain after BS including the transversus abdominis plane block (TAPB), the erector spinae plane block (ESPB), the quadratus lumborum block (QLB), the external oblique intercostal block (EOIB), and the rectus sheath block (RB), aiming to summarized the respective and relative advantages of each nerve block for post-BS analgesia. The review concluded that TAPB is the optimized post-BS nerve block for somatic pain and ESPB relieves somatic and visceral pain which can both be combined with RB. Anterior QLB relieves visceral pain and EOIB can be done without the interference of fat. This review also identified key points for future research to improve post-BS nerve blocks. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a multifactorial disorder, with altered intestinal motility, visceral hypersensitivity, and dysfunction of the gut-brain axis. The aim of our study was to analyze the role of nitric oxide (NO) in the inhibitory effects of sodium butyrate on spontaneous contractility of proximal colon in a mouse model of IBS. IBS was induced by intracolonic infusion of acetic acid in the early postnatal period. Spontaneous contractions of proximal colon segments were studied in isometric conditions. The amplitude and frequency of colon contractions were higher in the IBS group. Sodium butyrate exerted inhibitory effects on colon contractions, which were less pronounced in IBS group. NO donors decreased spontaneous colon contractility and prevented the inhibitory effects of sodium butyrate in control and IBS groups. Nitric oxide synthase (NOS) inhibition by L-NAME increased contractile activity more effective in the control group and decreased the inhibitory action of sodium butyrate. In IBS group, preliminary application of L-NAME did not prevent sodium butyrate action. Our data indicate that butyrate exerts its inhibitory effects on colon motility at least partially through activation of NO synthesis. In the IBS model group, the NO-dependent mechanisms were less effective probably due to downregulation of NOS. [ABSTRACT FROM AUTHOR]

Background: Postoperative visceral pain is a common complication after endoscopic retrograde cholangiopancreatography (ERCP). In this study, we compared the analgesic and anti-inflammatory effects of oxycodone and fentanyl in children undergoing ERCP. Methods: A single-center, randomized, double-blind study was conducted at a tertiary care hospital affiliated with Shanghai Jiao Tong University. Eighty-two pediatric patients aged 2–18 years who were scheduled for elective ERCP were randomly assigned to receive either oxycodone (0.2 mg/kg) or fentanyl (2 μg/kg). The postoperative pain was evaluated after 10 min, 20 min, and 30 min in the post-anesthesia care unit (PACU) as well as 6 h and 24 h in the ward following ERCP. Additionally, inflammatory cytokines in the serum, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were examined by blood sampling at baseline, 6 h, and 24 h after ERCP. Results: Compared to fentanyl, children receiving oxycodone had significantly lower pain scores at 30 min, 6 h, and 24 h after ERCP, while the scores at 10 and 20 min were similar in both groups. We also found that fewer patients had pain scores ≥3 at 6 h and 24 h after the procedure in the oxycodone group [36.6% (15/41) vs. 61.0% (25/41) at 6 h, 34.1% (14/41) vs. 58.5% (24/41) at 24 h, p = 0.027 for both cases]. Furthermore, fewer children in the oxycodone group had elevated inflammatory cytokines (IL-6 at 6 h and TNF-α at 24 h after ERCP) compared to the fentanyl group. The incidence of postoperative vomiting was also lower among children receiving oxycodone [14.1% (7/41) vs. 24.4% (10/41), p = 0.032]. Conclusion: Oxycodone (0.2 mg kg−1) can provide effective analgesia and stable hemodynamics in children undergoing ERCP. This analgesic characteristic may be related to amelioration of inflammation after ERCP. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300074473. [ABSTRACT FROM AUTHOR]

