Abdominal Visceral Pain Research Articles

Not Just Cutting It—A Successful Interprofessional Cooperation Between Palliative Care, Pain and Neurosurgery in the Treatment of Intractable Cancer Pain (TH337)

•List three neurosurgical procedures that selectively intervene along the pain processing pathways and to describe their role in the treatment of intractable cancer pain.•Perform case analysis of different clinical cases of patients with intractable cancer pain and to appropriately make an interdisciplinary based patient selection for different neurosurgical procedures. There is a great importance to deliver good pain management to cancer patients suffering from advanced metastatic disease. Unfortunately, there are selected patients for whom pharmacotherapy does not achieve acceptable pain relief or is limited by marked side effects. These patients, may benefit from neurosurgical procedures that selectively intervene along the pain processing pathways. Patients with localized pain can benefit from selective percutaneous cordotomy, while patients who suffer from diffuse pain due to widespread disease are candidates for stereotactic radiofrequency cingulotomy. Patients with intractable abdominal or pelvic visceral pain can benefit from midline myelotomy. A careful patient selection is critical for the success of these procedures. An integrative team consisting of palliative care specialists, pain specialists and a neurosurgeon focused on this task provides a platform to optimize patients' selection. We will present our experience from the interdisciplinary evaluation of cancer patients undergoing neurosurgical interventions for intractable pain. We will review the clinical considerations guiding the choice of the therapeutic approach through representative clinical cases. This concurrent session will provide a review of ablative neurosurgical interventions; the current evidence for their use, their benefits, and risks. Through comprehensive case presentations and analysis, we will discuss patient selection considerations, patient safety and personal preferences guiding the assignment of each procedure to a specific patient.

Involvement of peripheral alpha2A adrenoceptor in the acceleration of gastrointestinal transit and abdominal visceral pain induced by intermittent deprivation of REM sleep

Many studies have associated sleep alterations with the severity of irritable bowel syndrome (IBS) symptoms, but the direct pathophysiological relationship has not been clarified. In addition, alterations in noradrenergic signaling have been implicated in the pathophysiology of IBS, and alpha2-adrenoceptors are potential treatment targets. We have previously shown that acceleration of gastrointestinal transit (GIT) elicited by intermittent rapid eye movement (REM) sleep deprivation stress may fulfill the profile of a model of IBS. Moreover, we showed hypernoradrenergic function in the brain of sleep-deprived mice. On the other hand, acetic acid-induced writhes indicate visceral pain features of IBS model animals. In this study, using mice, we investigated whether intermittent REM sleep deprivation stress causes changes in acetic acid-induced writhing and whether the number of writhes and GIT are improved by administration of the hydrophilic clonidine analogue, ST-91. Mice were deprived of REM sleep intermittently using the small-platform method (20h/day) for 3days. The intermittent REM sleep deprivation stress elicited acceleration of GIT and the increased number of writhes was significantly improved by ST-91 treatment. The ID50 values of ST-91 on the GIT in cage-control mice and intermittent REM sleep-deprived mice were 0.24 and 0.70mg/kg, respectively. In addition, the ID50 values of ST-91 on the writhes in cage-control mice and intermittent REM sleep-deprived mice were 0.52 and 0.73mg/kg, respectively. Further, the expression of alpha2A-adrenoceptor was decreased in the distal ileum of intermittent REM sleep-deprived mice compared to that in cage-control mice. Moreover, the effects of ST-91 on GIT and writhes in cage-control and intermittent REM sleep-deprived mice were decreased by the administration of BRL44408 (6mg/kg, i.p.), a selective alpha2A–adrenoceptor antagonist, and not by the administration of imiloxan (3mg/kg, i.p.), or JP-1302 (3mg/kg, i.p.), selective alpha2B-and alpha2C–adrenoceptor antagonists, respectively. These results suggest that the increase in GIT and writhes induced by intermittent REM sleep deprivation stress may serve as a model of diarrhea and visceral pain symptoms in IBS. Further, the onset of these symptoms may be related to the hypofunction of peripheral alpha2A–adrenoceptor.

