Scientific integrative medicine finds its roots in the seemingly simple but actually enormously difficult issue of how higher organisms maintain their integrity despite the vicissitudes of life. The great French experimentalist of the mid-nineteenth century and prototypical experimentalist, Claude Bernard, propounded its founding concept. Bernard introduced the idea of the “inner world” when he theorized that body systems function as they do to maintain a constant internal environment—what he called the milieu intérieur.
Bernard’s conception evolved over several years. He taught that a fluid environment of nearly constant composition bathes and nourishes the cells. Near the end of his life he postulated something more profound, that the body maintains the constant internal environment by myriad, continual, compensatory reactions. These compensatory reactions would tend to restore a state of equilibrium in response to any outside changes, enabling independence from the external environment. In response to perturbations of the inner world, body systems would react to counter those perturbations.
Bernard therefore not only introduced the notion of an apparently constant inner world but also a purpose for body processes. His Lectures on the Phenomena of Life Common to Animals and Vegetables (translated by Hoff, Guillemin, and Guillemin L) contains two of the most famous passages in the history of physiology, “The constancy of the internal environment is the condition for free and independent life…All the vital mechanisms, however varied they might be, always have one purpose, that of maintaining the integrity of the conditions of life within the internal environment.” These views might seem straightforward or even simple minded today, but they were revolutionary in the history of medical ideas.
Beginning about the turn of the twentieth century, the highly influential American physiologist, Walter B. Cannon, expanded on Bernard”s theory of the milieu intérieur. Bernard’s theory addressed the “why” of bodily processes by proposing that they help maintain a constant internal environment. Cannon’s work and ideas began to flesh out the “how.” In a series of magnificent experiments over about a quarter century, Cannon demonstrated for the first time the critical role that adrenaline (epinephrine) plays in maintaining the constancy of the inner world.
Cannon introduced and popularized three ideas that by now are well known and widely accepted. Each of these merits discussion, not only for their relevance to the themes of this article, which are obvious, but also to teach about how scientists think and about how theories, just like organisms, must adapt or perish. Each of Cannon’s canons has required modification to take into account experimental realities. The ideas are homeostasis, fight-or-flight responses, and the sympathoadrenal system.
Cannon invented the word homeostasis. By this term he referred to the stability of the inner world. The concept of homeostasis therefore was a direct extension from Bernard’s of the milieu intérieur. According to Cannon, the brain coordinates body systems, with the aim of maintaining a set of goal values for key internal variables. The core temperature is kept at 98.6 F, the serum sodium level at 140 mEq/L, the blood glucose level at 90 mg/dL, and so forth. Internal or external disturbances threatening homeostasis, by causing large enough deviations from the goal values, arouse internal nervous and hormone systems, induce emotional and motivational states, and generate externally observable behaviors, all of which have the goal of reestablishing homeostasis. According to the more recent concept of allostasis, however, no single set of ideal values exists for levels of internal variables.
According to Cannon, the brain responds to all emergencies in the same way, by evoking increased secretion of adrenaline. How could the same response help maintain homeostasis in very different situations, such as too low a blood sugar level (hypoglycemia) and too high a blood sugar level, as in shock from uncontrolled diabetes mellitus? Surely some effects would work against rather than toward homeostasis for at least some body functions at least some of the time. Cannon”s answer was that the body”s response to emergencies, with adrenaline dominating that response, in general, enhance long-term survival, even if in the short term aspects of the response moved some of the levels for key variables from the ideal values. Accumulating experimental evidence has challenged Cannon”s explanation by showing that there is no single response pattern for all threats to homeostasis.
Cannon’s theory of homeostasis presumes ideal long-term goal levels of monitored variables of the inner world. Cannon did not consider the possibility that the goal levels might themselves change. In emergencies, activation of the sympathicoadrenal system would change the levels of some monitored variables, as an unavoidable, temporary by-product.
According to a newer concept, called allostasis, organisms maintain stability through change. Allostasis comes from two Greek words that mean “other sameness.” This seems paradoxical. One way to grasp the meaning of the term is considering the analogy of a home heating, ventilation, and air conditioning (HVAC) system. You would set the thermostat lower in the winter and higher in the summer, because this would save money and minimize wear and tear on the HVAC components. In addition, physical comfort depends not only on temperature but also on relative humidity, which changes seasonally. Moreover, people vary in individual metabolic rates, heat production, and toleration of increased or decreased environmental temperature. Some people simply like it hot, and some do not. You would change the thermostat setting, as appropriate for cost-efficiency, humidity, and characteristics of the patients; however, at any chosen temperature, the thermostat would keep the temperature at about the chosen level—“other sameness.”
Just as the thermostat setting in a building depends on factors such as economy, relative humidity, air movement, and individual preferences, the allostatic approach as applied to regulation of the inner world of the body does not assume ideal single goals for individual variables monitored by the brain, such as core temperature, pulse rate, blood pressure, blood glucose, or blood oxygen. The settings can change.