Background Dyspareunia, defined as pain before, during or after intercourse, is a subset of female sexual dysfunction with overlapping gynecologic, urologic and psychosocial etiologies. Aim This study aimed to evaluate the impact of menstrual pain and visceral hypersensitivity on sexual function and to identify risk factors for sexual pain in healthy reproductive-age females. Methods In this prospective cohort study, we evaluated gynecologic and psychologic self-reported histories, validated sexual function questionnaires, and conducted a standardized gynecologic examination enhanced by quantitative sensory testing in reproductive-aged females with menstrual pain versus pain-free controls. Correlation analysis was conducted between the Female Sexual Function Index (FSFI) pain subdomain score and a priori hypothesized risk factors for dyspareunia: menstrual pain severity, experimentally provoked bladder sensitivity, anxiety, depression, pain catastrophizing, and vaginal pressure-pain sensitivity. Outcomes The primary outcome was severity of sexual pain as measured by the FSFI, comparing participants with moderate-to-severe dysmenorrhea (n = 99), dysmenorrhea with bladder hypersensitivity (n = 49) identified on non-invasive oral water challenge, and pain-free controls (n = 37). Results In our young (median age 22 [IQR 19, 29]), nulliparous, predominantly heterosexual cohort (78.3%, 144/185), 64.3% (119/185) engaged in sexual intercourse within the four-week recall period. The median total FSFI score was 27.2 (22.0, 30.2). Across groups, only the dysmenorrhea with bladder hypersensitivity phenotype met the threshold for sexual dysfunction as measured by total FSFI score (24.6 [20.0, 28.1], p  = 0.008). Dysfunction was driven by difficulties with lubrication and higher pain levels during and after intercourse. On physical examination, those with and without dyspareunia were largely indistinguishable, with little to no tenderness of the pelvic floor, bladder, uterus and uterosacral ligaments. Amongst the six hypothesized risk factors for sexual pain, only experimentally provoked bladder pain was significantly associated with the severity of dyspareunia (r = 0.41, corrected p  < 0.001). Clinical Implications Young, otherwise healthy individuals with dysmenorrhea and occult visceral hypersensitivity exhibit signs of sexual dysfunction and significantly higher rates of dyspareunia in the absence of reliable clinical examination findings. Strengths and Limitations Strengths include the use of a nonclinical sample of almost exclusively nulliparous females with no co-morbid pelvic pain diagnoses and prospective diary confirmation of dysmenorrhea severity. The study is limited by the narrow heteronormative, cisnormative sexual experience of penile-vaginal intercourse captured by the FSFI. Conclusion Sexual pain is more prevalent in those with dysmenorrhea with bladder hypersensitivity than isolated dysmenorrhea, suggesting visceral hypersensitivity may be a non-structural mechanistic driver for dyspareunia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the efficacy and disease outcome of vitamin D combined with fecal microbiota transplantation in patients with diarrhea-type irritable bowel syndrome ( IBS-D). METHODS: A total of 122 patients with IBS-D admitted into the hospital from May 2022 to Oct. 2023 were extracted to be divided into the control group and study group by the random number table method, with 61 cases in each group. On the basis of routine treatment, the control group received fecal microbiota transplantation, while the study group was given vitamin D combined with fecal microbiota transplantation. Clinical efficacy, gut microbiot, visceral sensitivity indices and recurrence rates in 3 months between two groups were compared. RESULTS: Totally 58 cases in the control group and 59 cases in the study group completed the study. The total effective rate of study group was higher than that of control group [ 94. 9% (56 / 59) vs. 81. 0% (47 / 58)], the difference was statistically significant (P<0. 05). After treatment, severity scale scores of IBS and total scores in the study group were lower than those in the control group, Bifidobacterium faecalis and Lactobacillus were higher than those in the control group, Enterococcus were lower than those in the control group, initial rectal sensation threshold, initial defecation impulse threshold and maximum tolerance capacity increased, serum 5-hydroxytryptamine and substance P levels were lower than those in the control group, the differences were statistically significant (P<0. 05). Among the two groups of patients with effective treatment, the recurrence rate of study group was lower than that of control group [5. 4% (3 / 56) vs. 19. 1% (9 / 47)], with statistically significant differences (P<0. 05). CONCLUSIONS: Vitamin D combined with fecal microbiota transplantation can improve clinical efficacy of patients with IBS-D, reduce the disease recurrence, regulate the gut microbiota and reduce the visceral hypersensitivity. [ABSTRACT FROM AUTHOR]

Cisplatin, a chemotherapeutic drug, is known for causing gastrointestinal disorders and neuropathic pain, but its impact on visceral sensitivity is unclear. Monosodium glutamate (MSG) has been shown to improve gastrointestinal dysmotility and neuropathic pain induced by cisplatin in rats. This study aimed to determine if repeated cisplatin treatment alters visceral sensitivity and whether dietary MSG can prevent these changes. Male Wistar HAN rats were treated with saline or cisplatin (2 mg/kg/week, ip) for 5 weeks, and visceral sensitivity to intracolonic mechanical stimulation was recorded after the final cisplatin administration (week 5) and one-week post-treatment (week 6). In a second cohort, rats treated with cisplatin or saline also received MSG (4 g/L) in their drinking water, and visceral sensitivity was evaluated on week 6. Finally, the untouched distal colon was obtained from a third cohort of animals one week after treatment to assess immunocyte infiltration. Cisplatin significantly increased colonic mechanical sensitivity on week 6 but not on week 5. MSG did not prevent cisplatin-induced visceral hypersensitivity on week 6 and even exacerbated it. On week 6, compared with the control, cisplatin (with or without MSG) did not modify the colonic infiltration of eosinophils, macrophages, neutrophils, or mast cells. Although MSG seems to be useful in ameliorating some of the adverse effects of cisplatin, such as gastrointestinal motility disturbances or neuropathic pain, it does not alleviate visceral pain. [ABSTRACT FROM AUTHOR]

