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Structural Organization and Neuropeptide Distribution in the Mammalian Enteric Nervous System, with Special Attention to Those Components Involved in Mucosal Reflexes

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Abstract

Gastrointestinal events such as peristalsis and secretion/absorption processes are influenced by the enteric nervous system, which is capable of acting largely independently from other parts of the nervous system. Several approaches have been used to further our understanding of the underlying mechanisms of specific enteric microcircuits. Apart from pharmacological and physiological studies, the deciphering of the chemical coding of distinct morphological and functional enteric neuron classes, together with a detailed analysis of their projections by the application of immunocytochemistry, of tracing, and of denervation techniques, have substantially contributed to our knowledge. In view of existing interspecies and regional differences, it is of major importance to expand our knowledge of the enteric nervous system in mammals other than the guinea-pig, the most commonly used experimental animal in this research area. This will increase our chances of finding a valid model, from which well-founded extrapolations can be made regarding the precise function of distinct enteric neuron types regulating motility and ion transport in the human gastrointestinal tract.

Introduction

Our understanding of the neurohumoral regulation of intestinal water and electrolyte transport has been furthered enormously by two findings: first, the discovery of neurotransmitter/modulator candidates other than norepinephrine and acetylcholine and, second, the insight that the enteric nerve plexuses play a key role in the processes controlling the proper consistency and composition of the luminal content within the gastrointestinal tract, as well as in whole-body water and electrolyte homeostasis, thus exposing the established view of an adrenergic-cholinergic balance as being oversimplified. Recent physiological findings provide evidence that mainly the intrinsic components of the enteric nervous system (ENS), i.e., the nerve networks embedded in the gut wall, mediate complex reflex activities involving motility, intestinal ion transport and mucosal blood flow [for review, see 14, 27, 33, 34, 35, 87]. Moreover, appropriate antisera for immunocytochemical staining have revealed that one neuron may contain a large spectrum of candidate neurotransmitters or neuromodulators. The concept of neurochemical coding [29], together with the use of specific denervation procedures [see [26]] in order to unravel the axonal projections, have shed a new light on the understanding of the organization of enteric microcircuits. Caution, however, must be exercised when extrapolating these recently acquired insights into the ENS of the guinea-pig to that of other mammals, including humans, since significant species differences exist with regard to the anatomical structure and the neurochemical coding, even between closely related species. Keeping this in mind, this short review has been structured so that it gives an update of the identified functional classes of enteric neurons in the guinea-pig, and provides a comparison with the data on the ENS of other mammals, for example the pig, which seems to bear close functional similarities to the human ENS [37]. Special attention will be paid to those neuron classes involved in transmural fluid and electrolyte transport.

Section snippets

Topographical organization of enteric nerve networks

The enteric nervous system (ENS) of small mammals such as the guinea-pig is built up of two ganglionated plexuses, the submucous or Meissner's plexus [47], and the myenteric or Auerbach's plexus [3](Fig. 1). In large mammals, however, a further division of the submucous plexus can be made, i.e., an inner submucous nerve network (Meissner's plexus), located close to the abluminal side of the lamina muscularis mucosae, and an outer one (Schabadasch' plexus), lying adjacent to the luminal side of

Classification of enteric neurons on the basis of cell shape

Several attempts have been made to classify enteric neurons according to their shape, location, and projections. This task was pioneered late last century by Dogiel [20], who distinguished three morphological neuronal cell types in methylene-blue stained tissue. Nowadays, his classification scheme still provides a solid base for more advanced studies. Using a silver-impregnation technique, Stach [for review, see [71]] was able to add to this classification 5 other neuron types in pig intestine

Neurochemical coding of functional enteric neuron classes

Elucidation of the chemical coding of enteric neurons has substantially contributed to our understanding of enteric microcircuits. Best known is the chemical coding of the enteric neurons in guinea-pig small intestine (see Fig. 3). Differences in their projection pattern and in the co-existence pattern of chemical substances have permitted the subdivision of enteric neurons into four main functional classes; i.e., (a) motor neurons innervating the gut musculature, (b) interneurons, (c)

A. Guinea-Pig Small Intestine

Both chemical (e.g., cholera toxin) and physical (e.g., distension) stimuli can initiate intrinsic and extrinsic reflex circuits that evoke, maintain, and adjust digestive and interdigestive patterns involving motility, secretion, absorption, and local vascular tone. It is generally believed that chiefly submucous neurons are involved in microcircuits regulating the transmucosal movement of substances, whereas myenteric neurons are mainly involved in propulsion of the luminal content.

The

Conclusions

Without wishing to detract from the various authors' achievements and commendable efforts in trying to elucidate the underlying mechanisms of the enteric microcircuits in guinea-pig, we should be cautious about generalizing conclusions. In the light of the observed regional and species differences, extrapolations from this sole experimental model to other species, regardless whether they are closely related or not, are still dubious. However, an in-depth analysis of the data obtained from the

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      The ENS has the capacity to adapt to microenvironmental influences and it continues to change significantly throughout its lifespan [38]. The ENS is organized into two major ganglionated networks, the myenteric and the submucous plexuses and into several aganglionated plexuses within the mucosa and muscularis, and underneath the serosa [39]. During the development of NEC, there are significant changes to the ENS. We have previously identified ENS abnormalities in NEC-afflicted human intestine [20].

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