Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.

INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.

Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment.

BACKGROUND: Non-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract. Here we examined the effects of the atypical cannabinoid abnormal cannabidiol (Abn-CBD) on wound healing, inflammatory cell recruitment and colitis in mice. METHODS: Colitis was induced in CD1 mice by a single intrarectal administration of trinitrobenzene sulfonic acid (TNBS, 4 mg/100 µl in 30 % ethanol) and Abn-CBD and/or the antagonists O-1918 (Abd-CBD), AM251 (CB1 receptor) and AM630 (CB2 receptor), were administered intraperitoneally (all 5 mg/kg, twice daily for 3 days). The degree of colitis was assessed macro- and microscopically and tissue myeloperoxidase activity was determined. The effects of Abn-CBD on wound healing of endothelial and epithelial cells (LoVo) were assessed in a scratch injury assay. Human neutrophils were employed in Transwell assays or perfused over human umbilical vein endothelial cells (HUVEC) to study the effect of Abn-CBD on neutrophil accumulation and transmigration. RESULTS: TNBS-induced colitis was attenuated by treatment with Abn-CBD. Histological, macroscopic colitis scores and tissue myeloperoxidase activity were significantly reduced. These effects were inhibited by O-1918, but not by AM630, and only in part by AM251. Wound healing of both HUVEC and LoVo cells was enhanced by Abn-CBD. Abn-CBD inhibited neutrophil migration towards IL-8, and dose-dependently inhibited accumulation of neutrophils on HUVEC. CONCLUSIONS: Abn-CBD is protective against TNBS-induced colitis, promotes wound healing of endothelial and epithelial cells and inhibits neutrophil accumulation on HUVEC monolayers. Thus, the atypical cannabinoid Abn-CBD represents a novel potential therapeutic in the treatment of intestinal inflammatory diseases.

Gastroesophageal reflux symptoms not responding to proton pump inhibitor: GERD, NERD, NARD, esophageal hypersensitivity or dyspepsia?

Gastroesophageal reflux (GER) is a common gastrointestinal process that can generate symptoms of heartburn and chest pain. Proton pump inhibitors (PPIs) are the gold standard for the treatment of GER; however, a substantial group of GER patients fail to respond to PPIs. In the past, it was believed that acid reflux into the esophagus causes all, or at least the majority, of symptoms attributed to GER, with both erosive esophagitis and nonerosive outcomes. However, with modern testing techniques it has been shown that, in addition to acid reflux, the reflux of nonacid gastric and duodenal contents into the esophagus may also induce GER symptoms. It remains unknown how weakly acidic or alkaline refluxate with a pH similar to a normal diet induces GER symptoms. Esophageal hypersensitivity or functional dyspepsia with superimposed heartburn may be other mechanisms of symptom generation, often completely unrelated to GER. Detailed studies investigating the pathophysiology of esophageal hypersensitivity are not conclusive, and definitions of the various disease states may overlap and are often confusing. The authors aim to clarify the pathophysiology, definition, diagnostic techniques and medical treatment of patients with heartburn symptoms who fail PPI therapy.

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives.

Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract.

The association between celiac disease and eosinophilic esophagitis in children and adults.

BACKGROUND: An association between eosinophilic esophagitis (EoE) and celiac disease (CD) has been suggested in the literature. Our aim was to confirm and quantify the association between these two diseases. METHODS: All patients in a large Canadian city diagnosed with EoE or CD over a five-year period were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated. RESULTS: Over the five-year study EoE was diagnosed in 421 patients and CD was diagnosed in 763 patients. The incidence of EoE ranged from 2.1 to 10.7 cases per 100,000 population. The incidence of CD ranged from 10.4 to 15.7 cases per 100,000 population. Among the EoE cohort, 83 (20%) cases of EoE and 245 (32%) cases of CD were diagnosed in pediatric patients. The incidence of EoE in the pediatric subpopulation ranged from 3.7 to 6.9 cases per 100,000 population. The incidence of CD in the pediatric subpopulation ranged from 9.5 to 22.7 cases per 100,000 population. The concomitant diagnosis of both EoE and CD was made in three patients, all of whom were pediatric males. The SIR for EoE in the CD cohort was 48.4 (95% CI = 9.73, 141.41) with a SIR for CD within the paediatric EoE cohort of 75.05 (95% CI = 15.08, 219.28). CONCLUSIONS: This study confirms the association between EoE and CD. However, this association may be limited to pediatrics where the risk of each condition is increased 50 to 75-fold in patients diagnosed with the alternative condition. The concomitant diagnosis of these conditions should be considered in pediatric patients with upper gastrointestinal symptoms.

