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Background Chronic constipation ( CC) is a common and severe gastrointestinal complaint in Parkinson's disease ( PD), but its pathogenesis remains poorly understood. This study evaluated functionally distinct submucosal neurons in relation to colonic motility and anorectal function in PD patients with constipation ( PD/ CC) vs both CC and controls. Methods Twenty-nine PD/ CC and 10 Rome III-defined CC patients were enrolled. Twenty asymptomatic age-sex matched subjects served as controls. Colonic transit time measurement and conventional anorectal manometry were evaluated in PD/ CC and CC patients. Colonoscopy was performed in all three groups. Colonic submucosal whole mounts from PD/ CC, CC, and controls were processed for immunohistochemistry with antibodies for vasoactive intestinal polypeptide ( VIP) and peripheral choline acetyltransferase, markers for functionally distinct submucosal neurons. The mRNA expression of VIP and its receptors were also assessed. Key Results Four subgroups of PD/ CC patients were identified: delayed colonic transit plus altered anorectal manometry (65%); delayed colonic transit (13%); altered manometric pattern (13%); and no transit and manometric impairment (9%). There were no differences in the number of neurons/ganglion between PD/ CC vs CC or vs controls. A reduced number of submucosal neurons containing VIP immunoreactivity was found in PD/ CC vs controls ( P<.05). VIP, VIPR1, and VIPR2 mRNA expression was significantly reduced in PD/ CC vs CC and controls ( P<.05). Conclusions and Inferences Colonic motor and rectal sensory functions are impaired in most PD/ CC patients. These abnormalities are associated with a decreased VIP expression in submucosal neurons. Both sensory-motor abnormalities and neurally mediated motor and secretory mechanisms are likely to contribute to PD/ CC pathophysiology. [ABSTRACT FROM AUTHOR]

Background Specialized endoderm-derived epithelial cells, that is, enteroendocrine cells ( EECs), are widely distributed throughout the gastrointestinal ( GI) tract. Enteroendocrine cells form the largest endocrine organ in the body and play a key role in the control of GI secretion and motility, the regulation of food intake, postprandial glucose levels and metabolism. EECs sense luminal content and release signaling molecules that can enter the circulation to act as classic hormones on distant targets, act locally on neighboring cells and on distinct neuronal pathways including enteric and extrinsic neurons. Recent studies have shed light on EEC sensory transmission by showing direct connections between EECs and the nervous system via axon-like processes that form a well-defined neuroepithelial circuits through which EECs can directly communicate with the neurons innervating the GI tract to initiate appropriate functional responses. Purpose This review will highlight the role played by the EECs in the complex and integrated sensory information responses, and discuss the new findings regarding EECs in the brain-gut axis bidirectional communication. [ABSTRACT FROM AUTHOR]