Operation of an HVAC system entails immediate and long-term costs. One immediate cost is that of the energy used to run the HVAC components. Long-term costs include those of maintaining and repairing the components, related to factors such as wear and tear, latent manufacturing defects, and planned obsolescence. Different allostatic settings entail different amounts of energy expenditure acutely or wear and tear chronically. According to the notion of allostatic load, it is by way of prolonged activation of effectors to maintain allostasis that chronic stress can contribute to the development of chronic degenerative diseases.
Fight or Flight Responses
Cannon also coined the phrase, “fight or flight.” He asserted that not only physical emergencies, such as blood loss from trauma, but also psychological emergencies, such as antagonistic encounters between members of the same species, evoke release of adrenaline into the bloodstream. To Cannon, the body”s responses to “fight” are the same as those to “flight.” Adrenaline exerts several important effects in different body organs, all of which, from Cannon”s point of view, maintain homeostasis in fight-or-flight situations. In the skeletal muscle of the limbs, adrenaline relaxes blood vessels, increasing local blood flow. This is important to provide metabolic fuels to exercising muscle and remove waste products of metabolism that would otherwise accumulate in skeletal muscle and interfere with performance. Adrenaline constricts blood vessels in the skin and promotes clotting; both effects minimize blood loss from physical trauma. Adrenaline releases the key metabolic fuel, glucose, by the liver into the bloodstream, via breakdown of the storage form of glucose, glycogen. (Claude Bernard discovered conversion of glycogen to glucose in the liver.) Adrenaline stimulates respiration, maximizing delivery of oxygen to the bloodstream via the lungs. Adrenaline removes the electrolyte, potassium ion, from the circulation, an effect that may also promote homeostasis, because trauma destroys cells, which contain high potassium ion concentrations, building up the potassium ion content in the surrounding fluid. From a psychological point of view, adrenaline intensifies emotional experiences and increases what Cannon called “reservoirs of power,” exerting anti-fatigue and energizing effects.
The fact that aggressive attack and fearful escape both involve adrenaline release into the bloodstream does not imply an equivalence of “fight” with “flight” from a physiological or biochemical point of view. On the contrary, emotion-associated behaviors such as aggressive attack, fearful flight, immobile terror, hopeless defeat, emotional fainting, and sexual activity differ importantly in internal physiological and biochemical patterns, just as they do in external appearances and behaviors. Conversely, an increase in the level of adrenaline in the bloodstream does not imply that the individual is having a fight-or-flight experience. For instance, adrenaline levels usually increase slightly just by a person’s standing up, and even a mild fall in the blood glucose level stimulates substantial adrenaline release. Because Cannon used only a single dependent variable, the adrenaline response, he could not appreciate the existence of the different physiological and biochemical patterns.
The Sympathoadrenal System
Cannon’s proposed the existence and functional unity of the sympathoadrenal (or “sympathoadrenomedullary” or “sympathico-adrenal”) system. He theorized that the sympathetic nervous system and the adrenal gland work together as a unit to maintain homeostasis in emergencies. This probably was the first proposal of the existence of an integrated nervous-hormone, or neuroendocrine, system.
To identify and quantify adrenaline release during stress, beginning in about 1919 Cannon developed and, over the next two decades, exploited an ingenious experimental setup. He would surgically excise the nerves supplying the heart of a laboratory animal such as a dog or cat. Then he would subject the animal to a stressor such as one of those listed above and record the heart rate response. With the nerves to the heart removed, he could deduce that if the heart rate increased in response to the perturbation, then the increase in heart rate must have resulted from the actions of a hormone. Finally, he would compare the results in an animal with intact adrenal glands with those in an animal from which he had removed the adrenal glands. From the difference in the heart rate between the two animals, he could infer further that the hormone responsible for the increase in heart rate came from the adrenal glands. Moreover, the amount of increase in the heart rate provided a measure of the amount of hormone released.
Because cutting the sympathetic nerves to the heart was an integral part of the experimental setup, Cannon could not appreciate the contribution of those nerves to regulation of the heart”s functions. The experimental design also prevented him from recognizing that disabling one component of the sympathoadrenal system would activate the other compensatorily. The notion spread afterward that the sympathoadrenal system is active only in emergencies. In fact, the parasympathetic nervous system, by way of release of its neurotransmitter, acetylcholine, works in a dynamic balance with the sympathetic nervous system, by way of release of its neurotransmitter, norepinephrine, to modulate the rate of the heartbeat, even in people at rest. Levels of adrenaline in the bloodstream, however, have not been found to correlate with resting heart rate.
