Anxiety and helplessness in the face of stress predisposes, precipitates, and sustains gastric ulceration
Introduction
That emotions influence the digestive system has been known scientifically for at least two centuries [116]. At the end of the last century, Pavlov discovered that the digestive system was also influenced by prior conditioning and learning-a fact that proved a foundation for much of psychology in this century. Selye [95] promoted gastric ulcer as the prototypic disease of ‘stress’-both mental and physical-a view fostered by a number of classic observations on the interaction of emotion and gastric functions [117]. The present paper (a) gives a brief history of the search for the ‘causes’ of gastric ulcer, (b) provides a review of our own research which reveals that vulnerability to gastric ulceration is modulated by psychologically meaningful experiences, and (c) offers a multifactorial perspective on the causes of gastric ulceration and the future of research on it. Although many distinguished researchers have contributed to this field and guided our thinking, limitations of space in this review allow us to cite only a few. The interested reader is directed also to broader reviews [28], [108].
Section snippets
Animal models, causality, and mechanisms
Much of the research on causes has used animal models because they provide an opportunity to demonstrate causality and mechanisms [108]. The primary animal for this research has been the rat, although, in light of more recent interests in bacterial factors, it could be argued that the pig [23] or other species might be useful [35]. Stress-ulcers in rats are different from those in humans in that they are most commonly gastric rather than duodenal, and they are generally transient, healing over
Traditional single factor causal models
‘Stress’ is a concept central to research on gastric ulceration, yet it is a concept that has challenged researchers ever since (e.g. [41]). It is not surprising then, that, researchers studying stress and gastric ulceration have employed a variety of instantiations of ‘stress’. Most early research was based upon the hope of finding a single causal factor for ulcerations. In these, stress was induced by either a physiological or a psychological stress challenge.
Newer concepts
Diathesis-stress models seem to be popular now as accounts of all pathologies. And, indeed, bases for this abound in the literature. We have already noted several factors predisposing to gastric ulceration when stressed. How these influence gastric vulnerability is neither always readily apparent nor direct. For example, Ader et al. [7] early showed that rats weaned early were more vulnerable to ulcerations. Some initially attributed this increased vulnerability to social-psychological trauma.
Strategy
Our own research strategy has been guided by Weiner’s perspective on ulcerogenicity and Selye’s notion of ‘pluricausality’. We have adopted a strategy of using a known ulcerogenic physical challenge and exploring how past experiences and psychologically important variations in those past experiences can be shown to predispose to increased or decreased vulnerability to the physical challenge. We have also sought to show that one can take signal elements from those past events and reinstate
Mechanisms
We have shown that the ulceration processes can be modulated by treatments that access psychological processes in all three of the ulcerative stages, predisposing, precipitating, and sustaining. It would be of interest to know the mechanisms through which these psychological processes effected their modulation. Unfortunately the mechanisms of the ulcerative process itself are not yet understood. Several of these have been explored by others and also by ourselves, and we shall only briefly
Predicting vulnerability
One challenge that has faced us is the enormous differences between individuals in vulnerability to RIW. It would be useful to find ways to either constrain this variability or to predict in advance the individual vulnerability [57]. Such prediction itself could, perhaps through genetic analysis, allow isolation of the variables critical in ulcerogenesis. Individual rats differ in a number of other behavioral and physiological variables — aggressive behaviors, defensive behaviors, sensitivity
Bacterial infection and the future
We have presented a series of studies showing that psychological factors modulate gastric erosions in rats and there are reasons to believe that these factors operate in humans as well. The general implication is that these experiments which explore the psychological manipulations that are effective modulators of gastric vulnerability can, when combined with physiological assays, give insights into the proximal mechanisms that might otherwise be overlooked or misinterpreted. This implies that
Future research
Something is modulating vulnerability to Hp and/or Hp related pathology. Among these, certainly past life stress events are important risk factors — as well as a number of social and behavioral factors [40]. Thus, any future research strategy for animal models that seeks to link our past research program to contemporary human disease process must study the interaction of (a) psychological modulators of the type we have validated as relevant, (b) immunological status and bacterial exposure, and
References (117)
Effects of exogenous administration of female sex hormones on gastric secretion and ulcer formation in the rat
Eur. J. Pharmacol.
(1984)- et al.
Plasma corticosterone and restraint induced gastric pathology: age-related differences after administration of corticotropin releasing factor
Life Sci.
(1989) - et al.
Free operant avoidance behavior and gastric ulceration in rats
Physiol. Behav.
(1973) - et al.
A study of the factors involved in the production of gastric ulcers by the restraint technique
Gastroenterology
(1960) - et al.
Search after neurobiological profile of individual-specific features of Wistar rats
Brain Res. Bull.
(1990) - et al.
Experimental psychosomatic disease states in monkeys. I. Peptic ulcer — ‘Executive monkeys’
J. Surg. Res.
(1964) - et al.
