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Roberto De Giorgio

Publications and source records attributed to Roberto De Giorgio.

At least 19 recordsLinked to original sources
PubMed2006

Enteric neuropathology of congenital intestinal obstruction: A case report.

Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system (ENS), although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations: the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second (2 years later) was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third (9 years after the hyperganglionosis was identified) disclosed a Ladd's band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd's band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital (partial) mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudo-obstruction.

Biopsy↗
PubMed2006

Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon.

BACKGROUND & AIMS: Hydrogen sulfide (H(2)S) has been suggested as a novel gasomediator. We explored its unknown neuromodulatory role in human and guinea-pig colon. METHODS: We used immunohistochemistry to detect H(2)S-producing enzymes cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS) in enteric neurons, Ussing chambers to measure mucosal ion secretion, and neuroimaging with voltage- and Ca(++)-sensitive dyes to record H(2)S effects on guinea-pig and human enteric neurons. RESULTS: More than 90% of guinea-pig and human submucous and myenteric neurons were colabeled for CSE and CBS. Myenteric interstitial cells of Cajal were CSE-immunoreactive. The exogenous H(2)S donor NaHS (0.2-2.5 mmol/L) concentration-dependently increased chloride secretion in human and guinea-pig submucosa/mucosa preparations, but not in the colonic epithelial cell line T84. The secretory response was reduced significantly by tetrodotoxin (0.5 micromol/L), capsaicin desensitization (10 micromol/L), and the transient receptor potentials vanilloid receptor 1 antagonist capsazepine (10 micromol/L). The endogenous H(2)S donor L-cysteine also induced secretion that was diminished significantly by capsaicin desensitization, the CBS inhibitor amino-oxyacetic acid, and the CSE inhibitor propargylglycine. NaHS increased spike discharge in 23% of guinea-pig and 36% of human submucous neurons, but had no effect on Ca(++) mobilization in cultured guinea-pig enteric neurons. This excitatory response was reduced significantly by capsaicin desensitization and capsazepine, but not by glibenclamide (10 micromol/L). CONCLUSIONS: The presence of H(2)S-producing enzymes in human and guinea-pig enteric neurons, the excitatory action on enteric neurons, and the prosecretory effects of NaHS suggest H(2)S as a novel gut-signaling molecule. Its action mainly involves transient receptor potentials vanilloid receptor 1 receptors on extrinsic afferent terminals, which in turn activate enteric neurons.

Adult↗
PubMed2006

Enteric neuroplasticity evoked by inflammation.

Neuroplastic changes in the enteric nervous system (ENS) may be observed in physiological states, such as development and aging, or occur as a consequence of different pathological conditions, ranging from enteric neuropathies (e.g., Hirschsprung's disease) to intestinal (e.g., inflammatory bowel disease) or extra-intestinal diseases (e.g., Parkinson's disease). Studying ENS plasticity may help to elucidate the pathophysiology of several diseases and have a bearing on the development of new pharmacological interventions. In the present review, we would like to focus on neuronal plasticity evoked by gastrointestinal inflammation occurring in inflammatory bowel disease and in a subset of patients with severe derangement of gut motility due to an enteric neuropathy characterized by an inflammatory infiltrate of the enteric plexuses. Major features of neuroplasticity within the enteric microenvironment encompass structural abnormalities ranging from nerve re-arrangement (e.g., hypertrophy and hyperplasia) to degeneration and loss of enteric ganglion cells; altered synthesis, content and release of neurotransmitters as well as up- or down-regulation of receptor systems; gastrointestinal dysfunction characterized by sensory-motor and secretory impairment of the gut. Interestingly, neuronal changes may also occur in segments of the gastrointestinal tract remote from the site of the original inflammation, e.g. the ileum may show neuroplastic changes during colitis. Sometimes, the inflamed site may even be outside the gut. Among potential mechanisms underlying ENS plasticity, neurotrophins and enteric glia deserve special attention. A better comprehension of ENS plasticity during inflammation could be instrumental to develop new therapeutic options for patients with IBD and inflammatory enteric neuropathies.

Animals↗
PubMed2005

Idiopathic Dyspepsia.