Neurólise do plexo celíaco

Os autores relatam a experiência com dez pacientes portadores de dor visceral abdominal alta, decorrente de tumores da cabeça do pâncreas, cisto do pâncreas, tumores das vias biliares, do estômago e do cólon e metástase abdominal, submetidos à neurólise do plexo celíaco, por via póstero-lateral, com álcool absoluto, sob neuroleptoanalgesia e controle radioscópico. Utilizando-se uma agulha de aortografia, tipo Santos, a cada lado, procedeu-se à neurólise bilateral do plexo celíaco, entrando-se a 8 cm da linha média, a altura do corpo vertebral de L1, na interseção da última costela e a uma angulação de 45º com a horizontal. Previamente à introdução do agente neurolítico, a cada lado, foram injetados 5 ml de xilocaína a 2% sem vasocontrictor, com a finalidade de obter confirmação clínica do perfeito posicionamento da agulho pelo desaparecimento da dor e pela hipotensão arterial leve. Após à injeção do álcool absoluto, introduzimos corticosteróides de depósito, a cada lado, para redução da nação inflamatória e da dor local. Todos os pacientes apresentaram melhora imediata da dor, sendo hipotensão arterial a complicação mais frequente, não lendo havido complicações neurológicas.

Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation.

Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies.

In Vitro Recording of Mesenteric Afferent Nerve Activity in Mouse Jejunal and Colonic Segments.

Afferent nerves not only convey information concerning normal physiology, but also signal disturbed homeostasis and pathophysiological processes of the different organ systems from the periphery towards the central nervous system. As such, the increased activity or 'sensitization' of mesenteric afferent nerves has been allocated an important role in the pathophysiology of visceral hypersensitivity and abdominal pain syndromes. Mesenteric afferent nerve activity can be measured in vitro in an isolated intestinal segment that is mounted in a purpose-built organ bath and from which the splanchnic nerve is isolated, allowing researchers to directly assess nerve activity adjacent to the gastrointestinal segment. Activity can be recorded at baseline in standardized conditions, during distension of the segment or following the addition of pharmacological compounds delivered intraluminally or serosally. This technique allows the researcher to easily study the effect of drugs targeting the peripheral nervous system in control specimens; besides, it provides crucial information on how neuronal activity is altered during disease. It should be noted however that measuring afferent neuronal firing activity only constitutes one relay station in the complex neuronal signaling cascade, and researchers should bear in mind not to overlook neuronal activity at other levels (e.g., dorsal root ganglia, spinal cord or central nervous system) in order to fully elucidate the complex neuronal physiology in health and disease. Commonly used applications include the study of neuronal activity in response to the administration of lipopolysaccharide, and the study of afferent nerve activity in animal models of irritable bowel syndrome. In a more translational approach, the isolated mouse intestinal segment can be exposed to colonic supernatants from IBS patients. Furthermore, a modification of this technique has been recently shown to be applicable in human colonic specimens.

Pain Outcomes in Patients Undergoing CT-Guided Celiac Plexus Neurolysis for Intractable Abdominal Visceral Pain.

The purpose of this study was to assess outcomes in patients who have undergone celiac plexus neurolysis (CPN) as treatment for refractory abdominal visceral pain at a tertiary care medical center. This study involved retrospective analysis of all patients who had undergone computed tomography (CT)-guided CPN over a 7-year period, as identified in the medical record. Cases were categorized into 1 of 3 groups-group 1: patients getting at least moderate improvement in pain but with improvements subsiding within 2 days; group 2: patients with some sustained pain relief but still requiring heavy doses of narcotics; group 3: patients with major or complete sustained reduction in pain where the narcotic dose was able to be reduced. One hundred thirty-eight cases were identified, 51 of which had no or insufficient follow-up, leaving 87 cases for analysis. Of the 87 cases, 31 (36%) were categorized as group 1, 21 (24%) as group 2, and 35 (40%) as group 3. There were no statistical differences in outcomes based on patient age, gender, time since diagnosis, or type of cancer. Documented postoperative complications were diarrhea (11 cases) and 1 case each of obtundation, hypotension, and presyncopal event. We conclude that patients undergoing CT-guided CPN for abdominal visceral pain achieve moderate or major short-term pain relief in a majority of cases. The procedure is safe with minimal complications.