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity.

The enteric nervous system contains excitatory and inhibitory neurons, which control contraction and relaxation of smooth muscle cells as well as gastrointestinal motor activity. Little is known about the exact cellular mechanisms of neuronal signal transduction to smooth muscle cells in the gut. Here we generate a c-Kit(CreERT2) knock-in allele to target a distinct population of pacemaker cells called interstitial cells of Cajal. By genetic loss-of-function studies, we show that interstitial cells of Cajal, which generate spontaneous electrical slow waves and thus rhythmic contractions of the smooth musculature, are essential for transmission of signals from enteric neurons to gastrointestinal smooth muscle cells. Interstitial cells of Cajal, therefore, integrate excitatory and inhibitory neurotransmission with slow-wave activity to orchestrate peristaltic motor activity of the gut. Impairment of the function of interstitial cells of Cajal causes severe gastrointestinal motor disorders. The results of our study show at the genetic level that these disorders are not only due to loss of slow-wave activity but also due to disturbed neurotransmission.

Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

AIMS: Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

New neostigmine-based behavioral mouse model of abdominal pain.

BACKGROUND: Animal models of visceral pain have gained much attention as an important tool to elucidate the possible mechanisms underlying functional gastrointestinal (GI) disorders. Here we report the development of a new, minimally invasive behavioral model of abdominal pain induced by ip administration of neostigmine in mice. METHODS: Spontaneous behavioral responses evoked by ip injection of neostigmine were compared to pain-related behaviors induced by acetic acid solution (ip), mustard oil (MO) and capsaicin (both ic). Pain behaviors were quantified by assessment of defined postures (licking of the abdomen, stretching, squashing of the abdomen and abdominal contractions). Neuronal activation of spinal cord was measured by determining the number of c-Fos-positive cells. RESULTS: Neostigmine (2.5 µg/kg, ip), acetic acid solution (ip), MO and capsaicin (both ic) induced spontaneous behavioral responses in mice, which were blocked by morphine (3 mg/kg, ip), suggesting the involvement of pain signaling pathways. Injection of neostigmine enhanced c-Fos expression in spinal cord neurons. CONCLUSION: The neostigmine model represents a new minimally invasive mouse model to study visceral pain. Based on the neuronal activation pattern in the spinal cord we suggest that this model may be used to study abdominal pain signaling pathways in the GI tract.

Brain-Gut Interactions in IBS.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated prevalence of 10-20%. Current understanding of the pathophysiology of IBS is incomplete due to the lack of a clearly identified pathological abnormality and due to the lack of reliable biomarkers. Possible mechanisms believed to contribute to IBS development and IBS like symptoms include physical stressors, such as infection or inflammation, psychological, and environmental factors, like anxiety, depression, and significant negative life events. Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review the current knowledge on the possible involvement of the BGA in IBS and discuss new directions for potential future therapies of IBS.

Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors.

BACKGROUND: Salvinorin A (SA) has a potent inhibitory action on mouse gastrointestinal (GI) motility and ion transport, mediated primarily by kappa-opioid receptors (KOR). The aim of the present study was to characterize possible antiinflammatory and antinociceptive effects of SA in the GI tract of mice. METHODS: Colonic damage scores and myeloperoxidase activity were determined after intraperitoneal (i.p.), intracolonic (i.c.), and oral (p.o.) administration of SA using the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis in mice. Additionally, KOR, cannabinoid (CB)1, and CB2 western blot analysis of colon samples was performed. The antinociceptive effect of SA was examined based on the number of behavioral responses to i.c. instillation of mustard oil (MO). RESULTS: The i.p. (3 mg/kg, twice daily) and p.o. (10 mg/kg, twice daily) administration of SA significantly attenuated TNBS and DSS colitis in mice. The effect of SA was blocked by KOR antagonist nor-binaltorphimine (10 mg/kg, i.p.). Western blot analysis showed no influence of SA on KOR, CB1, or CB2 levels. SA (3 mg/kg, i.p. and 10 mg/kg, i.c.) significantly decreased the number of pain responses after i.c. instillation of MO in the vehicle- and TNBS-treated mice. The antinociceptive action of SA was blocked by KOR and CB1 antagonists. The analgesic effect of i.c. SA was more potent in TNBS-treated mice compared to controls. CONCLUSIONS: Our results suggest that the drugs based on the structure of SA have the potential to become valuable antiinflammatory or analgesic therapeutics for the treatment of GI diseases.

