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1 Clinical Neuroscience Branch, Selye
defined stress as the nonspecific response of the body to any demand.
Stressors elicit both pituitary-adrenocortical and
sympathoadrenomedullary responses. One can test Selye's concept by
comparing magnitudes of responses at different stress intensities and
assuming that the magnitudes vary with stress intensity, with the
prediction that, at different stress intensities, ratios of increments
neuroendocrine responses should be the same. We measured arterial
plasma ACTH, norepinephrine, and epinephrine in conscious rats after
hemorrhage, intravenous insulin, subctaneous formaldehyde solution,
cold, or immobilization. Relative to ACTH increments, cold evoked large
norepinephrine responses, insulin large epinephrine responses, and
hemorrhage small norepinephrine and epinephrine responses, whereas
immobilization elicited large increases in levels of all three
compounds. The ACTH response to 25% hemorrhage exceeded five times
that to 10%, and the epinephrine response to 25% hemorrhage was two
times that to 10%. The ACTH response to 4% formaldehyde solution was
two times that to 1%, and the epinephrine response to 4%
formaldehyde solution exceeded four times that to 1%. These
results are inconsistent with Selye's doctrine of nonspecificity and
the existence of a unitary "stress syndrome," and they are more
consistent with the concept that each stressor has its own central
neurochemical and peripheral neuroendocrine "signature."
ACTH; norepinephrine; epinephrine
HANS SELYE in 1936 (31) reported that exposure to any
of several noxious agents produced the same syndrome: adrenal
enlargement, gastrointestinal ulceration, and thymicolymphatic
involution. From this pathological triad, he developed a theory of
stress that attained wide popularity and aroused intense research
interest but also incited controversy that persists to this day (32). He defined stress as the nonspecific response of the body to any demand
(33), emphasizing that the same pathological triad would result from
exposure to any stressor. In this report, we call this the doctrine of
nonspecificity.
Selye focused on the hypothalamic-pituitary-adrenocortical (HPA) system
as a key effector of the stress response. The HPA activation attending
stress was thought to be part of a constellation of stereotypical
neural and endocrine responses. Administration of ACTH can elicit all
three components of the pathological triad, and some have even defined
stress empirically as that which increases plasma ACTH concentrations
(8). Selye did not claim that ACTH, or high circulating levels of
adrenocortical steroids, can elicit the pathological triad.
Numerous studies, however, have demonstrated differential
neuroendocrine responses during exposure to different stressors. For
instance, glucopenia evokes selective adrenomedullary and pituitary-adrenocortical activation (10, 22, 23); orthostasis, hyperthermia, and cold exposure evoke selective sympathoneural activation (16, 27, 37); water deprivation evokes selective vasopressinergic activation (29); and manipulations of dietary salt
intake produce selective effects on renin-angiotensin-aldosterone system activity (17). Moreover, during exposure to different stressors,
sympathetic responses exhibit pronounced heterogeneity among
different organs (6, 36); response patterns also depend on the
duration and intensity of the stressor (24, 30) and vary with the
experience of the individual (13).
This patterning does not of itself refute the doctrine of
nonspecificity, because the different patterns could result from superimposition of different stressor-specific homeostatic responses on
the same nonspecific stress response. According to Selye's theory,
stress refers only to the nonspecific component revealed after
subtraction of the specific components from the total response. As
demonstrated mathematically in the
DISCUSSION, it is not possible to test
Selye's theory by comparing effector responses to single intensities
of different stressors.
Acceptance of certain assumptions, however, renders the doctrine of
nonspecificity amenable to experimental testing. This testing was the
main purpose of the present experiments. We assessed plasma ACTH and
catecholamine responses to different intensities of various stressors,
all of which are known to evoke increases in circulating ACTH levels.
By comparing ratios of differences in responses to low- and
high-intensity stressors above a threshold level of stressor intensity,
we examined the hypothesis that all stressors evoke the same
nonspecific response pattern, a hypothesis that has survived more than
half a century without undergoing a direct test.
All experiments described in the present study were approved by the
National Institute of Neurological Disorders and Stroke Animal Care and
Use Committee.
Male Sprague-Dawley rats (Taconic Farms, Germantown, NY), weighing
280-370 g, were maintained in an animal housing room at 22 ± 2°C and 40% humidity, with lights on from 0600 to 1800. The rats
were fed a normal laboratory diet. Tap water was provided ad libitum.
At least 4 days for acclimatization in the housing room elapsed before
the start of the experiment.