Thoracic surgery is associated with significant postoperative pain, which can hinder recovery and elevate morbidity risks. Traditionally, epidural anesthesia has been the cornerstone for pain management, but its drawbacks including technical challenges, side effects, and complications necessitate exploring alternative methods. This narrative review examined recent advances in perioperative analgesic strategies in thoracic surgery, focusing on regional anesthetic techniques like paravertebral blocks (PVBs), erector spinae plane blocks (ESPBs), intercostal blocks, and serratus anterior blocks. Each approach was evaluated for efficacy, safety, and impact on patient outcomes. PVB can provide effective unilateral analgesia with fewer systemic complications compared to epidurals. ESPB provides analgesia through a superficial, ultrasound-guided approach, minimizing risks and offering an alternative for various thoracic procedures. Intercostal blocks are effective but are limited by the need for multiple injections, increasing the complication risks. Serratus anterior blocks, targeting intercostal and thoracic nerves, show promise in managing lateral thoracic wall pain with a low complication rate. Advancements in surgical techniques including minimally invasive approaches further optimize pain control and recovery. A multimodal analgesic approach combining regional anesthesia and systemic therapies enhances outcomes by addressing somatic and visceral pain components. Despite the efficacy of epidural analgesia, alternative regional techniques offer comparable pain relief with fewer complications, suggesting their growing role in thoracic surgery. Collaborative efforts between surgical, anesthetic, and emergency teams are crucial for tailoring pain management strategies to individual patients, improving recovery and reducing long-term morbidity. Future research should continue exploring these methods to refine their application and broaden their accessibility. [ABSTRACT FROM AUTHOR]

Glomerular hyperfiltration is an early indicator of obesity-related glomerular disease. However, in adolescents, there are no quantifiable indicators of obesity and glomerular hyperfiltration. This study investigates the association between visceral adipose tissue and glomerular hyperfiltration in adolescents. This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES; 2011–2018), and adolescents aged 12–17 years were included. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) formed the independent variables while estimated glomerular filtration rate (eGFR) acted as the dependent variable. Their association was assessed using unadjusted and multivariate regression analyses, as well as subgroup and interaction analyses. Multivariate regression analysis revealed that VAT was positively associated with eGFR and glomerular hyperfiltration among adolescents. The incidence of glomerular hyperfiltration increased by 99 % in boys and 56 % in girls per 100 g of VAT increase. Additionally, VAT and eGFR exhibited a linear relationship in both boys (β = 5.63, p < 0.001) and girls (β = 2.72, p < 0.001). In US adolescents aged 12–17 years, VAT was positively correlated with eGFR and glomerular hyperfiltration. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Key Results Conclusions and Inferences Disorders of gut–brain interaction (DGBI) predominate in women, but little is known about sex differences in menses‐related or menopause symptoms.Using data from the Rome Foundation Global Epidemiology Survey, we assessed Rome IV DGBI symptoms in individuals in 26 countries who met criteria for ≥ 1 of 5 DGBI: irritable bowel syndrome (IBS), functional dyspepsia (FD), functional constipation (FC), functional diarrhea (FDr), or functional bloating (FB). Participants included pre‐ and post‐menopausal women with DGBI and age‐matched men. Odds ratios estimated sex and age differences for symptom by sex or pre‐ vs. post‐menopause in logistic regression; standardized mean difference (SMD) provided effect sizes.14,570 participants met criteria for ≥ 1 of the 5 DGBI. Women exceeded men in most symptoms. In FD, women stopped eating due to early satiety more than men (11.1 vs. 8.9 days/month, SMD 0.21). Symptoms were generally increased in premenopausal women and younger men compared to older counterparts; however, only premenopausal IBS, FD, and FC women reported increased constipation‐associated symptoms. Compared to premenopausal women, postmenopausal women had increased accidental stool leakage in IBS and FDr, and increased digital manual maneuvers in FC (18% vs. 25% frequency, SMD −0.25). IBS and FD had the most menses‐associated symptoms.Women had higher symptom frequency across the 5 DGBI compared to men. Our findings suggest that premenopausal women have greater visceral perception than postmenopausal women, although increased outlet symptoms in postmenopausal women indicate greater anorectal/pelvic dysfunction. While age alone has some influence on symptoms, female sex hormones may also increase visceral perception. [ABSTRACT FROM AUTHOR]

