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BODILY CHANGES
IN PAIN, HUNGER,
FEAR AND RAGE

BODILY CHANGES
IN PAIN, HUNGER,
FEAR AND RAGE

AN ACCOUNT OF RECENT RESEARCHES INTO THE FUNCTION OF EMOTIONAL EXCITEMENT

BY

WALTER B. CANNON

GEORGE HIGGINSON PROFESSOR OF PHYSIOLOGY IN HARVARD UNIVERSITY

NEW YORK AND LONDON
D. APPLETON AND COMPANY
1915

Copyright, 1915, by

D. APPLETON AND COMPANY

Printed in the United States of America

TO MY COLLABORATORS IN THESE RESEARCHES

DANIEL DE LA PAZ
ALFRED T. SHOHL
WADE S. WRIGHT
ARTHUR L. WASHBURN
HENRY LYMAN
LEONARD B. NICE
CHARLES M. GRUBER
HOWARD OSGOOD
HORACE GRAY
WALTER L. MENDENHALL

WITH PLEASANT MEMORIES OF OUR WORK TOGETHER

PREFACE

Fear, rage and pain, and the pangs of hunger are all primitive experiences which human beings share with the lower animals. These experiences are properly classed as among the most powerful that determine the action of men and beasts. A knowledge of the conditions which attend these experiences, therefore, is of general and fundamental importance in the interpretation of behavior.

During the past four years there has been conducted, in the Harvard Physiological Laboratory, a series of investigations concerned with the bodily changes which occur in conjunction with pain, hunger and the major emotions. A group of remarkable alterations in the bodily economy have been discovered, all of which can reasonably be regarded as responses that are nicely adapted to the individual’s welfare and preservation. Because these physiological adaptations are interesting both in themselves and in their interpretation, not only to physiologists and psychologists, but to others as well, it has seemed worth while to gather together in convenient form the original accounts of the experiments, which have been published in various American medical and physiological journals. I have, however, attempted to arrange the results and discussions in an orderly and consecutive manner, and I have tried also to eliminate or incidentally to explain the technical terms, so that the exposition will be easily understood by any intelligent reader even though not trained in the medical sciences.

My first interest in the conditions attending pain, hunger and strong emotional states was stimulated during the course of a previous series of researches on the motor activities of the alimentary canal. A summary of these researches appeared in 1911, under the title, “The Mechanical Factors of Digestion.” The studies recorded in the present volume may be regarded as a natural sequence of observations on the influence of emotional states on the digestive process, which were reported in that volume.

W. B. Cannon.

CONTENTS

LIST OF ILLUSTRATIONS

BODILY CHANGES IN PAIN, HUNGER, FEAR AND RAGE

CHAPTER I

THE EFFECT OF THE EMOTIONS ON DIGESTION

The doctrine of human development from subhuman antecedents has done much to unravel the complex nature of man. As a means of interpretation this doctrine has been directed chiefly toward the solving of puzzles in the peculiarities of anatomical structure. Thus arrangements in the human body, which are without obvious utility, receive rational explanation as being vestiges of parts useful in or characteristic of remote ancestors—parts retained in man because of age-long racial inheritance. This mode of interpretation has proved applicable also in accounting for functional peculiarities. Expressive actions and gestures—the facial appearance in anger, for example—observed in children and in widely distinct races, are found to be innate, and are best explained as the retention in human beings of responses which are similar in character in lower animals.

From this point of view biology has contributed much to clarify our ideas regarding the motives of human behavior. The social philosophies which prevailed during the past century either assumed that conduct was determined by a calculated search for pleasure and avoidance of pain or they ascribed it to a vague and undefined faculty named the conscience or the moral sense. Comparative study of the behavior of men and of lower animals under various circumstances, however, especially with the purpose of learning the source of prevailing impulses, is revealing the inadequacy of the theories of the older psychologists. More and more it is appearing that in men of all races and in most of the higher animals, the springs of action are to be found in the influence of certain emotions which express themselves in characteristic instinctive acts.

The rôle which these fundamental responses in the higher organisms play in the bodily economy has received little attention. As a realm for investigation the bodily changes in emotional excitement have been left by the physiologists to the philosophers and psychologists and to the students of natural history. These students, however, have usually had too slight experience in the detailed examination of bodily functions to permit them to follow the clues which superficial observation might present. In consequence our knowledge of emotional states has been meager.

