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... Nevertheless, vagal myenteric terminals could serve as a structure for the mediation of a 'short' axonal reflex. This arrangement bears some resemblance to that proposed, among others, by Delbro [17], although in the present case vagal myenteric terminals may include the receptory axon and the 'efferent' collateral within the same structural unit. ...
Wheat germ agglutinin-horseradish peroxidase conjugate (WGA-HRP) was injected into nodose ganglia of rats. In the esophagus and cardia, dense networks of anterogradely labeled fibers and beaded terminal-like arborisations were observed around myenteric ganglia after combined histochemistry for HRP and acetylcholinesterase. The muscularis externa and interna proper were free of label except for a few traversing fibers. Submucosal and mucosal labeling was rather sparse except for the most oral part of the esophagus, where a dense mucosal innervation was found. Control experiments including WGA-HRP injections into the cervical vagus nerve, nodose ganglion injections after supranodose vagotomy, and anterograde [3H]leucine tracing from the nodose ganglion indicated that all labeled fibers in the esophagus and cardia originated from sensory neurons in the nodose ganglion. Electron microscopy revealed that labeled vagal sensory terminals related to myenteric ganglia were mostly large, mitochondria-rich profiles located predominantly on the surface of the ganglia. Specialized membrane contacts connected sensory terminals with other unlabeled profiles possibly derived from intrinsic neurons. The polarity of these contacts suggested the vagal sensory terminals to be presynaptic to intrinsic neurons of the myenteric ganglia. A hypothesis is formulated postulating a mechanoreceptive role for 'myenteric' vagal sensory terminals, providing both the brainstem (via the vagus nerve) and, by synaptic action upon intrinsic neurons, the myenteric plexus with information on tension and motility of the esophagus and cardia.
... Modulation of the excitability of myenteric neurons via glutamate and SP probably released from IGLEs may influence esophageal peristalsis through enteric co-innervation of motor endplates in striated muscle ( Izumi et al. 2003;Neuhuber et al. 1994;Sang and Young 1997). Antidromic activation of vagal afferents results in tachykininergic responses in the esophagus and stomach as previously described (Delbro 1985;Kerr 2000). ...
Intraganglionic laminar endings (IGLEs) represent the only vagal mechanosensory terminals in the tunica muscularis of the esophagus and may be involved in local reflex control. We recently detected extensive though not complete colocalization of the vesicular glutamate transporter 2 (VGLUT2) with markers for IGLEs. To elucidate this colocalization mismatch, this study aimed at identifying markers for nitrergic, cholinergic, peptidergic, and adrenergic neurons and glial cells, which may colocalize with VGLUT2 outside of IGLEs. Confocal imaging revealed, besides substantial colocalization of VGLUT2 and substance P (SP), no other significant colocalizations of VGLUT2 and immunoreactivity for any of these markers within the same varicosities. However, we found close contacts of VGLUT2-positive structures to vesicular acetylcholine transporter, choline acetyltransferase, neuronal nitric oxide synthase, galanin, neuropeptide Y, and vasoactive intestinal peptide immunoreactive cell bodies and varicosities, as well as to glial cells. Neuronal perikarya were never positive for VGLUT2. Thus, VGLUT2 was almost exclusively found in IGLEs and may serve as a specific marker for them. In addition, many IGLEs also contained SP. The close contacts established by IGLEs to myenteric cell bodies, dendrites, and varicose fibers suggest that IGLEs modulate various types of enteric neurons and vice versa.
... The findings of both VGLUT1 (this study), VGLUT2 ( Neuhuber 2003, 2004) and SP (Kressel and Radespiel-Tro¨gerTro¨ger 1999; Raab and Neuhuber 2004) in IGLEs suggest that both glutamate and SP might be released from IGLEs and act on myenteric neurons. Tachykininergic responses elicited by antidromic activation of vagal afferents in esophagus and stomach as previously described (Delbro 1985; Kerr 2000) support this hypothesis. VGLUT1-ir in nitrergic (nNOS-ir) enteric neurons In search of the target of VGLUT1/nNOS-ir myenteric cell bodies we first examined the myenteric neuropil. ...
Encouraged by the recent finding of vesicular glutamate transporter 2 (VGLUT2) immunoreactivity (-ir) in intraganglionic laminar endings (IGLEs) of the rat esophagus, we investigated also the distribution and co-localization patterns of VGLUT1. Confocal imaging revealed substantial co-localization of VGLUT1-ir with selective markers of IGLEs, i.e., calretinin and VGLUT2, indicating that IGLEs contain both VGLUT1 and VGLUT2 within their synaptic vesicles. Besides IGLEs, we found VGLUT1-ir in both cholinergic and nitrergic myenteric neuronal cell bodies, in fibers of the muscularis mucosae, and in esophageal motor endplates. Skeletal neuromuscular junctions, in contrast, showed no VGLUT1-ir. We also tested for probable co-localization of VGLUT1-ir with markers of extrinsic and intrinsic esophageal innervation and glia. Within the myenteric neuropil we found, besides co-localization of VGLUT1 and substance P, no further co-localization of VGLUT1-ir with any of these markers. In the muscularis mucosae some VGLUT1-ir fibers were shown to contain neuronal nitric oxide synthase (nNOS)-ir. VGLUT1-ir in esophageal motor endplates was partly co-localized with vesicular acetylcholine transporter (VAChT)/choline acetyltransferase (ChAT)-ir, but VGLUT1-ir was also demonstrated in separately terminating fibers at motor endplates co-localized neither with ChAT/VAChT-ir nor with nNOS-ir, suggesting a hitherto unknown glutamatergic enteric co-innervation. Thus, VGLUT1-ir was found in extrinsic as well as intrinsic innervation of the rat esophagus.