Background μ opioid receptors ( μ ORs) are expressed by neurons and inflammatory cells, and mediate immune response. We tested whether activation of peripheral μ ORs ameliorates the acute and delayed phase of colitis. Methods C57 BL/6J mice were treated with 3% dextran sodium sulfate ( DSS) in water, 5 days with or without the peripherally acting μ OR agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin ( DAMGO) or with DAMGO+ μ OR antagonist at day 2-5, then euthanized. Other mice received DSS followed by water for 4 weeks, or DSS with DAMGO starting at day 2 of DSS for 2 or 3 weeks followed by water, then euthanized at 4 weeks. Disease activity index ( DAI), histological damage, and myeloperoxidase assay ( MPO), as index of neutrophil infiltration, were evaluated. Cytokines and μ OR mRNAs were measured with RT- PCR, and nuclear factor- kB ( NF- kB), the antiapoptotic factor Bcl- xL, and caspase 3 and 7 with Western blot. Key Results DSS induced acute colitis with elevated DAI, tissue damage, apoptosis and increased MPO, cytokines, μ OR mRNA, and NF- kB. DAMGO significantly reduced DAI, inflammatory indexes, cytokines, caspases, and NF- kB, and upregulated Bcl- xL, effects prevented by μ OR antagonist. In DSS mice plus 4 weeks of water, DAI, NF- kB, and μ OR were normal, whereas MPO, histological damage, and cytokines were still elevated; DAMGO did not reduce inflammation, and did not upregulate Bcl- xL. Conclusions & Inferences μ OR activation ameliorated the acute but not the delayed phase of DSS colitis by reducing cytokines, likely through activation of the antiapoptotic factor, Bcl- xL, and suppression of NF- kB, a potentiator of inflammation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nitric oxide (NO) and vasoactive intestinal peptide (VIP) are considered transmitters of non-adrenergic, non-cholinergic (NANC) relaxations in guinea-pig trachea, whereas the role of carbon monoxide (CO) is unknown. This study was designed to assess the participation of CO, and to investigate the localization of haem oxygenase-2 (HO-2), the CO-producing enzyme, in tracheal neurons.Experimental Approach: NANC responses to electrical field stimulation (EFS) at 3 and 10 Hz were evaluated in epithelium-free whole tracheal segments as intraluminal pressure changes. Drugs used were: L-nitroarginine methyl ester (L-NAME, 100 microM) to inhibit NO synthase (NOS), alpha-chymotrypsin (2 U ml(-1)) to inactivate VIP, zinc protoporphyrin-IX (ZnPP-IX, 10 microM) to inhibit HO-2, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), a soluble guanylyl cyclase inhibitor. For immunohistochemistry, tissues were exposed to antibodies to PGP 9.5, a general neuronal marker, HO-2 and NOS, and processed with an indirect immunofluorescence method.Key Results: alpha-Chymotrypsin did not affect NANC relaxations. ODQ inhibited NANC responses by about 60%, a value similar to that obtained by combining L-NAME and ZnPP-IX. The combination of ODQ, L-NAME and ZnPP-IX reduced the responses by 90%. Subpopulations of HO-2 positive neurons containing NOS were detected in tracheal sections.Conclusions and Implications: In the guinea-pig trachea, NANC inhibitory responses at 3 and 10 Hz use NO and CO as main transmitters. Their participation is revealed following inhibition of NOS, HO-2 and soluble guanylyl cyclase. The involvement of CO as a relaxing transmitter paves the way for novel therapeutic approaches in the treatment of airway obstruction. [ABSTRACT FROM AUTHOR]

Exogenously administered galanin inhibits cholinergic transmission to the longitudinal muscle and reduces peristaltic efficiency in the guinea pig ileum with a mechanism partially mediated by galanin receptor 1 (GAL-R1). We investigated the effect of exogenous galanin 1–16, which has high affinity for GAL-R1, on the ascending excitatory reflex of the circular muscle elicited by radial distension in isolated segments of guinea pig ileum. We used a three-compartment bath that allows dissecting the ascending pathway into the oral (site of excitatory motor neurons), intermediate (site of ascending interneurons) and caudal compartment (site of intrinsic primary afferent neurons). Galanin 1–16 (0.3–3 μmol L−1) applied to the oral compartment inhibited in a concentration-dependent manner the ascending excitatory reflex elicited by the wall distension in the caudal compartment. This effect was antagonized by the GAL-R1 antagonist, RWJ-57408 (1 and 10 μmol L−1). By contrast, galanin 1–16 was ineffective when added to the intermediate or caudal compartment up to 3 μmol L−1. GAL-R1 immunoreactive neurons did not contain neuron-specific nuclear protein, a marker for intrinsic primary afferent neurons. These findings indicate that GAL-R1s are present on motor neurons responsible for the ascending excitatory reflex, but not on ascending interneurons and intrinsic primary afferent neurons. [ABSTRACT FROM AUTHOR]

