Neuropharmacology of dyspepsia

Research project P 14295 Neuropharmacology of dyspepsia Peter HOLZER 06.03.2000 Functional dyspepsia refers to a condition which, in the absence of an organic cause, is associated with a host of upper abdominal symptoms including discomfort and pain. The aetiology of this common disorder is largely unknown, but increasing evidence suggests that an exaggerated gain of the viscerosensory system is an important mechanism. Despite this new approach, several key issues of visceral information processing to the brain are still poorly understood. This lack of knowledge relates, e.g., to (1) the type of stimuli that are processed by the visceral afferent system and that may give rise to dyspeptic complaints, (2) the identity of the afferent neurons that signal dyspepsia-associated stimuli to the brain, and (3) the transmitter mechanisms that are involved in the central processing of gastric mucosal insults. Most studies of gastric perception involve distension of the stomach, whereas chemical stimuli have been little studied. Since the central processing of acid challenge in the human oesophageal mucosa differs from that of oesophageal ballooh distension, it is important to explore the afferent signalling and central processing of chemical insults in the gastric mucosa. Hydrochloric acid (HCI) seems to be a particularly appropriate test stimulus because this chemical, together with pepsin, the primary aggressive factor in the upper gastrointestinal tract and because HO can induce pain, discomfort and nausea. The overall aim of this project proposal is hence to trace the afferent pathways activated by gastric acid challenge of the rat stomach, to elucidate the transmitters mechanisms involved in the central processing of gastric acid challenge and to search for inhibitory control mechanisms that could be exploited therapeutically to prevent gastric chernonociception. The specific aims of the proposal are (1) to map the medullary, mesencephalic, diencephalic and telencephalic nuclei that receive input from the acid- threatened stomach, using in situ hybridization autoradiography for c-fos m.RNA, a marker of neuronal excitation; (2) to explore if the central input from the acid-threatened stomach is carried by vagal afferents; (3) to identify the transmitters and their receptors which mediate the afferent signalling from the acid-threatened stomach to the cerebral n ` uclei, using antagonists for ionotropic and metabotropic glutamate receptors as well as antagonists for tachykinin NK,, NK2 aiid NK3 receptors; and (4) to elucidate inhibitory control systems that dampen the afferent input from the acid-threatened stomach to the cerebral nuclei, with emphasis on peripheral and central opioid receptors, alpha2 adrenoceptors and GABA., receptors. Given that functional dyspepsia, peptic ulcer and gastro-oesophageal reflux. represent disease entities with a major socio-economic impact, studies into the neuropharmacology of the afferent signalling of chemical insults in the gastric mucosa are badly needed to develop safe and effective strategies for the management of discomfort and pain in the upper gut.

This experimental project has revealed new mechanisms of gastric pain (dyspepsia). Its results may be particularly relevant to the understanding and treatment of functional dyspepsia, a condition that occurs in the absence of any organic cause, yet is associated with upper abdominal symptoms including discomfort and pain. The aetiology of this common disorder is largely unknown, but increasing evidence suggests that an exaggerated communication between the stomach and the brain (hyperactive gut-brain axis) is an important mechanism. Despite this conceptual advance, several key issues of pain transmission between the stomach and the brain are still poorly understood. For instance, we do not precisely know which stimuli in the stomach give rise to dyspeptic complaints, which afferent neurons signal dyspeptic stimuli to the brain, and which transmitter mechanisms are involved in the central processing of gastric mucosal insults. Most studies of gastric pain involve distension of the stomach, whereas chemical stimuli have been little investigated. Since the central processing of chemically and mechanically induced pain may differ, it is important to explore the afferent signalling and central processing of chemical insults in the gastric mucosa. Hydrochloric acid is a particularly appropriate test stimulus because it is the primary aggressive factor in the upper gastrointestinal tract and because it can induce pain, discomfort and nausea. In an experimental approach, this project set out to trace the afferent pathways activated by acid challenge of the stomach and to elucidate some of its peculiar properties. The major results of the project are as follows. (1) Acid-induced gastric nociception can be visualized with a histochemical imaging method. With this approach it is possible to observe those neurons in the brainstem which are activated when the stomach is exposed to a noxious concentration of acid. (2) The stomach has two neural connections with the brain, one via the vagal nerves and another via spinal nerves. Neuroanatomical investigations revealed that vagal afferent neurons signal gastric acid challenge to the brain. This result was confirmed in an independent study which, in addition, showed that pain caused by gastric distension is conveyed by spinal afferent neurons. (3) The imaging method used in this project was able to demonstrate that the signals from the acid-challenged stomach are relayed to higher centres in the brain, which are involved in emotional, circulatory and hormonal reactions. This observation suggests that gastric acid challenge affects many body and brain functions including mood. (4) Neuropharmacological experiments revealed that the transmission between vagal afferents and second-order neurons in the brainstem involves glutamate and neuropeptides such as substance P. (5) Functional dyspepsia is thought to involve hypersensitivity of the stomach to noxious stimuli, a scenario that may occur during and following gastritis. Experiments modelled on this idea revealed that pretreatment with proinflammatory cytokines, mimicking gastritis, enhance the sensitivity of the vagal afferent system to acid for several days. Functional dyspepsia is a common disorder that is difficult to treat. The advances of this project contribute to a better understanding of gastric pain and offer new options for its therapy.