The increasing dysfunction of the thyroid gland, particularly hypothyroidism, and its multifaceted effects on the gastrointestinal tract, such as potential changes in hormonal receptor sensitivity, neuromuscular disorders, and myopathy caused by infiltration of the colonic wall, lead to impaired bowel function. Although constipation remains the most common gastrointestinal complaint in hypothyroidism, hypomotility may contribute to excessive bacterial growth in the small intestine and the development of diarrhea. The aim is to study the role of visceral hypersensitivity and cortisol levels in patients with intestinal dysfunction in coexisting hypothyroidism and in those with constipation or diarrhea without thyroid dysfunction. Materials and methods. A total of 41 patients with hypothyroidism were examined, of whom 24 were diagnosed with persistent constipation and 17 with diarrhea, along with 36 patients with irritable bowel syndrome (IBS) (control group), of whom 22 had constipation and 14 had diarrhea. In all the patients, visceral hypersensitivity was assessed using the Visceral Sensitivity Index (VSI), and serum cortisol levels were measured by enzyme-linked immunosorbent assay (ELISA) using commercial kits from Sanguin (USA). Fecal calprotectin levels were assessed with the Human CALPE (Calprotectin) ELISA KIT by Elabscience (USA). Results. VSI was higher in patients with hypothyroidism and diarrhea and scored 66.0 (61.0; 68.0) points. In individuals with IBS and diarrhea without thyroid dysfunction, VSI was 58.0 (54.0; 62.0) points. Meanwhile, VSI was 65.0 (60.0; 69.0) points in patients with constipation due to hypothyroidism, whereas in IBS patients without thyroid dysfunction, it was significantly lower -- 24.0 (22.0; 26.0) points (p < 0.05). In the control group without bowel and thyroid pathology, VSI scored 15.0 (12.0; 18.0) points. The serum cortisol level in patients with hypothyroidism and diarrhea was 305.41 (270.24; 309.3) nmol/L, while in patients with IBS and diarrhea without thyroid dysfunction, it was 211.0 (205.0; 222.5) nmol/L. In patients with constipation due to hypothyroidism, the serum cortisol level was 310.625 (308.440; 337.285) nmol/L, whereas in IBS patients with constipation, it was 178.0 (172.0; 187.5) nmol/L. For healthy individuals, the cortisol level was 158.0 (152.0; 167.5) nmol/L. A direct correlation has been found between a high degree of visceral sensitivity and cortisol levels in patients with hypothyroidism and constipation, as well as an inverse correlation in patients with hypothyroidism and diarrhea. The obtained data may indicate a shift towards hypersensitivity and the development of symptoms characteristic of IBS. Conclusions. Visceral hypersensitivity is observed both in cases of diarrhea developing against the background of hypothyroidism and in irritable bowel syndrome with a similar clinical presentation. At the same time, in cases of constipation associated with hypothyroidism, hypersensitivity is also present but tends to be less pronounced in IBS with constipation. Patients with hypothyroidism, regardless of the presence of constipation or diarrhoea, have an increase in blood cortisol levels, while in some variants of IBS, they do not differ significantly from those of healthy individuals. A direct correlation was found between a high degree of visceral hypersensitivity and cortisol levels in hypothyroid patients with constipation and the opposite in hypothyroid patients with diarrhoea. [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disease. Recently, an increasing number of studies have shown that Toll-like receptor 4 (TLR4), widely distributed on the surface of a variety of epithelial cells (ECs) and immune sentinel cells in the gut, plays a vital role in developing IBS. Objectives: We sought to synthesize the existing literature on TLR4 in IBS and inform further study. Methods: We conducted a systematic search of the PubMed, Embase (Ovid), Scopus, Web of Science, MEDLINE, and Cochrane Library databases on June 8, 2024, and screened relevant literature. Critical information was extracted, including clinical significance, relevant molecular mechanisms, and therapeutic approaches targeting TLR4 and its pathways. Results: Clinical data showed that aberrant TLR4 expression is associated with clinical manifestations such as pain and diarrhea in IBS. Aberrant expression of TLR4 is involved in pathological processes such as intestinal inflammation, barrier damage, visceral sensitization, and dysbiosis, which may be related to TLR4, NF-κB, pro-inflammatory effects, and CRF. Several studies have shown that many promising therapeutic options (i.e., acupuncture, herbs, probiotics, hormones, etc.) have been able to improve intestinal inflammation, visceral sensitization, intestinal barrier function, intestinal flora, defecation abnormalities, and depression by inhibiting TLR4 expression and related pathways. Conclusion: TLR4 plays a crucial role in the development of IBS. Many promising therapeutic approaches alleviate IBS through TLR4 and its pathways. Strategies for targeting TLR4 in the future may provide new ideas for treating IBS. [ABSTRACT FROM AUTHOR]

