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PERSPECTIVES IN STRESS RESEARCH HANS SELYE* More than twenty years have passed since the description of "a syndrome produced by diverse nocuous agents." The literature on this reaction type—now known as the "general adaptation syndrome" (G.A.S.), or the "stress syndrome"— has been reviewed in several monographs (?, 2), so that we may dispense with an extensive bibliography here. The object ofthis article is to attempt a re-evaluation ofthe basic concepts as an aid in the search for new approaches to this problem. I. What Is Stress? Stress—like life itself—though very real, is not easy to define in precise terms. However, for working purposes we may say that stress is a state manifested by a specific syndrome which consists ofall the non-specifically induced changes in a biologic system. Thus stress has its own characteristic form of expression (the manifold morphologic, biochemical, and functional manifestations ofthe G.A.S.) but no particular, specific cause. For example, the pituitary responds rather selectively to stress by secreting ACTH; this illustrates the specificity ofthe reaction form. On the other hand, the fact that the most varied stressors can elicit ACTH secretion demonstrates the great non-specificity ofthe evocative stimulus. In our definition ofstress we had to specify "in a biologic system" because, in addition to systemic stress, which produces a G.A.S. by affecting the body as a whole, there is a local adaptation syndrome (L.A.S.), a topical stress reaction that develops when non-specific irritation is limited to a given region within the body. By virtue ofits localization, the latter type ofresponse is even more specific in * Institut de Médecine et de Chirurgie Expérimentales, Université de Montréal, Montréal, Canada. The experimental work on which this article is based was aided by a grant from the Gustavus and Louise Pfeiffer Research Foundation and by Grant No. A-i64i(Ri) from the National Institute of Arthritis and Metabolic Diseases, United States Public Health Service. 403 form than the G.A.S. in that it affects one part ofthe body selectively; yet here again the cause is non-specific. Essentially, stress is the consequence ofthe rate ofwear and tear in a biologic system; this "system" may be the organism as a whole (systemic stress) or one of its parts (topical stress). Since any kind of physiological activity (locomotion, heart beat, respiration, glandular secretion) produces some wear and tear, complete freedom from stress never occurs in living beings. It is quite erroneous, therefore, to think ofstress as a necessarily pathologic phenomenon. In our first paper, the G.A.S. should not have been called a "syndrome produced [only] by nocuous agents," but at that time our objective measurement ofstress had to depend upon gross structurallesions which were induced only by the most severe stressors. The phenomena ofaging depend upon the accumulated results oflife's wear and tear; yet stress is not identical with aging. The rate ofwear and tear is high in the active child and low in the resting oldster. Stress is not identical with the metabolic rate either; fuel consumption and heat production do not necessarily run parallel with wear and tear in living organisms, any more than they do in inanimate machines. The concept of the stressor agent (jjónos ofHippocrates) goes back to antiquity, but its operational definition as that which produces a G.A.S. (a co-ordinated syndrome with objectively measurable manifestations) helped us to make this concept amenable to modern experimental research . The interpretation ofstress as the "consequence ofthe rate ofwear and tear" grew out ofobservations made on the basis ofthe former operational definition. But biologic wear and tear are much more difficult to measure than are the manifold, accurately measurable manifestations of the G.A.S.; hence theheuristicvalue ofthe second, simpler, but non-operational definition is rather limited. In any event, whatever definition we prefer, stress is a separate manifestation of general vital activity, distinct from the phenomena ofaging and metabolic rate with which it has often been confused. A. THE "FIRST MEDIATOR(s) OF STRESS" In connection with the definition of stress, a few words should be said about its "first mediator(s)." We know that...


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