Idiopathic dyspepsia refers to pain and/or discomfort perceived in the epigastrium that is not secondary to organic, systemic, or metabolic diseases. Symptoms may overlap with those of gastroesophageal reflux disease and irritable bowel syndrome. Gastrointestinal motor disorders, hypersensitivity to mechanical or chemical stimuli, and psychosocial factors can act individually or in concert to induce the symptoms of dyspepsia. Accordingly, there is no single therapy, and treatment must be individualized. Eradication of Helicobacter pylori infection rarely achieves symptom improvement. Treatment of idiopathic dyspepsia should begin by reassuring the patient about the benign nature of the syndrome and educating them on the knowledge that has been achieved in recent years regarding potential causes of the syndrome. Both prokinetic and antisecretory drugs have been reported to improve dyspeptic symptoms, but results are not completely convincing. Although well-designed studies demonstrate superiority of proton pump inhibitors over placebo, it should be noted that patients with nonerosive gastroesophageal reflux disease were invariably included; when these patients are excluded, the benefit of antisecretory medications is questionable. We suggest that patients with idiopathic dyspepsia be initially treated according to the predominant symptom. Those with epigastric pain/burning should receive a trial with standard doses of proton pump inhibitors for 4 to 8 weeks, whereas prokinetic patients should be prescribed at recommended doses for similar periods of time to patients with nonpainful dyspeptic symptoms such as posprandial fullness, early satiety, nausea, or vomiting. Nonresponders may benefit from combination therapies or short trials with higher doses of drugs. Visceral analgesics and antidepressants can also be prescribed alone or in combinations with other therapeutic strategies. Recent studies demonstrate utility for psychologic therapy and hypnotherapy, although truly controlled studies are difficult in this area. Herbal medicines deserve further evaluation.

Journal Article↗
PubMed2005

Natural history of chronic idiopathic intestinal pseudo-obstruction in adults: a single center study.

BACKGROUND & AIMS: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare disease characterized by episodes resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders. Intestinal motor abnormalities have long been identified in CIIP patients. Little is known of the natural history of the disease in adults. This study evaluated the clinical course of CIIP over time. METHODS: Fifty-nine consecutive CIIP patients without underlying collagen, vascular diseases, or mitochondrial cytopathies were evaluated between 1985 and 2001. Family history, onset of digestive symptoms, previous surgeries, episodes suggestive of subacute intestinal obstruction, digestive symptoms, body mass index, and feeding habits were recorded. Small bowel manometry was performed by a perfusion technique, and abnormal motor patterns were visually identified. Full-thickness biopsies were available in 11 cases and were processed for immunohistochemical analysis of myogenic and neurogenic components of the gut wall. RESULTS: Patients were prospectively followed up for a median of 4.6 years (range, 1-13 years). Diagnosis was often made several years after symptom onset (median, 8 years). Thus, the majority of patients (88%) underwent useless and potentially dangerous surgeries (mean, 2.96 per patient). Manometry invariably showed abnormal motor patterns. Pathologic findings included neuropathies in all investigated cases and abnormalities of interstitial cells of Cajal in 5 of 11 cases. Long-term outcome was generally poor despite surgical and medical therapies; 4 patients died of disease-related complications, 4 underwent small bowel transplantation, almost one third required long-term home parenteral nutrition, and two thirds had some sort of nutritional limitations. CONCLUSIONS: CIIP is a severe, often unrecognized disease characterized by disabling and potentially life-threatening complications over time.

Adolescent↗
PubMed2005

5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum.

BACKGROUND & AIMS: The 5-hydroxytryptamine 7 (5-HT7) receptors mediate intestinal smooth muscle relaxation. In this study, we evaluated the expression of 5-HT7 receptors in the guinea pig ileum and their role in peristalsis and accommodation of the circular muscle. METHODS: We used immunohistochemistry and confocal microscopy with whole tissue and cultured myenteric neurons. Peristalsis was induced by delivering a solution into the oral end of an isolated ileal segment. The effect of the selective 5-HT7 receptor antagonist SB-269970 (100 nmol/L) on peristaltic activity was evaluated at 30, 60, and 90 minutes and compared with control. RESULTS: 5-HT7 receptor immunoreactivity was localized to numerous myenteric neurons, a few submucosal neurons, and a few smooth muscle cells of the ileum. In enteric cultured neurons, 5-HT7 receptor immunoreactivity was observed in subpopulations of after hyperpolarizing neurons and descending neurons as identified by neuron-specific nuclear protein or calbindin and neuronal nitric oxide synthase or vasoactive intestinal peptide antibodies, respectively. SB-269970 significantly increased the threshold pressure by 33.3% +/- 2.2% (P < .001) and by 27.2% +/- 1.6% (P < .05) at 60 and 90 minutes, respectively, without modifying the threshold volume. The accommodation significantly decreased by 27.5% both at 60 and 90 minutes (P < .05). CONCLUSIONS: Our results indicate that endogenous 5-HT is involved in the modulation of circular muscle accommodation during the preparatory phase of peristalsis via the activation of 5-HT7 receptors expressed by neurons in addition to smooth muscle cells. Overstimulation of these receptors leading to an exaggerated accommodation of circular muscle might contribute to abdominal symptoms in functional bowel disorders.