Background: Visceral hypersensitivity syndrome is a condition involving excessive perception of mechanical stimuli in the intestines. In patients suffering from this disorder, physiological bowel function causes pain and discomfort. Case summary: The patient presented is a 26-year-old man with severe gastrointestinal symptoms that were difficult to manage, such as heartburn, pressure in the esophageal region, a sensation of a gullet in the throat, food retention, and frequent belching. The man had been experiencing these symptoms intermittently for four years, during which time he had been treated without success. By way of exclusion, a diagnosis of visceral hypersensitivity was made, and a low dose of amitriptyline was administered. Psychological therapy was also recommended. This treatment brought significant improvement and resulted in the resolution of his complaints. Conclusions: Visceral hypersensitivity is strongly associated with psychosocial factors, which should be taken into account when treating patients with gastrointestinal disorders. Low doses of amitriptyline may be an effective treatment option. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a chronic disorder of the gastrointestinal tract. Its pathogenesis involves multiple factors, including visceral hypersensitivity and immune activation. NLRP3 inflammasome is part of the nucleotide-binding oligomerization domain-like receptor (NLR) family, a crucial component of the innate immune system. Preclinical studies have demonstrated that inhibiting NLRP3 reduces visceral sensitivity and IBS symptoms, like abdominal pain, and diarrhea, suggesting that targeting the NLRP3 might represent a novel therapeutic approach for IBS. This review aims to assess the NLRP3 inhibitors (tranilast, β-hydroxybutyrate, Chang-Kang-fang, paeoniflorin, coptisine, BAY 11-7082, and Bifidobacterium longum), highlighting the signaling pathways, and their potential role in IBS symptoms management was assessed. Although premature, knowledge of the action of synthetic small molecules, phytochemicals, organic compounds, and probiotics might make NLRP3 a new therapeutic target in the quiver of physicians' therapeutic choices for IBS symptoms management. [ABSTRACT FROM AUTHOR]

Abstract The Economy of action hypothesis postulates that bodily states rescale the perception of the individual’s environment’s spatial layout. The estimation of distances and slopes in navigation space (i.e. the space reachable by locomotion) is influenced by sensations relating to body condition and the metabolic cost of the actions. The results of the studies investigating the impact of pain on distance estimation remain inconclusive. 28 women suffering from chronic pain and fibromyalgia (FM), and 24 healthy women (HC) were assessed for musculoskeletal, neuropathic, and visceral pain by means of the Widespread Pain Index, the Symptom Severity Scale and an ad-hoc devised questionnaire for pain (the Verona Pain Questionnaire). In a VR-mediated task, they observed a 3D scenario and estimated the distance of a flag positioned at different distances (1, 2, 3, 4 or 5 m) on virtual ramps with either a 4% or 24% inclination in two different conditions: sitting and standing. Overestimation of distances in the steeper ramp condition was expected, if participants executed the task by internally simulating the movement. The results showed a dissociation between the effects of musculoskeletal and visceral-neuropathic pain on distance estimations. While, according to the Economy of Action hypothesis, the HCs estimated the distances as being farther away when the ramp was more inclined (i.e. with a 24% inclination), there was no effect related to the different ramp inclinations in the FM group. Furthermore, visceral and neuropathic pain were found to affect the performance of the FM group. These results suggest that chronic and widespread pain conditions, that typically characterize fibromyalgia, can affect space representations. In line with the Economy of Action hypothesis, bodily based estimation of distances is compromised in these patients.

PURPOSE: Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. METHODS: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. RESULTS: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. CONCLUSION: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052085).

Visceral pain (VP), from internal organs, is one of the main reasons for health consultations and represents a source of chronic pain. It can provoke referred musculoskeletal pain, viscero-somatic pain, hyperalgesia, and allodynia. The objective of this narrative review is to analyse the underlying mechanisms of somatic reflexed VP and viscero-visceral sensitisation processes that can occur in women with dysmenorrhea. The affectation of one viscera can lead to a sensitisation in those where metameric innervation is shared. In women with dysmenorrhea and painful menstrual periods, some studies find a concomitance increase in gastrointestinal pathologies. VP is a source of chronic pain, that favours the perception of referred pain in tissues where metameric innervation is shared. Women with dysmenorrhea have more possibilities to develop gastrointestinal pathologies like irritable bowel syndrome.

