Hons IM, Burda JE, Grider JR, Mawe GM, Sharkey KA. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig. Am J Physiol Gastrointest Liver Physiol 296: G717-G726, 2009. First published February 12, 2009 doi:10.1152/ajpgi.90472.2008.-Inflammatory bowel diseases (IBD) can involve widespread gastrointestinal dysfunction, even in cases in which inflammation is localized to a single site. The underlying pathophysiology of dysfunction in noninflamed regions is unclear. We examined whether colitis is associated with altered electrogenic ion transport in the ileal mucosa and/or changes in the properties of ileal submucosal neurons. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS), and the uninflamed ileum from animals was examined 3, 7, and 28 days later. Electrogenic ion transport was assessed in Ussing chambers. Intracellular microelectrode recordings were used to examine the neurophysiology of the submucosal plexus of the ileum in animals with colitis. Noncholinergic secretion was reduced by 33% in the ileum from animals 7 days after the induction of colitis. The epithelial response to vasoactive intestinal peptide (VIP) was unaltered in animals with colitis, but the response to carbachol was enhanced. Slow excitatory synaptic transmission was dramatically reduced in VIP-expressing, noncholinergic secretomotor neurons. This change was detected as early as 3 days following TNBS treatment. No changes to fast synaptic transmission or the number of VIP neurons were observed. In addition, cholinergic secretomotor neurons fired more action potentials during a given stimulus, and intrinsic primary afferent neurons had broader action potentials in animals with colitis. These findings implicate changes to enteric neural circuits as contributing factors in inflammation-induced secretory dysfunction at sites proximal to a localized inflammatory insult. submucosal plexus; electrogenic secretion; ion transport; synaptic transmission; vasoactive intestinal peptide THE INTEGRATIVE NERVE CIRCUITRY of the enteric nervous system (ENS) provides regulatory control of the gastrointestinal (GI) tract (16). The output of the ENS is modulated by extrinsic autonomic influences from the sympathetic and parasympathetic nervous systems. When the gut is diseased or damaged, the nervous system attempts to adapt to maintain the essential digestive and defensive functions of the GI tract. However, in chronic disease, gut function is frequently compromised. Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are relapsing and remitting chronic intestinal inflammatory conditions. They are the source of considerable morbidity, arising from disturbances of motility and secretion (10,20,54). These functional alterations develop throughout the GI tract, even at sites distant from a localized region of active inflammation (2,28,47,51). Abnormalities in function also occur during periods of remission from IBD, when the...

Background The enteric nervous system (ENS) possesses extensive synaptic connections which integrate information and provide appropriate outputs to coordinate the activity of the gastrointestinal (GI) tract. The regulation of enteric synapses is not well understood. Cannabinoid (CB)1 receptors inhibit the release of acetylcholine (ACh) in the ENS, but their role in the synapse is not understood. We tested the hypothesis that enteric CB1 receptors provide inhibitory control of excitatory neurotransmission in the ENS. Methods Intracellular microelectrode recordings were obtained from mouse myenteric plexus neurons. Interganglionic fibres were stimulated with a concentric stimulating electrode to elicit synaptic events on to the recorded neuron. Differences between spontaneous and evoked fast synaptic transmission was examined within preparations from CB1 deficient mice (CB1−/−) and wild-type (WT) littermate controls. Key Results CB1 receptors were colocalized on terminals expressing the vesicular Ach transporter and the synaptic protein synaptotagmin. A greater proportion of CB1−/− neurons received spontaneous fast excitatory post-synaptic potentials than neurons from WT preparations. The CB1 agonist WIN55,212 depressed WT synapses without any effect on CB1−/− synapses. Synaptic activity in response to depolarization was markedly enhanced at CB1−/− synapses and after treatment with a CB1 antagonist in WT preparations. Activity dependent liberation of a retrograde purine messenger was demonstrated to facilitate synaptic transmission in CB1−/− mice. Conclusions & inferences CB1 receptors inhibit transmitter release at enteric synapses and depress synaptic strength basally and in an activity-dependent manner. These actions help explain accelerated intestinal transit observed in the absence of CB1 receptors.

Objective To examine the frequency, natural history, and outcomes of 3 subtypes of abdominal pain (general abdominal pain, epigastric pain, localized abdominal pain) among patients visiting Canadian family practices.Design Retrospective cohort study with a 4-year longitudinal analysis. Setting Southwestern Ontario.Participants A total of 1790 eligible patients with International Classification of Primary Care codes for abdominal pain from 18 family physicians in 8 group practices. Main outcome measuresThe symptom pathways, the length of an episode, and the number of visits. ResultsAbdominal pain accounted for 2.4% of the 15,149 patient visits and involved 14.0% of the 1790 eligible patients. The frequencies of each of the 3 subtypes were as follows: localized abdominal pain, 89 patients, 1.0% of visits, and 5.0% of patients; general abdominal pain, 79 patients, 0.8% of visits, and 4.4% of patients; and epigastric pain, 65 patients, 0.7% of visits, and 3.6% of patients. Those with epigastric pain received more medications, and patients with localized abdominal pain underwent more investigations. Three longitudinal outcome pathways were identified. Pathway 1, in which the symptom remains at the end of the visit with no diagnosis, was the most common among patients with all subtypes of abdominal symptoms at 52.8%, 54.4%, and 50.8% for localized, general, and epigastric pain, respectively, and the symptom episodes were relatively short. Less than 15% of patients followed pathway 2, in which a diagnosis is made and the symptom persists, and yet the episodes were long with 8.75 to 16.80 months' mean duration and 2.70 to 4.00 mean number of visits. Pathway 3, in which a diagnosis is made and there are no further visits for that symptom, occurred approximately one-third of the time, with about 1 visit over about 2 months. Prior chronic conditions were common across all 3 subtypes of abdominal pain ranging from 72.2% to 80.0%. Psychological symptoms consistently occurred at a rate of approximately one-third. ConclusionThe 3 subtypes of abdominal pain differed in clinically important ways. The most frequent pathway was that the symptom remained with no diagnosis, suggesting a need for clinical approaches and education programs for care of symptoms themselves, not merely in the service of coming to a diagnosis. The importance of prior chronic conditions and psychological conditions was highlighted by the results. This article has been peer reviewed. Cet article a fait l'objet d'une révision par des pairs.

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