Animals↗
PubMed2005

Interactions between commensal bacteria and gut sensorimotor function in health and disease.

Commensal bacteria inhabiting the human intestine (i.e., intestinal microflora) participate in the development and maintenance of gut sensory and motor functions, including the promotion of intestinal propulsive activity. On the other hand, intestinal motility represents one of the major control systems of gut microflora, through the sweeping of excessive bacteria from the lumen. There is emerging evidence indicating that changes in this bidirectional interplay contribute to the pathogenesis of gut diseases, such as small intestinal bacterial overgrowth and intestinal pseudo-obstruction. Recent interest has also been directed to the potential role of intestinal microflora in the pathogenesis of the irritable bowel syndrome. Although the status of intestinal microflora in the irritable bowel syndrome remains unsettled, small intestinal bacterial overgrowth (as detected with breath testing) and increased fermentation of foods with gas production, provide indirect evidence that microflora may contribute to symptom generation in irritable bowel syndrome. The potential benefit of antibiotic and probiotic therapy is currently under investigation and opens new perspectives in irritable bowel syndrome treatment.

Bacterial Physiological Phenomena↗
PubMed2004

Delayed Gastric Emptying in Functional Dyspepsia.

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.

Journal Article↗
PubMed2004

Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.

BACKGROUND & AIMS: The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. METHODS: IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. RESULTS: Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

Abdominal Pain↗
PubMed2004

Inflammatory neuropathies of the enteric nervous system.

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Enteric Nervous System↗
PubMed2004

Intestinal transplantation for chronic intestinal pseudo-obstruction in adult patients.

Intestinal transplantation (ITx) has become a life-saving procedure for patients with irreversible intestinal failure who can no longer be maintained on parenteral nutrition (PN). This report presents the results of our experience on ITx in patients suffering from chronic intestinal pseudo-obstruction (CIPO). Between December 30, 2000 and May 30, 2003 six adult patients affected by CIPO underwent primary ITx at our Center. Pre-transplant evaluation, indication for ITx and surgical technique are reported. On December 30 2003, the mean follow-up was 25.0 months. No peri-operative deaths occurred in the study population and five out of six patients are alive, with 1-year patient and graft survival of 83.3% and 66.6%. Although our series is limited by the number of patients, our experience suggests that ITx transplantation should be considered in adult patients suffering from CIPO and PN life-threatening complication.

Adult↗
PubMed2004

Progress with novel pharmacological strategies for gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis. In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.

Animals↗
PubMed2004

Prokinetics in the treatment of acute intestinal pseudo-obstruction.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) is characterized by an acute obstruction of the large bowel that is unrelated to mechanical causes. The evidence that cholinesterase inhibitors are effective in relieving acute colonic pseudo-obstruction raised interest in the pharmacological management of this condition. This review analyzes the pharmacological treatment of patients with Ogilvie's syndrome. Intravenous neostigmine is the best pharmacological treatment, leading to rapid colonic decompression. New colokinetic agents, including 5-HT(4) receptor agonists and motilides, may represent other useful therapeutic options for Ogilvie's syndrome.

Animals↗
PubMed2003

Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility.

BACKGROUND & AIMS: The role of autoimmunity underlying paraneoplastic gut dysmotility remains unsettled. Because anti-Hu antibodies may impair enteric neuronal function, we tested whether anti-HuD-positive sera from patients with paraneoplastic gut dysmotility or commercial anti-HuD antibodies activated the apoptotic cascade in a neuroblastoma cell line and cultured myenteric neurons. METHODS: Anti-HuD antibodies from patients with severe paraneoplastic gut dysmotility were characterized by immunofluorescence and immunoblot. SH-Sy5Y neuroblasts and cultured myenteric neurons were exposed to sera containing anti-HuD antibodies or 2 commercial anti-HuD antibodies. Cells were processed for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) technique to evaluate apoptosis. Immunofluorescence was used to identify activated caspase-3 and apaf-1, along with microtubule-associated protein 2. RESULTS: In SH-Sy5Y cells, the percentage of TUNEL-positive nuclei observed after exposure to anti-HuD-positive sera (32% +/- 7%) or anti-HuD antibodies (23% +/- 2%) was significantly greater than that of control sera or fetal calf serum (P < 0.001). The time-course analysis showed a significantly greater number of apoptotic neuroblastoma cells evoked by the 2 commercial anti-HuD antibodies at 24, 48, and 72 hours versus controls. The number of TUNEL-positive myenteric neurons exposed to anti-HuD antibodies (60% +/- 14%) was significantly greater than that of fetal calf serum (7% +/- 2%; P < 0.001). Apaf-1 and caspase-3 immunolabeling showed intense cytoplasmic staining in a significantly greater proportion of cells exposed to anti-HuD-positive sera or to commercial anti-HuD antibodies compared with controls. CONCLUSIONS: Anti-HuD antibodies evoked neuronal apoptosis that may contribute to enteric nervous system impairment underlying paraneoplastic gut dysmotility. Apaf-1 activation suggests participation of a mitochondria-dependent apoptotic pathway.