Abstract The purpose of this study was to investigate the effects of different electrical stimulation methods (bilateral electroacupuncture (BEA), unilateral EA (UEA), transcutaneous electrical acustimulation (TEA, stimulation via surface electrodes placed at acupoints), and sacral nerve stimulation (SNS)) on visceral pain in a rodent model of irritable bowel syndrome (IBS). Ten-day-old male and female pups were treated with 0.2 ml of 0.5% acetic acid (AA) solution. Visceral sensitivity was assessed using an electromyogram (EMG) in response to graded colorectal distension. In the first experiment, bilateral EA at ST36 acupoint was performed with different parameters in male rats to determine the best stimulation parameters. In the second experiment, male rats were randomly assigned into the Sham, BEA, UEA, TEA, and SNS groups to determine the best stimulation method. Lastly, the AA-treated female rats were randomly assigned into the BEA and sham groups to investigate a potential treatment difference between the sexes. Two distinct sets of stimulation parameters were used: Set 1 (100 Hz, 0.5 ms pulse width, 0.1 s ON, 0.4 s OFF, 0.4–3.0 mA current) and Set 2 (25 Hz, 0.5 ms pulse width, 2 s ON, 3 s OFF, 0.4–3.0 mA current). Results (1) The parameter set of 100Hz was found to be most effective in reducing visceral pain. (2) Both acute UEA and TEA effectively relieved visceral pain, whereas acute SNS did not exhibit such an effect. (3) Acute BEA improved visceral pain in both male and female rats. Conclusions These findings suggest that transcutaneous ST36 stimulation is as effective as direct ST36 stimulation and unilateral ST36 stimulation is comparable to bilateral stimulation. Development of a novel therapy using unilateral transcutaneous ST36 stimulation is warranted.

Abstract Neuronal ensemble activity entrained by local field potential (LFP) patterns underlies a variety of brain functions, including emotion, cognition, and pain perception. Recent advances in machine learning approaches may enable more effective methods for analyzing LFP patterns across multiple brain areas than conventional time-frequency analysis. In this study, we tested the performance of two machine learning algorithms, AlexNet and the Transformer models, to classify LFP patterns in eight pain-related brain regions before and during acetic acid-induced visceral pain behaviors. Over short time windows lasting several seconds, applying AlexNet to LFP power datasets, but not to raw time-series LFP traces from multiple brain areas, successfully achieved superior classification performance compared with simple LFP power analysis. Furthermore, applying the Transformer directly to the raw LFP traces achieved significantly superior classification performance than AlexNet when using LFP power datasets. These results demonstrate the utility of the Transformer in the analysis of neurophysiological signals, and pave the way for its future applications in the decoding of more complex neuronal activity patterns.

Background: This study explored the potential of electrogastrography (EGG) and heart rate variability (HRV) as psychophysiological markers in experimental pain research related to the gut-brain axis. We investigated responses to the experience of pain from the visceral (rectal distension) and somatic (cutaneous heat) pain modalities, with a focus on elucidating sex differences in EGG and HRV responses. Methods: In a sample of healthy volunteers (29 males, 43 females), EGG and ECG data were collected during a baseline and a pain phase. Data were analyzed for changes in gastric myoelectrical activity and cardiac autonomic regulation, with special attention to sex-specific patterns and correlations with perceptual responses to visceral and somatic pain stimuli, assessed by visual analogue scale ratings. Results: Acute pain induced significant instability in EGG slow-wave frequency and amplitude, increased tachygastria, and decreased normogastric spectral power, without evidence of sex differences. HRV analyses revealed increases in SDNN, RMSSD, and pNN50 during pain, indicating sympathovagal regulation changes. While there were no significant sex differences in EGG responses, only female participants exhibited significant correlations between visceral pain unpleasantness and EGG alterations. HRV measures, particularly time-domain parameters, showed sex differences, independent of pain-induced autonomic reactivity. Conclusion: The experience of pain in the lower abdominal region may induce impaired gastric motility. EGG and HRV are sensitive to acute pain and offer insight into pain mechanisms along the gut-brain axis. While EGG responses were consistent across sexes, HRV revealed sex-specific differences, suggesting that autonomic regulation and gastric motility may be modulated differently by pain and psychosocial factors. Further research in patients with chronic visceral pain is warranted. [ABSTRACT FROM AUTHOR]