Conscious animals with an indwelling arterial catheter were exposed to
one of the following stressors: insulin (Ins); hemorrhage (Hem);
immobilization (Immo); formaldehyde solution (Form) injected subcutaneously to produce pain and tissue damage; cold exposure; physiological saline (Sal) injected subcutaneously after handling in
preparation for the injection; and painless intravenous Sal (without
handling) as a control.
Preparation of animals.
Twenty-four hours before the acute experiments, each rat was
anesthetized with pentobarbital sodium (40 mg/kg ip). Polyethylene catheters (PE-50) filled with heparinized 0.9% Sal (50 IU/ml) were
inserted into a femoral artery and, in some experiments, into a femoral
vein. The catheters were sutured in place and tunneled subcutaneously
to the nape, where they were attached to a metal spring. The cannulas
were flushed with heparinized 0.9% Sal (100 IU/ml, 0.2 ml) at the end
of light cycles (1700-1800).
Acute experiments.
All acute experiments began between 0800 and 0900 on the day after
operation. Each rat was assigned randomly to one of the experimental
treatments described below.
ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
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Abstract
Introduction
Methods
Results
Discussion
References
70°C and
analyzed within 3 wk.
Intravenous Sal. The neurochemical results for the various stressors were compared with those after intravenous injection of Sal as a control, as described below.
Handling and subcutaneous Sal. Even brief, gentle handling of conscious rats produces marked increases in plasma levels of catecholamines (18). Subcutaneous injection would also be expected to evoke a catecholaminergic response. Some animals underwent subcutaneous injection of physiological Sal, after handling to position the animal for the injection, as described below.
Insulin-induced hypoglycemia. After the baseline collection, the animals received 0.3 (n = 7; 313 ± 9.4 g final body wt), 1.0 (n = 5), or 3.0 (n = 7) IU/kg of insulin (Eli Lilly, Indianapolis, IN) or physiological Sal intravenously (0.1 ml solution/100 g body wt). Arterial blood samples were obtained at 15, 45, 75, and 105 min after insulin administration.
Formaldehyde solution-induced pain and tissue damage. After baseline samples were collected as described above, the animals received 1% formaldehyde solution (Baker, Phillipsburg, NJ; n = 6), 4% formaldehyde solution (n = 7; 344 ± 11.3 g final body wt), or Sal (n = 5) subcutaneously into the right leg (0.1 ml/100 g body wt). Arterial blood samples were obtained at 15, 45, 75, 105, and 135 min after formaldehyde solution administration.
Nonhypotensive and hypotensive hemorrhage. The experiment began with collection of a baseline arterial blood sample. The animals were bled to either 10 (n = 6) or 25% (n = 7) of estimated blood volume (EBV), with EBV calculated from the equation, EBV = 0.06 × body weight (g) ± 0.77 (21). Arterial blood samples were obtained 15, 45, 105, and 135 min after hemorrhage.
Cold exposure.
The experiment began with collection of a baseline arterial blood
sample at room temperature (24 ± 2°C) outside the cold chamber. The unshaved animal was then carefully transferred (<30 s) from its
home cage (placed next to cold chamber) into the cold chamber [chamber temperature 4 (n = 9)
or 3°C (n = 7)] and
kept in the chamber for 3 h. Arterial blood samples were collected
during exposure to cold at 15, 45, 105, and 165 min. After 3 h, the
cooling system in the cold chamber was switched off, the doors of the cold chamber were opened, and room temperature was attained inside the
chamber after 
10 min. Arterial blood samples were obtained 15, 45, and 105 min after cold exposure. To assess effects of the transfer
itself, three rats in a control group were exposed to room temperature
for 1 h in the chamber.
Immobilization. The experiment began with collection of a baseline arterial blood sample. Each animal then underwent 2 h of Immo, which consisted of taping the rat's limbs to a metal frame with hypoallergic tape (18, 19). Arterial blood samples samples were obtained at 15, 30, 45, 75, 105, and 120 min during Immo.
Assays. Plasma concentrations of norepinephrine (NE) and epinephrine (Epi) were assayed using reverse-phase liquid chromatography with electrochemical detection after partial purification by adsorption on alumina (5, 12, 14). Catechol concentrations in each sample were corrected for recovery of the internal standard, dihydroxybenzylamine. The limits of detection for NE and Epi were 2-4 pg (30 fmol) per volume injected.