Apoptosis↗
PubMed2003

Bradykinin B2 receptors mediate contraction in the normal and inflamed human gallbladder in vitro.

BACKGROUND & AIMS: The components of the kinin system, including kinongens, kininogenases, and B(2) and B(1) receptors, are expressed and activated during inflammation. Here, we investigated the expression of the kinin B(2) receptor messenger RNA, kininogen and kallikrein immunoreactivity, and the ability of kinins to contract control and inflamed gallbladders in vitro. METHODS: Human gallbladders, obtained from patients undergoing cholecystectomy either for acute cholecystitis secondary to gallstone disease or during elective gastro-entero-pancreatic surgery (controls), were processed for reverse-transcription polymerase chain reaction analysis, kallikrein and kininogen immunohistochemistry, binding studies, and in vitro contractility studies. RESULTS: Tissue expression of B(2) receptor messenger RNA and specific binding of [(3)H]-bradykinin increased significantly in acute cholecystitis compared to controls. Kallikrein immunoreactivity was detected in the epithelium and infiltrating leukocytes, whereas kininogen immunoreactivity in the lumen of blood vessels and interstitial space. Bradykinin contracted isolated strips of control and acute cholecystitis gallbladders. In acute cholecystitis tissue, efficacy of bradykinin was higher than that of control gallbladders and similar to that of cholecystokinin. The contraction induced by bradykinin was significantly attenuated by B(2) receptor antagonism but not by cyclooxygenase inhibition and B(1), muscarinic, or tachykinin receptor antagonism. CONCLUSIONS: All the components of the kinin system are expressed in the human gallbladder. Bradykinin is a powerful spasmogen via B(2) receptor activation in the normal and, especially, in the inflamed human gallbladder.

Adrenergic beta-Antagonists↗
PubMed2003

Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by alpha2-adrenoceptors in the presence of experimental colitis.

1 This study investigates the influence of intestinal inflammation on: (1) the control of intestinal neurotransmission and motility by prejunctional alpha(2)-adrenoceptors and (2) the expression of intestinal alpha(2)-adrenoceptors. Experimental colitis was induced by intrarectal administration of 2,4-dinitrobenzenesulphonic acid (DNBS) to rats. 2 UK-14,304 inhibited atropine-sensitive electrically evoked contractions of ileal and colonic longitudinal muscle preparations. UK-14,304 acted with similar potency, but higher efficacy, on tissues from DNBS-treated animals; its effects were antagonized with greater potency by phentolamine than rauwolscine. 3 Electrically induced [(3)H]noradrenaline release from ileal preparations was reduced in the presence of colitis. Tritium outflow was decreased by UK-14,304 and stimulated by rauwolscine or phentolamine: these effects were enhanced in preparations from animals with colitis. 4 Reverse transcription-polymerase chain reaction and Western blot assay demonstrated the protein expression of alpha(2A)-adrenoceptors in mucosal and muscular tissues isolated from ileum and colon. The induction of colitis increased alpha(2A)-adrenoceptor expression in both ileal and colonic muscular layers, without concomitant changes in mucosal tissues. 5 Induction of colitis reduced gastrointestinal propulsion of a charcoal suspension in vivo. In this setting, the gastrointestinal transit was inhibited by intraperitoneal (i.p.) UK-14,304 and stimulated by i.p. rauwolscine. After pretreatment with guanethidine, the stimulant action of rauwolscine no longer occurred, and UK-14,304 exerted a more prominent inhibitory effect that was antagonized by rauwolscine. 6 The present results indicate that, in the presence of intestinal inflammation, prejunctional alpha(2)-adrenoceptors contribute to an enhanced inhibitory control of cholinergic and noradrenergic transmission both at inflamed and noninflamed distant sites. Evidence was obtained that such modulatory actions depend on an increased expression of alpha(2A)-adrenoceptors within the enteric nervous system.

Acetylcholine↗