Cannon became so convinced that the sympathetic nervous system and adrenal gland functioned as a unit that in the 1930s he formally proposed that the sympathetic nervous system uses the same chemical messenger—adrenaline—as does the adrenal gland. He recognized that stimulation of sympathetic nerves produced effects somewhat different from those produced by injected adrenaline. After he obtained evidence for either release of a substance other than adrenaline during stimulation of sympathetic nerves, or else conversion of adrenaline to a different substance in the target cells, Cannon erroneously backed the latter view. He proposed two forms of the released chemical messenger, excitatory “sympathin E” and inhibitory “sympathin I.” In 1939, he wrote that adrenaline was indeed the chemical messenger of the sympathetic nerves. Differences in organ responses to adrenaline and to “sympathin” would be due to conversion of the latter to another substance in the activated target cells.
This mistake may have cost Cannon a Nobel Prize. In 1946, a year after his death, the Swedish physiologist, U.S. von Euler, correctly identified the chemical messenger of the sympathetic nerves in mammals as not adrenaline but norepinephrine, adrenaline’s chemical precursor, and for this discovery von Euler did share the Nobel Prize for Physiology or Medicine in 1970.
Cannon’s notion of a unitary sympathoadrenal system persists to this day. Many situations, however, entail differential regulation of the sympathetic nervous system (SNS) and adrenomedullary hormonal system (AHS). At least one clinical disorder—fainting—features a combination of shutdown of sympathetic nervous system outflows to the cardiovascular system yet marked stimulation of the adrenomedullary hormonal system. Researchers in the area have come to question the validity of the notion of a unitary sympathoadrenal system, although clinicians often continue to lump together the two components.
The Wisdom of the Body: Is There a Unitary Stress Response?
A concept related to the idea of a unitary sympathoadrenal system is that there is a unitary stress response. Beginning in the 1930s, the East European physiologist, Hans Selye, popularized stress as a scientific idea. Selye viewed all forms of stress as leading to (or being identical with) a stereotyped pathological response pattern, including enlargement of the adrenal glands, shrinkage of the thymus gland (associated with atrophy of the lymph nodes and inhibition of inflammatory or immune responses), and ulcers or bleeding in the stomach or gastrointestinal tract. Selye defined stress as the nonspecific response of the body to any demand imposed upon it. It was later demonstrated that these changes are associated with, and to at least some extent result from, activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Steroids released into the circulation from the adrenal cortex contribute to resistance but may also be responsible for pathological changes. Selye’s concept that prolonged stress can produce physical disease and mental disorders is now widely accepted.
More than a half century elapsed before Selye’s doctrine of nonspecificity underwent experimental testing, which failed to confirm it. Nevertheless, modern lay literature and medical websites continue to accept the notion of a unitary stress response. For instance, a recent Google search yielded about 21,000,000 hits for “the stress response.” According to Yahoo! Health, “The stress response is the set of physical and emotional changes the human body makes in response to a threat or stress. It sometimes is called the “fight-or-flight” response.” (As indicated above, it was Cannon who introduced the latter phrase.)
After adequately sensitive assay methods for plasma levels of norepinephrine (NE) and epinephrine (EPI) became available, evidence rapidly accumulated for different noradrenergic vs. adrenergic responses in different situations. A new concept began to emerge, in which the sympathetic nervous system plays key roles in appropriate redistribution of blood flows in situations such as orthostasis, cold exposure, mild blood loss, locomotion, exercise, altered salt intake, and water immersion; and the adrenomedullary hormonal system (AHS) responds to global or metabolic threats, such as hypoglycemia, hemorrhagic hypotension, exercise beyond an anaerobic threshold, asphyxiation, emotional distress, and shock. Evidence also accumulated for an association of SNS activation with active escape, avoidance, or attack and an association of AHS activation with passive, immobile fear.
More generally, according to a recently proposed concept, stress responses have a kind of “primitive specificity,” and the AHS and SNS can respond differentially, depending on the type and intensity of the stressor as sensed by the organism and interpreted in light of experience. Instead of the sympathoadrenal system becoming active only in emergencies, tonic sympathetic nervous outflow to several vascular beds, organs, and glands is present even under resting conditions, and everyday experiences such as orthostasis, locomotion, the post-prandial state, and exposure to altered environmental temperature can alter sympathoneural outflows, with little or no activation of the AHS. On the other hand, even a slight amount of glucoprivation, posing an overall metabolic challenge, evokes mainly an adrenomedullary response, without generalized SNS activation.
An Adrenocortical-Adrenomedullary Effector System?
In response to situations that stimulate adrenomedullary secretion, there is a concurrent activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. As discussed below, the association of AHS with HPA activation seems closer than that of AHS with SNS activation.