Abdominal pain presents an onerous reality for millions of people affected by gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a new analgesic drug target with OTR expression upregulated on colon‐innervating nociceptors in chronic visceral hypersensitivity states, accessible via luminal delivery. However, the low gastrointestinal stability of OTR's endogenous peptide ligand oxytocin (OT) is a bottleneck for therapeutic development. Here, we report the development of potent and fully gut‐stable OT analogues, laying the foundation for a new area of oral gut‐specific peptide therapeutics. Ligand optimisation guided by structure‐gut‐stability‐activity relationships yielded highly stable analogues (t1/2>24 h, compared to t1/2<10 min of OT in intestinal fluid) equipotent to OT (~3 nM) and with enhanced OTR selectivity. Intra‐colonic administration of the lead ligand significantly reduced colonic mechanical hypersensitivity in a concentration‐dependent manner in a mouse model of chronic abdominal pain. Moreover, oral administration of the lead ligand also displayed significant analgesia in this abdominal pain mouse model. The generated ligands and employed strategies could pave the way to a new class of oral gut‐specific peptides to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs. [ABSTRACT FROM AUTHOR]

Chronic visceral pain stems from internal organs and is frequently associated with functional gastrointestinal disorders, like irritable bowel syndrome (IBS). Since the underlying mechanisms of visceral pain remain largely unclear, clinical management is often limited and ineffective. Comprehensive research into the pathogenesis of visceral pain, along with the development of personalized therapeutic strategies, is crucial for advancing treatment options. Studies suggest that imbalances in purinergic receptors and neural circuit function are closely linked to the onset of visceral pain. In this review, we will explore the etiology and pathological mechanisms underlying visceral pain, with a focus on ion channels, epigenetic factors, and neural circuits, using functional gastrointestinal disorders as case studies. Finally, we will summarize and evaluate emerging treatments and potential initiatives aimed at managing visceral pain. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon‐projecting sensory neurons suggests that non‐neuronal cells may contribute to TRPV4‐mediated nociceptor stimulation.Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+ imaging when cultured alone or co‐cultured with colonic mucosa.Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co‐cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+ to GSK1016790A compared with neurons cultured alone.Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics. [ABSTRACT FROM AUTHOR]

Medical devices made of substances (MDMS) have recently gained great popularity in several specialties of internal medicine, including gastroenterology. In the last decades this discipline has known relevant advances in the cure of severe diseases, such as peptic ulcer, gastroesophageal reflux disease and chronic hepatitis C, thanks to the revolutionary development of new drugs able to act on single receptors changing a particular cell function or blocking microbial and viral replication. However, there are many gastroenterological illnesses that are difficult to treat with traditional medicinal products because of their complex and poorly known pathophysiology, which comprises altered motility, visceral hypersensitivity, gut dysbiosis, intestinal mild inflammation with impaired immune function, increased mucosal permeability and abnormal brain-gut interaction. They are mainly represented by esophageal functional disorders (reflux hypersensitivity, functional heartburn), functional dyspepsia, irritable bowel syndrome, functional constipation and functional diarrhea. Traditional drugs do not provide a definitive resolution of these disorders with a multifactorial pathogenesis and they can benefit from the use of MDMS, which seem to have the ability to act on different factors thanks to the synergistic action of their various components. International medical literature already reports many clinical trials performed with the well-known standards for evaluating their efficacy and safety in a great part of the above-mentioned conditions. [ABSTRACT FROM AUTHOR]

Background: Dysmenorrhoea‐Related Pelvic Pain (DRPP) is a common condition, which may or may not include bladder‐related symptoms. Primary health care practitioners (PHCP) rely heavily on language for diagnosis of DRPP‐related conditions. However, there are no established pain descriptors to assist PHCP to determine whether an individual's DRPP may include a bladder component. Aims: To identify differences in the use of pain descriptors in women with DRPP with and without a co‐existing bladder pain component, through an exploratory study of the language of pelvic pain in women. Materials and Methods: A cross‐sectional online survey of Australian and New Zealand women (n = 750, ages 18–49) who have self‐identified pelvic pain. Free text and predetermined pain descriptors used by women with a self‐perceived bladder pain component (DRPPB+, n = 468) were compared to those without bladder pain (DRPPB−, n = 282). Statistical analysis included Pearson χ2, logistic regression and analysis of variance tests using StataCorp Stata Statistical Software combined with qualitative data from AntConc concordance software. Results: Within free‐form text, bloating (P = 0.014) and pressure (P = 0.031) were used more commonly to describe dysmenorrhoea in women with DRPPB+, while the word excruciating (P < 0.001) was more commonly used by women with DRPPB−. From a pre‐determined list of descriptors, pounding (P < 0.001), tingling (P < 0.001), stabbing (P = 0.010), burning (P = 0.002) and cramping (P = 0.021) were more commonly used by women with DRPPB+, than women with DRPPB−. Conclusions: Systematic patterns of word use should encourage practitioners to further enquire about bladder symptoms that may co‐exist with dysmenorrhoea. Knowledge of these words may be useful in targeting diagnostic and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca2+ channels to mediate Ca2+ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors. [ABSTRACT FROM AUTHOR]