Preliminary study on attitudes, opinions and knowledge of Italian veterinarians with regard to abdominal visceral pain in dogs

ObjectiveTo determine the attitudes, opinions and knowledge of Italian veterinarians regarding abdominal visceral pain in canine practice. Study designProspective online survey. MethodsAn online questionnaire was created on a Google Form spreadsheet and the weblink was circulated to Italian veterinarians on several mailing lists. The questionnaire, which was available between November 2012 and July 2013, comprised 18 closed, semi-closed and open questions divided into five sections (aetiology, recognition and assessment, drug choices for canine visceral pain, general knowledge about pain management and desire for further education, and demographic information). ResultsA total of 527 responses to the questionnaire were completed. Pancreatitis (19%), gastroenteritis (17%) and gastrointestinal obstructions or foreign bodies (9%) were highlighted as the most frequent causes of abdominal visceral pain. Posture, gait and movement changes (32%) and physiological changes (31%) were commonly quoted for pain recognition and assessment. Most respondents (74%) did not use pain scoring systems. Pancreatitis and peritonitis were considered the most painful abdominal conditions. Opioids (40%), nonsteroidal anti-inflammatory drugs (21%) and tramadol (20%) were cited as drugs for the management of visceral pain. A large percentage of respondents (97%) believed that their knowledge regarding pain management required improvement. There is practitioner interest for more continuing education in the subject. Most respondents were women (66%), aged between 25 and 40 years (57%). Internal medicine (56%), surgery (34%) and anaesthesiology (29%) were the main three speciality areas of interest in this study. Conclusions and clinical relevanceThis online survey represents the opinion of a small number of Italian veterinarians regarding the assessment and treatment of canine abdominal visceral pain. The results show that Italian veterinarians are aware of the main causes and clinical signs of canine visceral pain. Pain-scoring systems are not often used for the recognition and assessment of pain; however, according to these veterinarians, visceral pain is commonly diagnosed.

Effects of Buscopan on human gastrointestinal smooth muscle activity in an ex vivo model: Are there any differences for various sections?

Hyoscine butylbromide (Buscopan ®) is clinically used as an anticholinergic antispasmodic for the treatment of abdominal cramping or visceral pain associated with cramps. However, the spasmolytic efficacy on contractile activity of human gastrointestinal smooth muscle from various sections remains unclear. We aimed to investigate the potentially selective actions of Buscopan on different bowel segments, as well as muscular layers and contractile states. Human smooth muscle tissues of the esophagus, gastric corpus and antrum, jejunum, ileum and colon were obtained. Isometric measurements of circular and longitudinal muscle strips were performed to determine effects of Buscopan on spontaneous activity and induced-contractions by 30mM KCl, 10μM bethanechol and electrical field stimulation (EFS). Buscopan concentration-dependently (10−9–10−5M) inhibited smooth muscle activity, particularly in spasticity evoked by bethanechol and EFS but not high K+. The inhibiting effects were mainly responsible for the antagonism on muscarinic M2 and M3 receptors (IC50 values: 3.1×10−5M vs. 0.9×10−5M). The sensitivity toward Buscopan revealed a tendency of increasing from the esophagus, gastric corpus and antrum to the colon, jejunum and ileum. There was a reversed gradient of mRNA and protein expression of muscarinic M2 and M3 receptors from the blocking effects of Buscopan, which could be ascribed to the fact that a higher concentration of Buscopan was needed to antagonize the spastic contraction to reach the equipotent inhibitory rate in the region with higher muscarinic receptor activity. The findings of different inhibitory effectiveness on various parts of the gastrointestinal tract provide a potential guideline for the clinical application.

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.

Histamine Receptor H1–Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n= 28) or placebo (n= 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P= .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P= .0004). In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.

Medical Abdominal Visceral Pain in Dogs

Abdominal visceral pain of medical origin is one of the most frequent reasons for request of medical treatment in humans. Its control is of paramount importance not only for ethical reasons, but also because, if untreated, pain can cause a stress response leading to alterations concerning many organs and apparatuses. Causes of acute or chronic medical visceral pain in men are numerous, with pain originating from various regions of the body. Considering the similarities with regard to the nervous system between humans and other mammals, it is very likely that pathological conditions that cause visceral pain in men are painful in animals as well. Despite this, in veterinary practice medical visceral pain is rarely considered and poorly treated, often for the difficulty in its identification and for a lack of specific guidelines addressing this specific topic. Moreover, no detailed and specific information on this subject are available in the current literature. The present review lists the main pathologies likely responsible of medical abdominal visceral pain in the canine species, trying to summarize, for each considered condition, the available information regarding the pathogenesis and the management of pain.