Cytokines and irritable bowel syndrome: where do we stand?

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, which presents with one or more gastrointestinal symptoms without any structural or organic abnormality. The etiology and pathophysiological mechanisms of IBS remain uncertain. Residual or reactivated inflammation at the molecular level is considered the underlying mechanism of post-infectious IBS. On the other hand, genetic variations in the immunological components of the body, including cytokine gene polymorphisms, are proposed as a potential mechanism of IBS even in patients without previous gastrointestinal infection. Several studies have suggested imbalanced cytokine signaling as an etiology for IBS. In this review, recent findings on cytokine profiles and cytokine gene polymorphisms in patients with IBS are described and the role of cytokines in animal models of IBS is discussed.

Eosinophilic colitis: an update on pathophysiology and treatment.

BACKGROUND: Primary eosinophilic gastrointestinal disorders, a spectrum of inflammatory conditions, occurs when eosinophils selectively infiltrate the gut in the absence of known causes for such tissue eosinophilia. These may be classified into eosinophilic esophagitis, eosinophilic gastroenteritis and eosinophilic colitis (EC). This review focuses on EC: its pathogenesis, epidemiology, clinical presentation, diagnosis and current approach to treatment. SOURCES OF DATA: A literature review published in English was performed using Pubmed, Ovid, Google scholar search engines with the following keywords: eosinophilic gastrointestinal disorder, EC, eosinophils, colitis and gastrointestinal. AREAS OF AGREEMENT: The basis for primary EC appears related to increased sensitivity to allergens, principally as a food allergy in infants and a T lymphocyte-mediated event in adults. Endoscopic changes are generally modest, featuring edema and patchy granularity. AREAS OF CONTROVERSY: Clear clinical and pathological diagnostic criteria of EC and its management strategy. GROWING POINTS: Intestinal involvement of EC is primarily mucosal, presenting as a mild self-limited proctitis in infants and self-limited colitis in young adults. Therapeutic approaches based on case reports tend to use either elimination diets to avoid a presumed allergen; agents traditionally used in inflammatory disease or targeted drugs like anti-histamines or leukotriene receptor antagonists. AREAS TIMELY FOR DEVELOPING RESEARCH: Prospective randomized controlled trials addressing the disease natural history, possible preventive methods and effective medical approach and long-term prognosis are required.

Eosinophilic colitis: epidemiology, clinical features, and current management.

Primary eosinophilic gastrointestinal disorders (EGIDs) represent a spectrum of inflammatory gastrointestinal disorders in which eosinophils infiltrate the gut in the absence of known causes for such tissue eosinophilia. EGIDs can be subgrouped as eosinophilic esophagitis (EE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC). The least frequent manifestation of EGIDs is EC. EC is a heterogeneous entity with a bimodal age distribution, presenting with either an acute self-limited bloody diarrhea in otherwise healthy infants or as a more chronic relapsing colitis in young adults. The pathophysiology of primary EC appears related to altered hypersensitivity, principally as a food allergy in infants and T lymphocyte-mediated (i.e. non-IgE associated) in young adults. In adults, symptoms include diarrhea, abdominal pain, and weight loss. Endoscopic changes are generally modest, featuring edema and patchy granularity. Although standardized criteria are not yet established, the diagnosis of EC depends on histopathology that identifies an excess of eosinophils. Therapeutic approaches are based on case reports and small case series, as prospective randomized controlled trials are lacking. Eosinophilic colitis in infants is a rather benign, frequently food-related entity and dietary elimination of the aggressor often resolves the disorder within days. Adolescent or older patients require more aggressive medical management including: glucocorticoids, anti-histamines, leukotriene receptors antagonists as well as novel approaches employing biologics that target interleukin-5 (IL-5) and IgE. This review article summarizes the current knowledge of EC, its epidemiology, clinical manifestations, diagnosis, and treatment.