Plasma levels of ACTH-(1
39) were measured in duplicate without prior
extraction, using a commercially available RIA kit (ICN Biomedicals)
(26). The intra-assay coefficient of variation was <5%.
Data analyses. Results are presented as means ± SE. P < 0.05 defined statistical significance.
Plasma levels of ACTH, NE, and Epi were assayed before, during, and after exposure to the stressor. Changes in levels of ACTH, Epi, and NE were analyzed either by one- or two-way ANOVA for repeated measures. An area under the curve (AUC) was calculated based on concentration × time as a measure of the magnitude of the response. Thus each animal provided one data point, the AUC, for each dependent variable. Total AUCs for plasma catecholamines and plasma ACTH were calculated by rectangular integration. Net AUCs from the baseline were calculated as the difference between total AUCs and basal AUCs. For statistical purposes, the length of testing for all stressors was limited to the duration of Immo (2 h). Differences among stressors or neuroendocrine measures were also assessed by ANOVA as appropriate, as were responses to different stressor intensities. Independent-means t-tests were used for examining differences in responses to stressors at two intensities.| |
RESULTS |
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Introduction
Methods
Results
Discussion
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At their highest intensities, all the stressors increased levels of ACTH, NE, and Epi significantly compared with levels after intravenous Sal (Figs. 1-5). Although Immo evoked large increases in plasma levels of ACTH, NE, and Epi, other stressors induced disproportionately large NE or Epi responses compared with ACTH responses. Thus cold evoked large NE responses, whereas low-dose Ins evoked large Epi responses. There was no effect of the transfer of rats into the cold chamber on plasma NE, Epi, or ACTH (data not shown). The plasma catecholamine and ACTH results in the rats receiving intravenous Sal postoperatively were similar to those previously reported in conscious, unrestrained rats (18).
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The 4% Form concentration elicited about a twofold larger plasma ACTH response and about a fourfold larger plasma Epi response than did the 1% concentration, the differences for both variables being statistically significant (P < 0.05 for ACTH, P < 0.01 for Epi).
Hem evoked small NE and Epi responses relative to ACTH responses. The 25% Hem elicited about a fivefold larger ACTH response than did the 10% Hem (P < 0.01). There were no differences in plasma NE or Epi responses to 10 and 25% Hem.
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DISCUSSION |
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The present results, based on several experiments involving various intensities of different stressors and multiple peripheral and central neurochemical-dependent measures, demonstrate the marked heterogeneity of neuroendocrine responses. Ins, regardless of dose, markedly stimulated adrenomedullary secretion, as reflected by plasma Epi levels, with much less intense sympathoneural activation, as reflected by plasma NE levels; cold exposure produced much larger proportionate increments in plasma NE levels than in plasma Epi or ACTH levels; Hem produced large ACTH responses but relatively small NE and Epi responses; and Immo increased plasma levels of all three compounds. In addition, although ACTH and Epi responses to Ins were highly correlated, ACTH and Epi responses to other stressors were more weakly correlated or were not related at all, despite significant increases in ACTH levels and therefore HPA activation in response to all the stressors.
Heterogeneity does not disprove the doctrine of nonspecificity. As noted above, this heterogeneity does not of itself support or refute Selye's stress theory. The stress response was thought to occur in three stages, the "general adaptation syndrome" (GAS), consisting of "alarm," "resistance," and "exhaustion." Selye (33) wrote that the GAS denoted the whole response, of which the alarm, resistance, and exhaustion stages were merely successive phases. In other words, although during the different stages of the GAS the intensity of the response might vary, the neural and endocrine pattern would be the same, regardless of the stage. The stressors used by Selye and his students (33) included acute manipulations, several of which are used in the present study, hemorrhage, cold, insulin, and immobilization.
To explain the heterogeneity of neuroendocrine responses to stressors, Selye hypothesized the existence of specific reactions. Only after subtraction of these from consideration could one identify the core, nonspecific, shared element, the stress, and its stereotypical consequence, the stress response.The doctrine of nonspecificity cannot be disproved. No one appears to have considered formally the possibility or impossibility of disproving the doctrine of nonspecificity.