A recent meta-analysis formally and comprehensively assessed the clinical and preclinical literature in which plasma EPI, adrenocorticotropin (ACTH), and NE responses to stressors were measured in the same studies. Magnitudes of responses were categorized according to the following criteria. If there was no significant change in the plasma levels of the dependent variable, a score of 0 was assigned. If there was a statistically significant increase, but less than a doubling, of the pre-stress baseline level, a score of 1 was assigned. If there was at least a doubling of the baseline value, up 3 times the baseline value, a score or 2 was assigned. If there were a large increase, from 3 up to 10 times the baseline value, a score of 3 was assigned. If there was a massive increase to ≥ 10 times the baseline value, a score of 4 was assigned. For each stressor, the average across studies was used, without weighting studies by numbers of subjects. A total of 15 different stressors were identified for which the available literature satisfied the above criteria.
Mean EPI responses were strongly positively correlated with mean ACTH responses (Figure 1, Left) and less strongly with NE responses (Figure 1, Right).
Figure 1. ACTH and NE responses (Left) Mean values for plasma levels of epinephrine (EPI) and corticotrophin (ACTH) across 15 different stressors. Equation is for the line of best fit. (Right) Mean values for plasma levels of epinephrine (EPI) and norepinephrine (NE) across 15 different stressors. Equation is for the line of best fit.
Plasma EPI responses were larger than expected for NE responses during hypoglycemia and smaller than expected for NE responses during cold exposure without hypothermia, orthostasis, and active escape/avoidance. Plasma NE responses were larger than expected for ACTH responses during cold exposure without hypothermia and severe/exhausting exercise and smaller than expected for ACTH responses during hypoglycemia.
The results of this meta-analysis indicate a close association between adrenomedullary and HPA responses across a variety of stressors. This association seems to be if anything stronger than that between adrenomedullary and sympathetic noradrenergic responses. The findings therefore favor the concept of a unitary adrenal system over that of a unitary sympathoadrenal system.
The analysis also supports the notion of “primitive specificity,” according to which stress responses occur in relatively specific neuroendocrine patterns. By promoting homeostasis, such patterning would have provided clear advantages in natural selection and therefore evolved. In contrast, Cannon’s and Selye’s theories, based as they are on the same stereotyped responses regardless of the stress, do not account adequately for outliers in the scatter plots relating EPI to NE and NE to ACTH responses.
Meta-analysis of the available literature therefore supports a closer association of adrenomedullary with HPA than with SNS responses across a variety of stressors. There seems to be at least as good justification for the concept of coordinated adrenocortical-adrenomedullary responses and for coordinated adrenomedullary-sympathoneural responses.
Conclusions: The Wisdom of the Body
Walter Cannon’s concepts of homeostasis, fight-or-flight responses, and a unitary sympathoadrenal system have been extremely fruitful and thereby valuable theories. Each has required some modifications.
What of the “wisdom of the body?” What are the “goals” of body systems? Does the body “want” to regulate the temperature of its blood, the concentrations of glucose and oxygen, and so forth? Teleology is the doctrine that an overall design or purpose determines natural phenomena. Bernard”s theory of the milieu intérieur contains an element of teleology, not in the sense of asserting the application of a Creator”s supernatural will, but in the sense of imputing an overall purpose for the operations of body systems. Continuing this tradition, Cannon wrote, in his The Way of an Investigator, “My first article of belief is based on the observation, almost universally confirmed in present knowledge, that what happens in our bodies is directed toward a useful end.”
The themes of compensatoriness, adaptiveness, and purposiveness of stress responses correspond roughly to mechanistic, Darwinian, and teleological views. Purposiveness, while helpful in deriving testable hypotheses, cannot constitute the essence of a rigorously scientific stress theory, since all the elements of such a theory should be both necessary and testable, and how does one prove the necessity and existence of purposiveness? Compensatoriness alone, while possibly adequate for a parsimonious definition of stress, seems inadequate to explain why and how stress responses evolved, as much evidence suggests they did. A scientific theory of stress therefore should avoid including the notion of purposiveness and transcend the notion of compensatoriness to include the survival advantage of adaptiveness.
This logic is the basis for the homeostatic definition of stress, according to which stress is a condition where expectations, whether genetically programmed, established by prior learning, or deduced from circumstances, do not match the current or anticipated perceptions of the internal or external environment, and this discrepancy between what is observed or sensed and what is expected or programmed elicits patterned, compensatory responses.
Thus, Cannon’s concepts about homeostasis, fight-or-flight responses, the sympathoadrenal system, and even the wisdom of the body, have all evolved, and they continue to incite and inspire researchers more than a half century after his death.
The contents of this article were adapted from (1) Goldstein DS. Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine. Baltimore, MD: The Johns Hopkins University Press, 2006; and (2) Goldstein DS, Kopin IJ. Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: A meta-analysis. Endocr. Regul. 2008;42:111-119.
This research was supported by the intramural research program of the NINDS, NIH.
David Goldstein – Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 USA.