Prednisolone and budesonide for short- and long-term treatment of microscopic colitis: systematic review and meta-analysis.

BACKGROUND & AIMS: The incidence of microscopic colitis and its disease burden are increasing, yet there is limited systematic information addressing the use of conventional corticosteroids and budesonide in microscopic colitis. We performed a systematic review and meta-analysis on the short- and long-term efficacy of corticosteroids in treatment of microscopic colitis. METHODS: Randomized controlled trials that met predetermined selection criteria were included. Articles were identified through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, proceedings of major gastroenterology meetings, and reference lists of trials and review articles. RESULTS: Eight randomized trials were identified. A total of 248 patients were randomized to corticosteroid versus placebo. The intervention was budesonide in 7 trials and prednisolone in 1 trial. Budesonide was significantly more effective than placebo for short-term clinical response (risk ratio [RR], 3.07; 95% confidence interval [CI], 2.06-4.57) and long-term clinical response (RR, 3.22; 95% CI, 1.05-9.89). Prednisolone was not superior to placebo for short-term clinical response (RR, 2.00; 95% CI, 0.38-10.58). Histologic improvement was seen with both short- and long-term budesonide (RR, 3.76; 95% CI, 2.00-7.06, and RR, 2.50; 95% CI, 1.25-4.98, respectively). Symptom relapse occurred in 46%-80% of patients within 6 months of treatment cessation. Withdrawal because of adverse effects occurred in 4.4% of patients, with no difference between study groups (P = .55). CONCLUSIONS: Both short- and long-term treatment with budesonide is effective and well-tolerated for microscopic colitis. However, the rate of symptom relapse once budesonide is discontinued is high. Further studies are needed to determine optimal treatment duration, dose, and withdrawal procedure.

What is nonacid reflux disease?

Proton pump inhibitors (PPIs) are the gold standard treatment for gastroesophageal reflux disease. In clinical practice, failure of PPIs occurs frequently, and may affect up to 30% of patients in a typical gastroenterology practice. Multichannel impedance monitoring combined with pH monitoring helps to detect nonacid reflux, and if symptoms correlate with these nonacid reflux episodes, nonacid reflux disease can be diagnosed. In contrast to PPIs, reflux inhibitors target transient lower esophageal sphincter relaxations, which are involved in the pathophysiology of reflux disease and may be the appropriate future treatment for nonacid reflux disease. The present article discusses the current understanding of nonacid reflux disease, its diagnosis and treatment.

Juvenile polyposis of the stomach--a novel cause of hypergastrinemia.

BACKGROUND: A 38-year-old female presented with a 3-year history of postprandial abdominal pain, refractory nausea, vomiting and hematemesis. She appeared malnourished and her symptoms were refractory to previous treatment with acid-suppressive drugs, prokinetics and antiemetics. Her medical history was significant for a diagnosis of juvenile polyposis syndrome at the age of 14 resulting in a transverse colectomy, and a diagnosis of Crohn's disease in her residual colon at the age of 35 resulting in a total colectomy. INVESTIGATIONS: Physical examination, blood analysis, esophagogastroduodenoscopy with biopsy, abdominal endoscopic ultrasound, abdominal CT scan, MRI, 24 h urine analysis, MIBG scintigraphy, ocreotide scintigraphy, fluorodeoxyglucose-PET scan and genetic testing for defined polyposis syndromes (SMAD4, BMPR1A). DIAGNOSIS: Juvenile polyposis syndrome with outlet obstruction of the stomach and excessive hypergastrinemia. MANAGEMENT: Continuous acid-suppressive therapy, prokinetic therapy and total parenteral nutrition. Repetitive endoscopic polypectomy (also known as debulking) was performed twice and was followed by gastrectomy with duodenoesophageal anastomosis.

The novel endomorphin degradation blockers Tyr-Pro-DClPhe-Phe-NH (EMDB-1) and Tyr-Pro-Ala-NH (EMDB-2) prolong endomorphin-2 action in rat ileum in vitro.

