Central Neural Control of Gastric Mucosal Defense

The use of histamine 2-receptor blockers and the discovery of Helicobacter pylori infection in the stomach and subsequent antibiotic therapy have greatly reduced the incidence and recurrence of gastric and duodenal ulcers. However, gastric ulcers (stress gastritis) of varying severity are seen in 15 to 30 percent of patients in hospital critical care units where they can severely complicate the recovery of critically ill patients. To date, the mechanisms responsible for the development of stress ulcers remain to be defined, but the etiology appears to be multifactorial.

The main aim of the research carried out in the laboratory is to understand the central and peripheral cellular and molecular mechanisms involved in the etiology of stress ulcers. The specific focus is on control by the central nervous system of gastric mucosal defence. These mechanisms are studied in a rat model of stress-induced gastric ulcers. Stress is induced by cold water restraint (CWR) which produces macroscopic and microscopic ulceration within two hours. Studies from this and other laboratories have identified neurotensin, a centrally occuring neurotransmitter/neuromodulator, and other components of the mesolimbic system as key elements involved in central control of mucosal defence. Administration of neurotensin into the cerebrospinal fluid or directly into the mesolimbic nuclei protects the mucosa against CWR injury induced in rats by reducing gastric acid secretion, enhancing endogenous gastric mucosal prostaglandin generation, and maintaining mucosal blood flow. The protective effect of neurotensin can be attenuated by depleteing the nuclei of dopamine with 6-hydroxydopamine, or by pharmacological blockade of dopamine and adrenergic receptors. These observations suggest that exogenous neurotensin acts via dopaminergic and adrenergic pathways in the central nervous system. We have recently observed that the level of endogenous neurotensin in the nucleus accumbens (part of the mesolimbic system) is reduced by CWR and that this change is accompanied by a parallel decrease in neurotensin mRNA levels. In addition, during CWR, neurotensin receptors are up-regulated, so that the number of neurotensin specific binding sites in the nucleus accumbens is increased. These changes support the hypothesis that neurotensin is involved in mucosal defence in vivo.

Research is directed toward 1) elucidating the steps/mechanisms linking events that occur in the mesolimbic nuclei during CRW to events in the periphery that result in gastric mucosal injury and 2) identifying the molecular mechanism(s) through which neurotensin exerts its protective effect. Such knowledge would allow identification of therapeutic interventions that may ameliorate gastric injury induced by stress.