The gastric enteral nervous system and mucosal injury

The enteric nervous system (ENS) is increasingly being regarded as an important factor in patho-physiological processes of the gastrointestinal tract.The stomach has a unique position for it is located at the entrance of the gut and therefore exposed to substances that can damage the mucosa, such as acid, alcohol and aspirin. The hypothesis is put forward that the gastric ENS may act as a sensor of mucosal damage and as a neuronal center coordinating the maintenance of mucosal homeostasis in response to a gastric insult. In this present project, therefore, the activation of gastric myenteric plexus neurons due to several injurious factors of the gastric mucosa will be investigated in the rat by immunohistochemical detection of c-Fos protein, a marker for neuronal stimulation. Damage of the gastric mucosa will be assessed by computerized planimetry and histologic examination of injured area and correlated with the extent of c-Fos expression. In particular, transmitters of the activated neurons will be determined in multiple labeling experiments by colocalizing them with c-Fos to identify their nature. Knowledge of the transmitter repertoire of an activated neuron, i.e. of its so-called neurochemical code, will then allow a basic characterization of its function and projection. In addition, the interaction of the gastric ENS with inputs from spinal sensory afferents in the stimulation of myenteric neurons will be elucidated. Calcitonin gene-related peptide, substance P and their receptors will be investigated as mediators in the pathways leading to neuronal activation. Ablation of these afferents by pretreatment with capsaicin will provide additional insight in their participation in myenteric neuron activation. Furthermore, the involvement of inflammatory mediators such as cytokines, prostanoids and histamine will be investigated as a possible cause of c-Fos expression. This project is the first systematic approach to elucidate the role of the intrinsic nervous system of the stomach to chemical injury of the gastric mucosa. Understanding the mechanisms underlying the neuronal response to a mucosal insult will be useful to test the hypothesis that the ENS plays a key role in the pathogenesis of gastrointestinal diseases.

Eating is an extremly hazardous way to make a living, biologically speaking. Amongst others,"the chemicals required to digest food are capable of breaking down the structure of the gut wall and the rest of the consumer`s body as well. It seems that minimizing these risks, while meeting the imperative to absorb nutrients, has influenced many of the design principles of the gastrointestinal tract". (Brookes and Costa 2002) Living under the latent threat of getting harmed by its gastric juice the stomach monitors mucosal homeostasis with a network of several populations of neurons, some of which are able to initiate a protective reaction towards mucosal insults. Of special interest is the ENS (enteric nervous system or "little brain"), because contrary to the other neurons (vagal and spinal afferents, sympathetic and efferent vagal system), that all derive from ganglia or nuclei outside the GI tract, ENS neurons exclusively originate in the wall of the gut. To explore the role, of the ENS in the GI tract we investigated ganglion cells of the ENS after challenging the stomach in vivo with acid for their expression of c-Fos, an immediate early gene that marks neuronal excitation. In multiple labelling experiments by means of fluorescence immunohistochemistery we determined the neurochemical code of the activated neurons in order to clarify the function they might fulfill in the response of the ENS to mucosal injury. Thus we could demonstrate, that intragstric acid stimulates intrinsic neurons of a certain distinct neuronal population, namely nitrergic neurons. Colocalization of NOS,VIP and NPY is an indication, that mucosal acid challenge induced an inhibitory pathway in the ENS that may be responsible for muscle relaxation. For the understanding of hypersenitivity and pain in the stomach we investigated the effect of intragastric acid on the expression of a nociception related receptor (TRPV1). TRPV1 was increased significantly in spinal afferent neurons, and may be a key molecule in the transduction of acid-induced nociception of the gastric mucosa and a mediator of visceral hypersensitivity. Little is known also about the transmitters, that encode noxious gastric stimuli in the spinal cord. Retrograde tracing experiments revealed, that intragastric acid stimulation induces the release of glutamate, SP and CGRP from capsaicin-sensitive sensory afferents in the dorsal horn of the spinal cord where the may be an important factor in gastric nociception and hyperalgesia. Hypersensitivity of primary afferent fibers supplying the gastrointestinal tract is believed to underlie symptoms of several functional bowel disorders, such as irritable bowel syndrome and gastric ulcer disease. Noxious gastric acid induces MAP-kinases signalling in gastric afferents. MAP kinases are enzymes known to tranduce and integrate extracellular signals into an intracellular response, to be essential for sensitiziation of nociceptors, for long-term potentiation, synaptic plasticity, thermal hyperalgesia, pain behaviour and hypersensitivity. Because these kinases play a major role in central and peripheral somatic sensitization they may be also involved in the sensitization of visceral sensory neurons. We could provide evidence, that neurons, supplying the acid threatened stomach react in different ways to the end of protecting the stomach. The understanding of the mechanisms underlying excitation of certain neurons, release of neurotransmitters, pain and hypersensitivity might be crucial to find new pharmacological targets to effectively treat patients with disorders of the gastrointestinal tract.