µ-,δ- andκ-opioid receptors (ORs) mediate the effects of endogenous opioids and opiate drugs. Here we report (1) the distribution ofµOR in the guinea-pig and human gastrointestinal tract in relation to endogenous ligands, to functionally distinct structures in the gut and toδOR andκOR; and (2) the ligand-inducedµOR endocytosis in enteric neurones using in vitro and in vivo models. In the guinea pig,µOR immunoreactivity is confined mainly to the myenteric plexus.µOR myenteric neurones are most numerous in the small intestine, followed by the stomach and the proximal colon.µOR immunoreactive fibres are dense in the muscle layer and the deep muscular plexus, where they are in close association with interstitial cells of Cajal. This distribution closely matches the pattern of enkephalin.µOR enteric neurones comprise functionally distinct populations of neurones of the ascending and descending pathways of the peristaltic reflex. In human gut,µOR immunoreactivity is localized to myenteric and submucosal neurones and to immune cells of the lamina propria.δOR immunoreactivity is located in both plexuses where it is predominantly in varicose fibres in the plexuses, muscle and mucosa, whereasκOR immunoreactivity appears to be confined to the myenteric plexus and to bundles of fibres in the muscle.µOR undergoes endocytosis in a concentration-dependent manner, in vitro and in vivo. PronouncedµOR endocytosis is observed in neurones from animals that underwent abdominal surgery that has been shown to induce delay in gastrointestinal transit. We can conclude that all three ORs are localized to the enteric nervous system with differences among species, and thatµOR endocytosis can be utilized as a means to visualize enteric neurones activated by opioids and sites of opioid release. [ABSTRACT FROM AUTHOR]

Galanin actions are mediated by distinct galanin receptors (GAL-R), GAL-R1, -R2 and -R3. We investigated the role of GAL-R1 in gastric motility and the expression of GAL-R1 in the rat stomach. In vivo, in urethane-anaesthetized rats, galanin (equipotent for all GAL-Rs) induced a short inhibition of gastric motility, followed by increase in tonic and phasic gastric motility; the latter was significantly reduced by the GAL-R1 antagonist, RWJ-57408. Galanin 1–16 (high affinity for GAL-R1 and -R2) induced a long-lasting decrease of intragastric pressure, which was not modified by RWJ-57408. In vitro, galanin and galanin 1–16 induced increase of intragastric pressure that was not affected by RWJ-57408. Tetrodotoxin (TTX) did not suppress the galanin excitatory effect, whereas the effect of galanin 1–16 on gastric contraction was increased by TTX- or N-nitro-L-arginine, an inhibitor of nitric oxide synthase. GAL–R1 immunoreactivity was localized to cholinergic and tachykinergic neurons and to neurons immunoreactive for nitric oxide synthase or vasoactive intestinal polypeptide. This study suggests that an extrinsic GAL-R1 pathway mediates the galanin excitatory action, whereas an extrinsic, non GAL-R1 pathway is likely to mediate the galanin inhibitory effect in vivo. GAL-R1 intrinsic neurons do not appear to play a major role in the control of gastric motility. [ABSTRACT FROM AUTHOR]

Taste signalling molecules are found in the gastrointestinal (GI) tract suggesting that they participate to chemosensing. We tested whether fasting and refeeding affect the expression of the taste signalling molecule, α-transducin (Gαtran ), throughout the pig GI tract and the peptide content of Gαtran cells. The highest density of Gαtran -immunoreactive (IR) cells was in the pylorus, followed by the cardiac mucosa, duodenum, rectum, descending colon, jejunum, caecum, ascending colon and ileum. Most Gαtran -IR cells contained chromogranin A. In the stomach, many Gαtran -IR cells contained ghrelin, whereas in the upper small intestine many were gastrin/cholecystokinin-IR and a few somatostatin-IR. Gαtran -IR and Gαgust -IR colocalized in some cells. Fasting (24 h) resulted in a significant decrease in Gαtran -IR cells in the cardiac mucosa (29.3 ± 0.8 versus 64.8 ± 1.3, P < 0.05), pylorus (98.8 ± 1.7 versus 190.8 ± 1.9, P < 0.0 l), caecum (8 ± 0.01 versus 15.5 ± 0.5, P < 0.01), descending colon (17.8 ± 0.3 versus 23 ± 0.6, P < 0.05) and rectum (15.3 ± 0.3 versus 27.5 ± 0.7, P < 0.05). Refeeding restored the control level of Gαtran -IR cells in the cardiac mucosa. In contrast, in the duodenum and jejunum, Gαtran -IR cells were significantly reduced after refeeding, whereas Gαtran -IR cells density in the ileum was not changed by fasting/refeeding. These findings provide further support to the concept that taste receptors contribute to luminal chemosensing in the GI tract and suggest they are involved in modulation of food intake and GI function induced by feeding and fasting., (© 2013 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)