Effects of morphine and naloxone on stress ulcer formation and gastric acid secretion
Eur. J. Pharmacol.
(1986) - et al.
The neurobiology of stress ulcers
Brain Res. Rev.
(1991) - et al.
Restraint stress in biomedical research: An update
Neurosci. Biobehav. Rev.
(1994) - et al.
Effect of water-immersion stress on gastric secretion and mucosal blood flow in rats
Gastroenterology
(1979)
Stomach ulcerations and emotionality in selected strains of rats
J. Psychosom. Res.
Interactions amongst factors which influence severity of gastric ulceration in rats
Physiol. Behav.
Parallelism among stress effects on ulcer, immunosuppression and analgesia: Commonality of mechanisms?
J. Physiol. (Paris)
Some psychosomatic causal factors of restraint-in-water stress ulcers
Physiol. Behav.
Stress rest cyclicity in the pathogenesis of restraint-induced gastric ulcers in rats
Physiol. Behav.
Hypothalamo-pituitary-adrenal manipulations and stress ulcerations in rats
Psychoneuroendocrinology
Serial stressors: prior exposure to a stressor modulates its later effectiveness on gastric ulceration and corticosterone release
Behav. Neur. Biol.
Some behavioral factors related to the effects of cold-restraint stress in rats: a factor analytic regression approach
Physiol. Behav.
Differing mechanisms for proactive effects of intermittent and single shock on gastric ulceration
Physiol. Behav.
Prediction of individual vulnerability to stress-induced gastric ulcerations in rats: A factor analysis of selected behavioral and biological indices
Physiol. Behav.
The ulcerogenic effect of a rest period after exposure to water-restraint stress in rats
Behav. Neur. Biol.
The effect of conflict and shock stress on stomach ulceration in the rat
J. Psychosom. Res.
Conflict duration, feeding schedule and strain differences in conflict-induced gastric ulcers
Physiol. Behav.
Activity-stress ulcer in the rat: frequency and chronicity
Physiol. Behav.
Strain, age, but not gender, influence ulcer severity induced by water-restraint stress
Physiol. Behav.
Reduced incidence of stress ulcer in germ-free Sprague Dawley rats
Life Sci.
Shock predictability and gastric secretion in the chronic fistula rat
Physiol. Behav.
Food deprivation, shock stress and stomach lesions in the rat
Physiol. Behav.
Daily feeding schedule and housing on incidence of activity-stress ulcer
Physiol. Behav.
Effect of the intestinal bacterial flora on acute gastric stress ulceration
Gastroenterology
Predictable and unpredictable shock: behavioral measures of aversion and physiological measures of stress
Psychol. Bull.
Age at maternal separation and gastric erosion susceptibility in the rat
Psychosom. Med.
Chronobiologic factors in experimental stress ulcer
Chronobiol. Int.
Plasma pepsinogen level as a predictor of susceptibility to gastric erosions in the rat
Psychosom. Med.
Effects of early experience and differential housing on behavior and susceptibility to gastric erosions in the rat
J. Comp. Physiol. Psychol.
Effects of prenatal maternal handling and differential housing on offspring emotionality, plasma corticosterone levels, and susceptibility to gastric erosions
Psychosom. Med.
Social factors affecting emotionality and resistance to disease in animals. 1. Age of separation from the mother and susceptibility to gastric ulcers in the rat
J. Comp. Physiol. Psychol.
Gastric lesions in food-restricted young rats
Proc. Soc. Exp. Biol. Med.
L’ulcere experimental de constrainte du rat blanc. Analyse des principaux facteurs determinants
Arch. Med. Appet. Dig.
Avoidance behavior and the development of gastroduodenal ulcers
J. Exp. Anal. Behav.
Ulcerogenic mechanism of ethanol and the action of sulphanilyl floride on the rat stomach in-vivo
J. Pharm. Pharmacol.
Helicobacter pylori virulence and genetic geography
Science
Development of gastric ulcers in rats following stress termination
J. Comp. Physiol. Psychol.
Dissimiliarity of the mechanisms for the evocation of escape and avoidance responding
Anim. Learn. Behav.
The effect of premature weaning on the sensitivity of rats to experimental erosions of the gastric mucosa
Physiol. Bohemoslov.
Gastric campylobacter-like organisms: Their role in gastric disease of laboratory animals
Lab. Anim. Sci.
Gastric ulcers in swine. A potential model for study of gastric ulcer in man
J.A.M.A.
Gastric motility is a major factor on cold restraint-induced lesion formation in rats
Am. J. Physiol.
Gastric lesions secondary to long-distance running
Dig. Dis. Sci.
Central nervous system and gut interactions: Dopamine and experimental gastroduodenal lesions
J. Gastroenterol. Hepatol.
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