5:36 PM, Abstract No. 93 - Pain outcomes in patients undergoing CT-guided celiac plexus neurolysis

To assess outcomes in patients who have undergone celiac plexus neurolysis (CPN) as treatment for malignant abdominal visceral pain at a tertiary care medical center. There is limited data on CPN outcomes using modern techniques with CT guidance. All patients who had undergone CT-guided CPN over a 7-year period were identified using the Montage data and analytics system. The electronic medical record for each case was thoroughly examined and consolidated into a case summary. All statements related to the patient’s visceral pain and CPN procedure (including from clinicians, patients, and/or discharge summaries) were considered relevant for incorporation into the case summary. Cases were then categorized into one of 3 groups. Group 1: No relief or temporary but unsustained relief (defined as patients getting at least moderate improvement in pain, but with improvements subsiding within 2 days); Group 2: Moderate relief (patient with some sustained pain relief but still requiring heavy doses of narcotics); Group 3: Major relief (patient with major or complete sustained reduction in pain and significant reduction in narcotic burden); Complications potentially related to the CPN were also documented. 138 cases were identified, 51 of which had no or insufficient follow-up, leaving 87 cases for analysis. This included 49 inpatient cases and 38 outpatient cases. Of the 87 cases, 31 (36%) were categorized as Group 1, 21 (24%) as Group 2, and 35 (40%) as Group 3. There were no statistical differences in outcomes based on patient age, gender, time since diagnosis, or type of cancer. Documented post-operative complications were diarrhea (11 cases) and one case each of obtundation, hypotension, and pre-syncopal event. Patients undergoing CT-guided CPN for abdominal visceral pain achieve moderate or major short-term pain relief in a majority of cases. The procedure is safe with minimal complications.

Celiac Plexus Neurolysis Using Three Different Techniques for Upper Abdominal Metastatic Pain: Comparison the Effectiveness of the Block

33 patients [13 female] with metastatic intractable upper Abdominal Cancer Pain were treated with celiac plexus neurolytic block with 60% alcohol. Aim of study is to observe the effectiveness of three different techniques of celiac plexus block, unilateral paravertibral, bilateral paravertibral and Paravertibral transaortic approach of celiac plexus blocks under C- arm guidance. Satisfactory pain relief occurs in all three techniques but out- come of transaortic approach a little better than other methods. Pain intensity was assessed by VRS and VAS Scale. Celiac plexus blocks are a suitable technique for upper abdominal visceral metastatic pain. Its effects are prolonged and also increase bowel movement, improve appetite and reduced morphine consumption. This is an initial study and numbers of subject are few. So more study required to get conclusive result. Skilled manpower and appropriate case selection is mandatory for successful results. DOI: http://dx.doi.org/10.3329/bmj.v41i2.18800 Bangladesh Medical Journal 2012 Vol. 41 No. 2: 23-26

Mechanisms underlying the analgesic effect of moxibustion on visceral pain in irritable bowel syndrome: a review.

Irritable bowel syndrome (IBS) is a functional bowel disorder that causes recurrent abdominal (visceral) pain. Epidemiological data show that the incidence rate of IBS is as high as 25%. Most of the medications may lead to tolerance, addiction and toxic side effects. Moxibustion is an important component of traditional Chinese medicine and has been used to treat IBS-like abdominal pain for several thousand years in China. As a mild treatment, moxibustion has been widely applied in clinical treatment of visceral pain in IBS. In recent years, it has played an irreplaceable role in alternative medicine. Extensive clinical studies have demonstrated that moxibustion for treatment of visceral pain is simple, convenient, and inexpensive, and it is being accepted by an increasing number of patients. There have not been many studies investigating the analgesic mechanisms of moxibustion. Studies exploring the analgesic mechanisms have mainly focused on visceral hypersensitivity, brain-gut axis neuroendocrine system, and immune system. This paper reviews the latest developments in moxibustion use for treatment of visceral pain in IBS from these perspectives. It also evaluates potential problems in relevant studies on the mechanisms of moxibustion therapy to promote the application of moxibustion in the treatment of IBS.