In a well-known review, Munck et al. (25) argued persuasively against Selye's concept of "diseases of adaptation," pointing out correctly that glucocorticoids produce potent anti-inflammatory effects, in contrast with Selye's view that collagen diseases, allergy, and rheumatic diseases result from an abnormal or excessive GAS. Munck also correctly noted that, after the 1960s, the concept of diseases of adaptation was largely ignored. The review did not consider the validity of Selye's doctrine of nonspecificity. It can be shown mathematically that, without simplifying assumptions, the doctrine of nonspecificity cannot be disproved. Consider responses of effector systems, A and B, e.g., ACTH and Epi, to the different stressors, x and y. The overall magnitude of the response of effector system A to stress x (Ax) is the sum of the nonspecific component (x · an) and the specific component (x · ax), where x is a particular intensity of the stressor and an and ax are constants relating the intensity of the stress to the nonspecific and specific components of the response. (Most stimulus-response curves approximate a linear relationship between the magnitude of the response and the logarithm of the stimulus intensity.) The nonspecific and specific components of the response of effector system B can be represented similarly. Thus, for stressors x and y and responses A and B
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Assumptions rendering the doctrine of nonspecificity testable. Inspection of Eq. 4 indicates that if the constants ax, bx, ay, and by were all equal to zero (or were very small with respect to an and bn), then one could test the doctrine of nonspecificity. Assuming the constants for the specific components (ax, bx, ay, and by) were small relative to the constants for the nonspecific component (an and bn) would be tantamount to assuming that above the threshold intensity, t, the specific components would contribute negligibly to the overall responses of the effector systems. In this situation, regardless of the stressor, the ratio of the intensity-related increment in the value for effector system A to the intensity-related increment in the value for effector system B would be a constant, namely, an/bn.
Another assumption would also enable testing of the doctrine of nonspecificity. This assumption is that the magnitudes of both the specific and nonspecific components vary directly with the intensity of the stressor over the whole range of stressor intensities, i.e., that there is no ceiling for the specific component and no threshold for the nonspecific component. The reasoning is as follows. If one considers ratios of values for the dependent variables at different stressor intensities
![<IT>A</IT><SUB><IT>X</IT></SUB>/<IT>A</IT><SUB><IT>x</IT></SUB> = [(<IT>X</IT> − t) ⋅ <IT>a</IT><SUB>n</SUB> + <IT>X</IT> ⋅ <IT>a</IT><SUB><IT>x</IT></SUB>]/[(<IT>x</IT> − t) ⋅ <IT>a</IT><SUB>n</SUB> + <IT>x</IT> ⋅ <IT>a</IT><SUB><IT>x</IT></SUB>]](/content/vol275/issue4/fulltext/R1247/img013.gif)
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A test of the doctrine of nonspecificity. Even with simplifying assumptions, appropriate testing of the doctrine of nonspecificity would require a very complex study, involving multiple stressors at different intensities and multiple simultaneously assessed dependent measures. Although an enormous literature describes effects of graded intensities of stressors on neuroendocrine-dependent measures, none would apply to the issue of the validity of the doctrine of nonspecificity.
As demonstrated mathematically above, the doctrine of nonspecificity could be tested, given one of two assumptions about the existence of a threshold stressor intensity for the nonspecific response or the magnitude of the specific response above the threshold stressor intensity. In the present study, for some stressors, the data obtained were inconsistent with both assumptions and therefore irrelevant as tests of the doctrine of nonspecificity. For instance, there appeared to be a threshold for enhanced ACTH responses to Ins; yet Epi responses continued to increase substantially above the threshold. This would be reasonable, since one might expect an intensity-related increase in the need for a specific, hormonal adrenergic response as a glucose counterregulatory mechanism; however, the Ins results could not be used to test the doctrine of nonspecificity, because the obtained data did not fit either assumption. The results about Immo also could not be applied, because the intensity of the stressor was not varied quantitatively. The results about cold could not be applied, because the specific noradrenergic component appeared to predominate regardless of stressor intensity. This would be consistent with a specific, noradrenergic neuronal response to conserve heat and expend energy; however, the responses of ACTH levels were so small, the nonspecific component could have contributed only negligibly to the overall response. The data about ACTH and Epi responses to Hem and Form did seem to fit the assumptions required to test the doctrine of nonspecificity. Figure 6 depicts the summary data in forms related to the theoretical predictions. As shown in Fig. 6A), for plasma Epi, the ratio of the response for the more severe Hem to the less severe Hem was smaller than the ratio of the response for the more severe Form to the less severe Form. The doctrine of nonspecificity would predict that the difference between Hem and Form would also obtain for plasma ACTH; in fact, however, for plasma ACTH, the ratio of the response for the more severe Hem to the less severe Hem was much larger than the ratio for the more severe Form to the less severe Form. As shown in Fig. 6B), the increment in plasma Epi levels between the two intensities of Form was larger than the increment in plasma ACTH levels; yet the increment in plasma Epi levels between the two intensities of Hem was smaller than the increment in plasma ACTH levels. Thus, by both tests, the doctrine of nonspecificity failed to predict the experimental results for Hem and Form.