There are, of course, many surface manifestations of excitement. The contraction of blood vessels with resulting pallor, the pouring out of “cold sweat,” the stopping of saliva-flow so that the “tongue cleaves to the roof of the mouth,” the dilation of the pupils, the rising of the hairs, the rapid beating of the heart, the hurried respiration, the trembling and twitching of the muscles, especially those about the lips—all these bodily changes are well recognized accompaniments of pain and great emotional disturbance, such as fear, horror and deep disgust. But these disturbances of the even routine of life, which have been commonly noted, are mainly superficial and therefore readily observable. Even the increased rapidity of the heart beat is noted at the surface in the pulsing of the arteries. There are, however, other organs, hidden deep in the body, which do not reveal so obviously as the structures near or in the skin, the disturbances of action which attend states of intense feeling. Special methods must be used to determine whether these deep-lying organs also are included in the complex of an emotional[*] agitation.

[*]In the use of the term “emotion” the meaning here is not restricted to violent affective states, but includes “feelings” and other affective experiences. At times, also, in order to avoid awkward expressions, the term is used in the popular manner, as if the “feeling” caused the bodily change.

Among the organs that are affected to an important degree by feelings are those concerned with digestion. And the relations of feelings to the activities of the alimentary canal are of particular interest, because recent investigations have shown that not only are the first stages of the digestive process normally started by the pleasurable taste and smell and sight of food, but also that pain and great emotional excitement can seriously interfere with the starting of the process or its continuation after it has been started. Thus there may be a conflict of feelings and of their bodily accompaniments—a conflict the interesting bearing of which we shall consider later.

Emotions Favorable to Normal Secretion of the Digestive Juices

The feelings or affective states favorable to the digestive functions have been studied fruitfully by Pawlow,[1] of Petrograd, through ingenious experiments on dogs. By the use of careful surgical methods he was able to make a side pouch of a part of the stomach, the cavity of which was wholly separate from the main cavity in which the food was received. This pouch was supplied in a normal manner with nerves and blood vessels, and as it opened to the surface of the body, the amount and character of the gastric juice secreted by it under various conditions could be accurately determined. Secretion by that part of the stomach wall which was included in the pouch was representative of the secretory activities of the entire stomach. The arrangement was particularly advantageous in providing the gastric juice unmixed with food. In some of the animals thus operated upon an opening was also made in the esophagus so that when the food was swallowed, it did not pass to the stomach but dropped out on the way. All the pleasures of eating were thus experienced, and there was no necessity of stopping because of a sense of fulness. This process was called “sham feeding.” The well-being of these animals was carefully attended to, they lived the normal life of dogs, and in the course of months and years became the pets of the laboratory.

By means of sham feeding Pawlow showed that the chewing and swallowing of food which the dogs relished resulted, after a delay of about five minutes, in a flow of natural gastric juice from the side pouch of the stomach—a flow which persisted as long as the dog chewed and swallowed the food, and continued for some time after eating ceased. Evidently the presence of food in the stomach is not a prime condition for gastric secretion. And since the flow occurred only when the dogs had an appetite, and the material presented to them was agreeable, the conclusion was justified that this was a true psychic secretion.

The mere sight or smell of a favorite food may start the pouring out of gastric juice, as was noted many years ago by Bidder and Schmidt[2] in a hungry dog which had a fistulous opening through the body wall into the stomach. This observation, reported in 1852, was confirmed later by Schiff and also still later by Pawlow. That the mouth “waters” with a flow of saliva when palatable food is seen or smelled has long been such common knowledge that the expression, “It makes my mouth water,” is at once recognized as the highest testimony to the attractiveness of an appetizing dish. That the stomach also “waters” in preparation for digesting the food which is to be taken is clearly proved by the above cited observations on the dog.

The importance of the initial psychic secretion of saliva for further digestion is indicated when, in estimating the function of taste for the pleasures of appetite, we realize that materials can be tasted only when dissolved in the mouth and thereby brought into relation with the taste organs. The saliva which “waters” the mouth assures the dissolving of dry but soluble food even when it is taken in large amount.

The importance of the initial psychic secretion of gastric juice is made clear by the fact that continuance of the flow of this juice during digestion is provided by the action of its acid or its digestive products on the mucous membrane of the pyloric end of the stomach, and that secretion of the pancreatic juice and bile are called forth by the action of this same acid on the mucous membrane of the duodenum. The proper starting of the digestive process, therefore, is conditioned by the satisfactions of the palate, and the consequent flow of the first digestive fluids.