Nonorganic pain and visceral hyperalgesia in childhood

Visceral pain is different from the somatic one: visceral receptors have different functional engagement, the nociception degree differ from one organ to another, the few visceral afferent fibers are predominantly unmyelinated and have an extensive divergence in the central nervous system; the responses involve autonomic activation. The matrix of abdominal visceral pain, functional at birth, is overburdened by mechanical, chemical, osmotic impulses; overlapping infections or inflammation, by the released mediators create the conditions for acquiring the peripheral and central “sensibility” and the “pain memory”; behavioral and emotional factors can aggravate the visceral pain matrix hyperreactivity. In this pathogenic context it defines nonorganic pain and its severe form, visceral hyperalgesia. Genetic peculiarities influence the pain sensitivity. Based on the biopsychosocial model of functional disorders, Rome III criteria tagged the abdominal functional pain and the irritable bowel syndrome as a positive diagnosis and not a diagnosis of exclusion. Nonorganic pain, often associated with recurrent abdominal pain is among the most common medical problems encountered in pediatrics. Most patients with mild pain have a good evolution over time; a small percentage present serious and sometimes disabling symptoms. Pediatricians frequently have difficulties in delineation the diagnosis of nonorganic pain and that, sometimes, involves treatment failure. The authors present the epidemiological data, the pathophysiological mechanisms involved, the clinical approach and the therapeutic options on nonorganic pain and visceral hyperalgesia in children.

Disodium Cromoglycate Reverses Colonic Visceral Hypersensitivity and Influences Colonic Ion Transport in a Stress-Sensitive Rat Strain

The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.

Dor visceral abdominal: aspectos clínicos

JUSTIFICATIVA E OBJETIVOS: O abdomen e o local mais frequente das sindromes dolorosas agudas ou cronicas, de dor referida de origem em estruturas distantes ou de dor decorrente de lesoes sistemicas. A dor visceral abdominal ocorre por tensao ou estiramento da parede das visceras ocas ou da capsula das visceras parenquimatosas e pela tracao ou estiramento peritoneal. O diagnostico e o tratamento complexos motivaram este estudo. Os pacientes com dor abdominal cronica usualmente sao subtratados e subdiagnosticados. O tratamento interdisciplinar visa minimizar o sofrimento do paciente, aliviar a dor e melhorar sua qualidade de vida. CONTEUDO: Como as doencas viscerais podem determinar dores de varios tipos e, habitualmente, desafiam os medicos no seu diagnostico e tratamento, os autores descreveram de forma pratica, as caracteristicas dolorosas e as associacoes com as doencas mais incidentes. CONCLUSAO: O tratamento interdisciplinar com a associacao das medidas farmacologicas aos procedimentos de medicina fisica e reabilitacao e ao acompanhamento psicologico diminui o sofrimento e as incapacidades e melhora a qualidade de vida.

Non-Specific Abdominal Pain and Air Pollution: A Novel Association

BackgroundWe studied whether short-term exposure to air pollution was associated with non-specific abdominal pain in epidemiologic and animal studies.MethodsPatients visiting the emergency department with non-specific abdominal pain were identified in Edmonton (1992 to 2002, n = 95,173) and Montreal (1997 to 2002, n = 25,852). We calculated the daily concentrations for ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and particles <10 (PM10) or <2.5 (PM2.5) µm. A case crossover study design was used to estimate the odds ratio (OR) and 95% confidence interval (CI) associated with an increase in the interquartile range of the air pollutants. We investigated differential effects by age and sex. Mice were gavaged with urban particle extracts. In animal models, colonic motility was tested, and visceral abdominal pain was measured using a writhing test, and behavioral response to oil of mustard and neostigmine. Motility and pain was measured acutely (1.5 hours after gavage) and chronically (7-days and 21-days after gavage).ResultsEmergency department visits for non-specific abdominal pain were primarily by women between the ages of 15–24 years. Individuals aged 15 to 24 years were at increased risk of non-specific abdominal pain in Edmonton (same day CO: OR = 1.04, 95% CI = 1.02–1.06; and NO2: OR = 1.06, 95% CI = 1.03–1.09). The risk of air pollution among 15–24 year olds in Montreal was significantly positive (same day CO: OR = 1.11, 95% CI = 1.05–1.17; NO2: OR = 1.09, 95% CI = 1.01–1.16; SO2: OR = 1.17, 95% CI = 1.10–1.25; PM2.5: OR = 1.09, 95% CI = 1.04–1.15). Abdominal pain was increased by an acute gavage of pollution extract but not to chronic exposure to pollutants. Colonic transit was delayed following chronic but not acute exposure with the pollutants.ConclusionsEpidemiological and animal data suggest that short-term exposure to air pollution may trigger non-specific abdominal pain in young individuals.

Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons

Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS.