Background and Aim: Exosome‐like nanoparticles (ELNs) have emerged as crucial mediators of intercellular communication, evaluated as potential bioactive nutraceutical biomolecules. We hypothesized that oral ELNs have some therapeutic effect on irritable bowel syndrome (IBS). Methods: In our study, ELNs from tea (Camellia sinensis) leaves were extracted by differential centrifugation. We investigated the role of ELNs by assessing visceral hypersensitivity, body weight, bowel habits, tight junctions, and corticotropin‐releasing hormone (CRH) in rats subjected to water avoidance stress (WAS) to mimic IBS with and without ELNs (1 mg/kg per day) for 10 days. Results: The average diameter of ELNs from LCC, FD and MZ tea tree were 165 ± 107, 168 ± 94, and 168 ± 108 nm, the concentration of ELNs were 1.2 × 1013, 1 × 1013, and 1.5 × 1013 particles/mL, respectively. ELNs can be taken up by intestinal epithelial cells. In WAS rats, ELNs significantly restored weight, recovered tight junctions, decreased CRH, and CRH receptor 1 expression levels and inhibited abdominal hypersensitivity in comparison to positive control. Conclusions: Oral tea‐derived ELN improves symptoms of IBS by potentially modulating the CRH pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Visceral pain due to abdominal malignancies or pancreatitis is common in both people and animals. In human medicine, the celiac plexus block or neurolysis are performed in subjects with intractable visceral pain. Ultrasonographic-guided percutaneous techniques for block and/or neurolysis have been described in people. The aim of this study is to describe a percutaneous ultrasound-guided technique to localize the celiac plexus in a pig cadaveric model. The described technique was effective in localizing the celiac plexus in all subjects. Following anatomical and clinical studies, its role in veterinary analgesia should be assessed. Celiac plexus (CP) block (CPB) and neurolysis (CPN) are interventional techniques employed in human analgesia to control visceral pain originating from the upper abdomen. Visceral pain is common in animals and its treatment is challenging. A percutaneous ultrasound (US)-guided approach to the CP has been reported in people but not in veterinary species. The objective of this study is to describe a US-guided percutaneous approach to the CP in a porcine cadaveric model. Cadavers were positioned in right lateral recumbency. The vertebral body of the last thoracic vertebra (T15) was identified (in transverse view) with a left cranial abdominal US scan. Under US guidance, an 18 G Tuohy needle was inserted parallel and ventral to the transverse process of T15. The transducer was gently slid and tilted to have an in-plane view while introducing the needle through the epaxial muscle layer. Once the T15 body was contacted, the needle was advanced towards the ventral surface of the vertebra, and if loss of resistance was present, 2 mL of dye (China Ink) was injected. A laparotomy was performed, and the dyed tissue dissected for histological preparation from 14 cadavers. In all samples submitted for histological study, tissue belonging to the CP was found. The percutaneous ultrasound-guided approach to the CP was effective in localizing the CP in all subjects. Future studies are warranted to identify the clinical utility of this technique in veterinary species. [ABSTRACT FROM AUTHOR]

Background and Aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2‐arachidonoyl glycerol, 2‐AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress‐related model of visceral hypersensitivity induced by the selective corticotropin‐releasing factor receptor subtype 1 (CRF1) agonist, cortagine. Methods: Male Sprague–Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl‐ethanolamide, AEA), oleoyl‐ethanolamide (OEA) and palmitoyl‐ethanolamide (PEA)], and 2‐AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine. Key Results: URB597 inhibited cortagine‐induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2‐AG did not change. URB597 did not modify cortagine‐induced defecation/diarrhea versus vehicle. Conclusions and Inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress‐related visceral hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: An impaired intestinal barrier with the activation of corticotropin‐releasing factor (CRF), Toll‐like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models. Methods: The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague–Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)‐ and CRF‐induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163. Key Results: Intraperitoneal PD149163 (160, 240, 320 μg kg−1) prevented LPS (1 mg kg−1, subcutaneously)‐induced visceral hypersensitivity and colonic hyperpermeability dose‐dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg−1, intraperitoneally). Peripheral atropine, bicuculline (a GABAA receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), astressin2‐B (a CRF receptor subtype 2 [CRF2] antagonist), and intracisternal SB‐334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model. Conclusions and Inferences: PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D2, GABAA, orexin, CRF2, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms. [ABSTRACT FROM AUTHOR]

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