The facts brought out experimentally in studies on lower animals are doubtless true also of man. Not very infrequently, because of the accidental swallowing of corrosive substances, the esophagus is so injured that, when it heals, the sides grow together and the tube is closed. Under these circumstances an opening has to be made into the stomach through the side of the body and then the individual chews his food in the usual manner, but ejects it from his mouth into a tube which is passed through the gastric opening. The food thus goes from mouth to stomach through a tube outside the chest instead of inside the chest. As long ago as 1878, Richet,[3] who had occasion to study a girl whose esophagus was closed and who was fed through a gastric fistula, reported that whenever the girl chewed or tasted a highly sapid substance, such as sugar or lemon juice, while the stomach was empty, there flowed from the fistula a considerable quantity of gastric juice. A number of later observers[4] have had similar cases in human beings, especially in children, and have reported in detail results which correspond remarkably with those obtained in the laboratory. Hornborg[4] found that when the little boy whom he studied chewed agreeable food a more or less active secretion of gastric juice invariably started, whereas the chewing of an indifferent substance, as gutta-percha, was followed by no secretion. All these observations clearly demonstrate that the normal flow of the first digestive fluids, the saliva and the gastric juice, is favored by the pleasurable feelings which accompany the taste and smell of food during mastication, or which are roused in anticipation of eating when choice morsels are seen or smelled.

These facts are of fundamental importance in the serving of food, especially when, through illness, the appetite is fickle. The degree of daintiness with which nourishment is served, the little attentions to esthetic details—the arrangement of the dishes, the small portions of food, the flower beside the plate—all may help to render food pleasing to the eye and savory to the nostrils and may be the deciding factors in determining whether the restoration of strength is to begin or not.

Emotions Unfavorable to the Normal Secretion of the Digestive Juices

The conditions favorable to proper digestion are wholly abolished when unpleasant feelings such as vexation and worry and anxiety, or great emotions such as anger and fear, are allowed to prevail. This fact, so far as the salivary secretion is concerned, has long been known. The dry mouth of the anxious person called upon to speak in public is a common instance; and the “ordeal of rice,” as employed in India, was a practical utilization of the knowledge that excitement is capable of inhibiting the salivary flow. When several persons were suspected of crime, the consecrated rice was given to them all to chew, and after a short time it was spit out upon the leaf of the sacred fig tree. If anyone ejected it dry, that was taken as proof that fear of being discovered had stopped the secretion, and consequently he was adjudged guilty.[5]

What has long been recognized as true of the secretion of saliva has been proved true also of the secretion of gastric juice. For example, Hornborg was unable to confirm in his little patient with a gastric fistula the observation by Pawlow that when hunger is present the mere seeing of food results in a flow of gastric juice. Hornborg explained the difference between his and Pawlow’s results by the different ways in which the boy and the dogs faced the situation. When food was shown, but withheld, the hungry dogs were all eagerness to secure it, and the juice very soon began to flow. The boy, on the contrary, became vexed when he could not eat at once, and began to cry; then no secretion appeared. Bogen also has reported the instance of a child with closed esophagus and gastric fistula, who sometimes fell into such a passion in consequence of vain hoping for food that the giving of the food, after the child was calmed, was not followed by any flow of the secretion.

The inhibitory influence of excitement has also been seen in lower animals under laboratory conditions. Le Conte[6] declares that in studying gastric secretion it is necessary to avoid all circumstances likely to provoke emotional reactions. In the fear which dogs manifest when first brought into strange surroundings he found that activity of the gastric glands may be completely suppressed. The suppression occurred even if the dog had eaten freely and was then disturbed—as, for example, by being tied to a table. When the animals became accustomed to the experimental procedure, it no longer had an inhibitory effect. The studies of Bickel and Sasaki[7] confirm and define more precisely this inhibitory effect of strong emotion on gastric secretion. They observed the inhibition on a dog with an esophageal fistula, and with a side pouch of the stomach, which, as in Pawlow’s experiments, opened only to the exterior. In this dog Bickel and Sasaki noted, as Pawlow had, that sham feeding was attended by a copious flow of gastric juice, a true psychic secretion, resulting from the pleasurable taste of the food. In a typical instance the sham feeding lasted five minutes, and the secretion continued for twenty minutes, during which time 66.7 cubic centimeters of pure gastric juice were produced.

On another day a cat was brought into the presence of the dog, whereupon the dog flew into a great fury. The cat was soon removed, and the dog pacified. Now the dog was again given the sham feeding for five minutes. In spite of the fact that the animal was hungry and ate eagerly, there was no secretion worthy of mention. During a period of twenty minutes, corresponding to the previous observation, only 9 cubic centimeters of acid fluid were produced, and this was rich in mucus. It is evident that in the dog, as in the boy observed by Bogen, strong emotions can so profoundly disarrange the mechanisms of secretion that the pleasurable excitation which accompanies the taking of food cannot cause the normal flow.