Efficacy of renal denervation with a standard EP catheter in the 24-h ambulatory blood pressure monitoring—long-term follow-up

Resistant hypertension (HTN), defined as ambulatory blood pressure (BP) above 140/90 mmHg in spite of the concurrent use of three or more antihypertensive drugs, is a serious global health issue. It has been estimated that it may affect 20% to 30% of the HTN population [1]. Only about 30% of these patients are actually adequately controlled according to the target BP. A critical factor in resistant HTN is the hyperactivity of the sympathetic nervous system, which increases progressively and in parallel with HTN stages, indicating that more advanced stages of HTN have a greater adrenergic activity [2]. Recent research could show that catheter-based renal sympathetic denervation is effective in BP lowering in patients with resistant hypertension [3–7]. Usually, a special ablation catheter (Symplicity®, Flex-Catheter, Medtronic/Ardian Inc. USA) is used for this purpose. We could recently show that sympathetic denervation with a standard electrophysiology (EP) catheter is also effective in reduction of blood pressure during 3month follow-up (FU) [7]. The aim of this study was to evaluate the efficacy (measured in the 24-h ambulatory BPmonitoring) and safety of renal sympathetic denervation by using a standard EP catheter during long-term FU (12 months) with a larger group of patients. Therefore, 30 patients with drug-resistant hypertension despite treatment with at least four antihypertensive drugs (mean 6) were treated with RF ablation of the renal artery for sympathetic denervation. Baseline evaluation of patients included physical examination, review of medications, basic blood chemistries (including serum creatinine and proteinuria), and 24-h ambulatory BP measurement. All patients have had secondary forms of hypertension excluded. Baseline parameters and comorbidity of patients are shown in Table 1. The method of the ablation procedure with a standard EP catheter has been previously described indetail [7]. In brief, renal artery stenosiswas excludedby renal angiogram via femoral access. After this, a standard steerable radiofrequency (RF) ablation catheter with a 7-French diameter (Marinr®; Medtronic Inc., Minneapolis, MN, USA) was introduced into both renal arteries, consecutively. We applied six low-power RF applications along the length of each renal artery to create lesions (up to 1 min each). Energy delivery was titrated up to a maximum of 8–13 watts under continuously monitoring of impedance and temperature. During RF ablation, we administered intravenous unfractionated heparin with an activated clotting time target range between 250 and 300 s. Aspirin (100 mg per day) was given at least for 3 months following the procedure. Since RF ablation was accompanied by diffuse visceral abdominal pain, patients received intravenous analgesia (fentanyl at doses up to 0.15 mg and midazolam at doses up to 4 mg). The final renal angiogram at procedure termination showed only renal artery irregularities which were not flow limiting. The median fluoroscopy time in our study was 7.5±3.4 min. We did not observe any complications or side effects during FU. The mean reduction of 24-h ambulatory BP was −15.5 mmHg in systolic BP (p=0.01) and −3.4 mmHg in diastolic BP (p=0.03) at 1 month (n=30), −25.5 mmHg in systolic BP (p=0.0001) and −10.9 mmHg in diastolic BP (p=0.01) at 3 months (n=30), −24.1 mmHg in systolic BP (p=0.0003) and −10.6 mmHg in diastolic BP (p=0.002) at 6 months (n=20), and −15 mmHg in systolic BP (p=0.04) and −4.3 mmHg in diastolic BP (not significant) at 12 months (n=10). The results are shown in Fig. 1. In six patients the number of different drugs could be reduced (−1 in five patients, −2 in one patient) and in one patient the medication increased from 5 to 6 different drugs at 6-month FU. All other patients received unchanged doses of antihypertensive drugs. Serum creatinine and proteinuria as markers of renal function remained stable in the FUperiod. Renal duplex sonography performed at 3 and at 12 months revealed no renal artery stenosis or other abnormalities in all patients. The blood-pressure-lowering in our study was a little less than described in the Symplicity HTN trials that found a reduction in officebased BP of −32/−12 mmHg after 6 months [8] and −27/−17 mmHg after 12 months [3]. However, these differences might be due to methodical aspects. In contrast to the measurement of office-based BP by the Symplicity HTN-1 and HTN-2 investigators, we used 24-h ambulatory BP measurements for our analysis, possibly depicting more real life proportions of blood-pressure-lowering. In fact, the 24-h BP monitoring, which was available in 20 patients of the Symplicity HTN-2 trial at 6 months, showed only a decrease of −11/−7 mmHg from baseline to 6 months follow-up [8], underscoring the efficacy of our approach. Furthermore, after 6 months, 80% of our patients were responders to our treatment, defined by a reduction in BP of 10 mm Hg ormore, which is comparable with the response rate of 84% in the HTN-2 trial. However, we recognize that the small number of patients, especially