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An alternative proposal: primitive specificity of stress responses. The present results are more consistent with an alternative proposal: that each stressor has a neurochemical "signature," with quantitatively if not qualitatively distinct central and peripheral mechanisms. These neurochemical changes would occur not in isolation but in concert with physiological, behavioral, and even experiential changes. In evolutionary terms, natural selection would have favored this patterning of stress responses by enhancing the protection and propagation of genes (4). We call this "primitive specificity."
In line with the notion of stressor-specific alterations in central neurotransmission, Lachuer et al. (20) reported differential early time course activation of brain stem catecholaminergic groups in response to various stressors. Ceccatelli and Orazzo (2) reported increased expression of enkephalin mRNA and neurotensin mRNA in the paraventricular nucleus after ether exposure and after immobilization but not after swimming or exposure to cold; none of the stressors increased corticotropin-releasing hormone (CRH) mRNA expression. Romero et al. (28) reported stressor-specific responses of oxytocin, CRH, and vasopressin accumulation after colchicine blockade of axonal transport. Gaillet et al. (7) noted that the involvement of noradrenergic ascending pathways in stress-induced HPA activation depends on the type of stressor.Possible limitations of present experiments. Assessing the extent of experienced "distress" in laboratory animals is at best difficult. If one accepts that emotional distress increases plasma levels of Epi and ACTH, then prior experience with the preparation has indicated little if any distress in conscious, unrestrained animals 1 day after insertion of an indwelling arterial cannula. Studies over the past 5 years have involved preparations for stress testing and blood and microdialysate sampling beginning 24 h after surgical placement of catheters and a microdialysis probe (1). After this period of recovery, food and water intake and plasma levels of catecholamines, corticosterone, and ACTH averaged about the same to those in animals studied 48 h after surgery (34). In humans, arterial plasma concentrations of Epi and ACTH return postoperatively to preoperative values within 24 h of surgery, without further changes during the subsequent 2 days (35).
Hypothermia induced by pentobarbital sodium anesthesia and heat loss during catheter implantation probably did not affect responses of levels of NE, Epi, or ACTH during cold exposure beginning 22-24 h after the surgery. Body temperature was maintained by using a heating lamp throughout the surgery, and there was no evidence that by the time of the acute study the animals were hypothermic (36.8 ± 0.2°C). Moreover, arterial plasma levels of ACTH and catecholamines at 1 day after catheter implantation under halothane anesthesia (11) averaged about the same as at 1 day after catheter implantation under pentobarbital sodium anesthesia in the present study (60.8 ± 7.6 vs. 49.5.8 ± 5.9 pg/ml). Future studies in this area should focus on further examination of the notion of stressor-specific patterns of central neurotransmitter release and regional neuronal activation and on altered responsiveness of organisms with specific genetic changes. Meanwhile, we hope that the present findings spur attempts to elaborate concepts that incorporate the specific and nonspecific elements of stress responses and that yield testable hypotheses.Perspectives
The present findings emphasize the stressor specificity of neuroendocrine response patterns. Although Selye defined stress as the nonspecific response of the body to any demand, the present analysis has demonstrated the untestability of this idea, unless one accepts certain assumptions; yet given these assumptions, the doctrine of nonspecificity did not predict the present empirical results. According to an alternative "homeostatic" theory of stress (9), survival advantages afforded by multiple, shared effectors have led to the evolution of primitively specific generators for patterned neuroendocrine responses to different stressors. Studies relating neurochemical alterations in specific brain pathways with simultaneously monitored dependent neuroendocrine, physiological, and behavioral variables should enable identification of the components and elucidate the regulation of these patterns. Moreover, studies of appropriate animal models and human pedigrees should elucidate the genetic bases of these patterns and provide insights about the mechanisms underlying the predisposition to develop clinical stress-related disorders.| |
FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: D. S. Goldstein, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bldg. 10, Rm. 6N252, Bethesda, MD 20892-1424.
Received 30 March 1998; accepted in final form 2 June 1998.
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References
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AUC) for plasma NE, Epi, and ACTH for Form and Hem. Doctrine of
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