The endogenous opioid system is involved in the control of gastrointestinal (GI) motility. The potential use of endogenous MOR ligands, endomorphins (EMs), as therapeutics is limited because of their rapid enzymatic degradation and short duration of action. Targeting enzymatic degradation is an approach to prolong EM activity. In the present study, we characterized the effects of novel blockers of EM degradation in GI tissue preparation in vitro. The effects of actinonin, diprotin A (DIP) and the novel peptide EM degradation blockers Tyr-Pro-DClPhe-Phe-NH(2) (EMDB-1), Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3) on EM-2-mediated inhibition of electrically induced cholinergic twitch contractions were compared in rat ileum in vitro using an organ bath. EMDB-1 and EMDB-2 significantly prolonged the inhibitory effect of EM-2 on smooth muscle contractility in rat ileum. EMDB-2 extended the EM-2 action for up to 60 min compared to 10 min in controls and was more potent than the conventional peptidase inhibitor DIP. EMDB-1 and EMDB-2 are potent EM degradation blockers, which prolong the inhibitory effects of EM-2 on smooth muscle contractility in rat ileum. These novel compounds may be of future use when targeting the endogenous opioid system in the treatment of GI motility disorders such as diarrhea.

Microscopic colitis -- a common cause of diarrhoea in older adults.

Diarrhoeal diseases are common in older populations and often markedly affect their quality of life. Although there are numerous potential causes, microscopic colitis (MC) is increasingly recognised as a major diagnostic entity in older individuals. MC is comprised of two distinct histological forms - collagenous colitis and lymphocytic colitis, both of which frequently occur in older populations. Recent studies suggest that between 10 and 30% of older patients investigated for chronic diarrhoea with an endoscopically normal appearing colon will have MC. It is unclear why MC is more common in older populations, but it is associated with both autoimmune disorders and several drugs that are commonly used by seniors. A definitive diagnosis can only be made with colonic biopsies. Since MC was first described in 1976 and only recently recognised as a common cause of diarrhoea, many practising physicians may not be aware of this entity. In this review, we outline the epidemiology, risk factors associated with MC, its pathophysiology, the approach to diagnosis and the management of these individuals.

Novel endomorphin analogues with antagonist activity at the mu-opioid receptor in the gastrointestinal tract.

Opioid bowel dysfunction (OBD) summarizes common adverse side effects of opiate-based management of pain. A promising therapeutic approach to prevent OBD and other opioid-related disorders of the gastrointestinal (GI) tract is the co-administration of opiates with peripherally-restricted mu-opioid receptor (MOR)-selective antagonists. The aim of this study was to investigate the selectivity and efficacy of three novel peptide antagonists: antanal-1, antanal-2, and antanal-2A at MOR in the GI tract in vitro and in vivo. The effects of the antanals on GI motility were studied in vitro, using isolated preparations of mouse ileum and colon and in vivo, by measuring colonic propulsion in mice. Additionally, in vitro stability against enzymatic degradation and blood-brain barrier (BBB) permeability using the hot plate test in mice were examined. The antanals significantly reduced the inhibitory effect of the MOR agonists endomorphin-2, morphine, and loperamide on mouse ileum and colon contractions in vitro and blocked morphine-induced decrease of colonic bead expulsion in vivo. The hot plate test in mice showed that the antagonist activity of all antanals was restricted to the periphery. Antanal-1, antanal-2, and antanal-2A are promising MOR antagonists with limited BBB permeability, which may be developed into future therapeutics of opioid-related GI dysfunction.

Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis.

BACKGROUND: Activation of cannabinoid (CB)(1) receptors results in attenuation of experimental colitis. Our aim was to examine the role of CB(2) receptors in experimental colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB(2) receptor-deficient (CB(2) (-/-)) mice. METHODS: Mice were treated with TNBS to induce colitis and then given intraperitoneal injections of the CB(2) receptor agonists JWH133, AM1241, or the CB(2) receptor antagonist AM630. Additionally, CB(2) (-/-) mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB(2) receptor was also performed in animals with TNBS and dextran sodium sulfate colitis. RESULTS: Intracolonic installation of TNBS caused severe colitis. CB(2) mRNA expression was significantly increased during the course of experimental colitis. Three-day treatment with JWH133 or AM1241 significantly reduced colitis; AM630 exacerbated colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CB(2) (-/-) mice. CONCLUSIONS: We show that activation of the CB(2) receptor protects against experimental colitis in mice. Increased expression of CB(2) receptor mRNA and aggravation of colitis by AM630 suggests a role for this receptor in normally limiting the development of colitis. These results support the idea that the CB(2) receptor may be a possible novel therapeutic target in inflammatory bowel disease.