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  • 11
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    Online Resource
    Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 308, No. 6 ( 2015-03-15), p. G525-G531
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 308, No. 6 ( 2015-03-15), p. G525-G531
    Abstract: Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03] , however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus ( P 〈 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00175.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477329-6
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  • 12
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    GABA B R expressed on vagal afferent neurones inhibit gastric mechanosensitivity in ferret proximal stomach
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 281, No. 6 ( 2001-12-01), p. G1494-G1501
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 281, No. 6 ( 2001-12-01), p. G1494-G1501
    Abstract: GABA B -receptor (GABA B R) agonists reduce transient lower esophageal sphincter relaxation (TLESR) and reflux episodes through an action on vagal pathways. In this study, we determined whether GABA B R are expressed on vagal afferent neurones and whether they modulate distension-evoked discharge of vagal afferents in the isolated stomach. Vagal mehanoreceptor activity was recorded following distensions of the isolated ferret proximal stomach before and after perfusion with the GABA B R-selective agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA). Retrograde labeling and immunohistochemistry were used to identify GABA B R located on vagal afferent neurones in the nodose ganglia. Vagal afferent fibers responded to isovolumetric gastric distension with an increase in discharge. The GABA B -receptor agonists baclofen (5 × 10 −5 M) and 3-APPiA (10 −6 to 10 −5 M) but not muscimol (GABA A -selective agonist: 1.3 × 10 −5 M) significantly decreased afferent distension-response curves. The effect of baclofen (5 × 10 −5 M) was reversed by the GABA B -receptor antagonist CGP 62349 (10 −5 M). Over 93% of retrogradely labeled gastric vagal afferents in the nodose ganglia expressed immunoreactivity for the GABA B R. GABA B R expressed on vagal afferent fibers directly inhibit gastric mechanosensory activity. This is likely a contributing mechanism to the efficacy of GABA B -receptor agonists in reducing TLESR and reflux episodes in vivo.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.2001.281.6.G1494
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477329-6
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  • 13
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    Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons within thoracolumbar dorsal root ganglia
    Wiley ; 2007
    In:  The Journal of Comparative Neurology Vol. 500, No. 5 ( 2007-02-10), p. 863-875
    Details
    In: The Journal of Comparative Neurology, Wiley, Vol. 500, No. 5 ( 2007-02-10), p. 863-875
    Type of Medium: Online Resource
    ISSN: 0021-9967 , 1096-9861
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/cne.v500:5
    DOI: 10.1002/(ISSN)1096-9861
    DOI: 10.1002/cne.21204
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1474879-4
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  • 14
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    Metabotropic Glutamate Receptors as Novel Therapeutic Targets on Visceral Sensory Pathways
    Frontiers Media SA ; 2011
    In:  Frontiers in Neuroscience Vol. 5 ( 2011)
    Details
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 5 ( 2011)
    Type of Medium: Online Resource
    ISSN: 1662-4548
    URL: Article
    DOI: 10.3389/fnins.2011.00040
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2011
    detail.hit.zdb_id: 2411902-7
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  • 15
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    Nitric Oxide as an Endogenous Peripheral Modulator of Visceral Sensory Neuronal Function
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 22 ( 2009-06-03), p. 7246-7255
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 22 ( 2009-06-03), p. 7246-7255
    Abstract: Nitric oxide (NO) plays important roles in CNS and smooth muscle function. Here we reveal an additional function in peripheral sensory transmission. We hypothesized that endogenous NO modulates the function of gastrointestinal vagal afferent endings. The nonselective NO synthase (NOS) inhibitor N G -nitro- l -arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)–cGMP pathway was confirmed using the sGC inhibitor 1 H -[1,2,4]oxadiazolo[4,3-a] quinoxaline-1-one and the cGMP phosphodiesterase 5′ inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor S -nitroso- N -acetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.6099-08.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 16
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    GABA B receptors on vagal afferent pathways: peripheral and central inhibition
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 280, No. 4 ( 2001-04-01), p. G658-G668
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 280, No. 4 ( 2001-04-01), p. G658-G668
    Abstract: To investigate GABA B receptors along vagal afferent pathways, we recorded from vagal afferents, medullary neurons, and vagal efferents in ferrets. Baclofen (7–14 μmol/kg iv) reduced gastric tension receptor and nucleus tractus solitarii neuronal responses to gastric distension but not gastroduodenal mucosal receptor responses to cholecystokinin (CCK). GABA B antagonists CGP-35348 or CGP-62349 reversed effects of baclofen. Vagal efferents showed excitatory and inhibitory responses to distension and CCK. Baclofen (3 nmol icv or 7–14 μmol/kg iv) reduced both distension response types but reduced only inhibitory responses to CCK. CGP-35348 (100 nmol icv or 100 μmol/kg iv) reversed baclofen's effect on distension responses, but inhibitory responses to CCK remained attenuated. They were, however, reversed by CGP-62349 (0.4 nmol icv). In conclusion, GABA B receptors inhibit mechanosensitivity, not chemosensitivity, of vagal afferents peripherally. Mechanosensory input to brain stem neurons is also reduced centrally by GABA B receptors, but excitatory chemosensory input is unaffected. Inhibitory mechano- and chemosensory inputs to brain stem neurons (via inhibitory interneurons) are both reduced, but the pathway taken by chemosensory input involves GABA B receptors that are insensitive to CGP-35348.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.2001.280.4.G658
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477329-6
    SSG: 12
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  • 17
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    Gastric vagal afferent modulation by leptin is influenced by food intake status : Leptin and gastric vagal afferent satiety signals
    Wiley ; 2013
    In:  The Journal of Physiology Vol. 591, No. 7 ( 2013-04-01), p. 1921-1934
    Details
    In: The Journal of Physiology, Wiley, Vol. 591, No. 7 ( 2013-04-01), p. 1921-1934
    Type of Medium: Online Resource
    ISSN: 0022-3751
    URL: Article
    DOI: 10.1113/jphysiol.2012.247577
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2013
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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  • 18
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    T1431 The NO Pathway in Gastroesophageal Vagal Afferent Endings
    Elsevier BV ; 2008
    In:  Gastroenterology Vol. 134, No. 4 ( 2008-4), p. A-554-
    Details
    In: Gastroenterology, Elsevier BV, Vol. 134, No. 4 ( 2008-4), p. A-554-
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1016/S0016-5085(08)62585-8
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
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  • 19
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    Peripheral neural targets in obesity : Peripheral neural targets in obesity
    Wiley ; 2012
    In:  British Journal of Pharmacology Vol. 166, No. 5 ( 2012-07), p. 1537-1558
    Details
    In: British Journal of Pharmacology, Wiley, Vol. 166, No. 5 ( 2012-07), p. 1537-1558
    Type of Medium: Online Resource
    ISSN: 0007-1188
    URL: Article
    DOI: 10.1111/j.1476-5381.2012.01951.x
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 2029728-2
    SSG: 15,3
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  • 20
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    Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 292, No. 2 ( 2007-02), p. G501-G511
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 292, No. 2 ( 2007-02), p. G501-G511
    Abstract: Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1–10 μM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001–10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00353.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477329-6
    SSG: 12
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