... Alluding to the paradigm of local effector function of peptidergic thin caliber primary afferent fibers (Holzer 1988), a similar local effector function was also proposed for IGLEs, thus suggesting that IGLEs may be considered to be complex vagal sensor-effector structures (Neuhuber 1987). Earlier results indicating that axon reflexes in the gastrointestinal tract are mediated by vagal afferents were taken as support for this proposal (Delbro 1985). In a similar vein, the fact that IGLEs and IMAs in the fundic stomach were sometimes seen to originate from the same parent axon suggested an axon reflex arrangement, with IMAs as sensors and IGLEs as the efferent branch (Berthoud and Powley 1992). ...
Understanding the innervation of the esophagus is a prerequisite for successful treatment of a variety of disorders, e.g., dysphagia, achalasia, gastroesophageal reflux disease (GERD) and non-cardiac chest pain. Although, at first glance, functions of the esophagus are relatively simple, their neuronal control is considerably complex. Vagal motor neurons of the nucleus ambiguus and preganglionic neurons of the dorsal motor nucleus innervate striated and smooth muscle, respectively. Myenteric neurons represent the interface between the dorsal motor nucleus and smooth muscle but they are also involved in striated muscle innervation. Intraganglionic laminar endings (IGLEs) represent mechanosensory vagal afferent terminals. They also establish intricate connections with enteric neurons. Afferent information is implemented by the swallowing central pattern generator in the brainstem, which generates and coordinates deglutitive activity in both striated and smooth esophageal muscle and orchestrates esophageal sphincters as well as gastric adaptive relaxation. Disturbed excitation/inhibition balance in the lower esophageal sphincter results in motility disorders, e.g., achalasia and GERD. Loss of mechanosensory afferents disrupts adaptation of deglutitive motor programs to bolus variables, eventually leading to megaesophagus. Both spinal and vagal afferents appear to contribute to painful sensations, e.g., non-cardiac chest pain. Extrinsic and intrinsic neurons may be involved in intramural reflexes using acetylcholine, nitric oxide, substance P, CGRP and glutamate as main transmitters. In addition, other molecules, e.g., ATP, GABA and probably also inflammatory cytokines, may modulate these neuronal functions.
Afferent neurons connecting the gastrointestinal tract with the brainstem and spinal cord are important for regulation and coordination of the various motor, absorptive and secretory functions of this organ system. Thus, afferent signals and feedback are as much important for, e.g., an orderly progression of swallowing (Falempin et al., 1986) as they are for defecation and continence (for reviews see Christensen, 1987; Gonella et al., 1987). Other gastrointestinal functions are also more or less dependent on, or influenced by, afferent information (for reviews see Mei, 1983, 1985; Roman and Gonella, 1987). Visceroafferent neurons not only transmit information from the periphery to the central nervous system, but seem to be involved also in local “effector” actions in various organs (for reviews see Dockray and Sharkey, 1986; Holzer et al., 1987; Maggi and Meli, 1988).
The digestive tract is the richest source of regulatory peptides outside the brain. Such peptides occur all along the gut in the neuroendocrine system which is composed of endocrine/paracrine cells disseminated in the epithelium and of intrinsic neurons that form continuous ganglionic chains in the submucosa and in the muscle layer. Some endocrine/paracrine cells, particularly in the stomach, still have not been associated with an identified regulatory peptide implying that our present knowledge is far from complete. The intracellular processing of regulatory peptide precursors involves multi-step proteolytic cleavage generating several fragments. In many instances more than one biologically active peptide is generated from one and the same precursor. In addition, certain endocrine/paracrine cells and neurons have been found to produce more than one peptide precursor and some are known to harbour 'classical' neurotransmitters, such as 5-hydroxytryptamine, histamine and GABA as well as regulatory peptides. Key questions for the future are the functional significance of the coexistence of multiple messengers within the same cells and the details of how the endocrine/paracrine cells and the neurons in the gut interact.
Glutamate has been identified as the main transmitter of primary afferent neurons. This was established based on biochemical, electrophysiological, and immunohistochemical data from studies on glutamatergic receptors and their agonists/antagonists. The availability of specific antibodies directed against glutamate and, more recently, vesicular glutamate transporters corroborated this and led to significant new discoveries. In particular, peripheral endings of various classes of afferents contain vesicular glutamate transporters, suggesting vesicular storage in and exocytotic release of glutamate from peripheral afferent endings. This suggests that autocrine mechanisms regulate sensory transduction processes. However, glutamate release from peripheral sensory terminals could also enable afferent neurons to influence various cells associated with them. This may be particularly relevant for vagal intraganglionic laminar endings, which could represent glutamatergic sensor-effector components of intramural reflex arcs in the gastrointestinal tract. Thus, morphological analysis of the relationships of putative glutamatergic primary afferents with associated tissues may direct forthcoming studies on their functions.
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