On another occasion Bickel and Sasaki started gastric secretion in the dog by sham feeding, and when the flow of gastric juice had reached a certain height, the dog was infuriated for five minutes by the presence of the cat. During the next fifteen minutes there appeared only a few drops of a very mucous secretion. Evidently in this instance a physiological process, started as an accompaniment of a psychic state quietly pleasurable in character, was almost entirely stopped after another psychic state violent in character.

It is noteworthy that in both the favorable and unfavorable results of the emotional excitement illustrated in Bickel and Sasaki’s dog the effects persisted long after the removal of the exciting condition. This fact, in its favorable aspect, Bickel[8] was able to confirm in a girl with esophageal and gastric fistulas; the gastric secretion long outlasted the period of eating, although no food entered the stomach. The influences unfavorable to digestion, however, are stronger than those which promote it. And evidently, if the digestive process, because of emotional disturbance, is for some time inhibited, the swallowing of food which must lie stagnant in the stomach is a most irrational procedure. If a child has experienced an outburst of passion, it is well not to urge the taking of nourishment soon afterwards. Macbeth’s advice that “good digestion wait on appetite and health on both,” is now well-founded physiology.

Other digestive glands than the salivary and the gastric may be checked in emotional excitement. Recently Oechsler[9] has reported that in such psychic disturbances as were shown by Bickel and Sasaki to be accompanied by suppressed secretion of the gastric juice, the secretion of pancreatic juice may be stopped, and the flow of bile definitely checked. All the means of bringing about chemical changes in the food may be thus temporarily abolished.

Emotions Favorable and Unfavorable to the Contractions of the Stomach and Intestines

The secretions of the digestive glands and the chemical changes wrought by them are of little worth unless the food is carried onward through the alimentary canal into fresh regions of digestion and is thoroughly exposed to the intestinal wall for absorption. In studying these mechanical aspects of digestion I was led to infer[10] that just as there is a psychic secretion, so likewise there is probably a “psychic tone” or “psychic contraction” of the gastro-intestinal muscles as a result of taking food. For if the vagus nerve supply to the stomach is cut immediately before an animal takes food, the usual contractions of the gastric wall, as seen by the Röntgen rays, do not occur; but if these nerves are cut after food has been eaten with relish, the contractions which have started continue without cessation. The nerves in both conditions were severed under anesthesia, so that no element of pain entered into the experiments. In the absence of hunger, which in itself provides a contracted stomach,[11] the pleasurable taking of food may, therefore, be a primary condition for the appearance of natural contractions of the gastro-intestinal canal.

Again just as the secretory activities of the stomach are unfavorably influenced by strong emotions, so also are the movements of the stomach; and, indeed, the movements of almost the entire alimentary canal are wholly stopped during great excitement. In my earliest observations on the movements of the stomach[12] I had difficulty because in some animals the waves of contraction were perfectly evident, while in others there was no sign of activity. Several weeks passed before I discovered that this difference was associated with a difference of sex. In order to be observed with Röntgen rays the animals were restrained in a holder. Although the holder was comfortable, the male cats, particularly the young males, were restive and excited on being fastened to it, and under these circumstances gastric peristaltic waves were absent; the female cats, especially if elderly, usually submitted with calmness to the restraint, and in them the waves had their normal occurrence. Once a female with kittens turned from her state of quiet contentment to one of apparent restless anxiety. The movements of the stomach immediately stopped, the gastric wall became wholly relaxed, and only after the animal had been petted and began to purr did the moving waves start again on their course. By covering the cat’s mouth and nose with the fingers until a slight distress of breathing is produced, the stomach contractions can be stopped at will. In the cat, therefore, any sign of rage or fear, such as was seen in dogs by Le Conte and by Bickel and Sasaki, was accompanied by a total abolition of the movements of the stomach. Even indications of slight anxiety may be attended by complete absence of the churning waves. In a vigorous young male cat I have watched the stomach for more than an hour by means of the Röntgen rays, and during that time not the slightest beginning of peristaltic activity appeared; yet the only visible indication of excitement in the animal was a continued quick twitching of the tail to and fro. What is true of the cat I have found true also of the rabbit, dog and guinea-pig[13]—very mild emotional disturbances are attended by abolition of peristalsis. The observations on the rabbit have been confirmed by Auer,[14] who found that the handling of the animal incidental to fastening it gently to a holder stopped gastric peristalsis for a variable length of time. And if the animal was startled for any reason, or struggled excitedly, peristalsis was again abolished. The observations on the dog also have been confirmed; Lommel[15] found that small dogs in strange surroundings might have no contractions of the stomach for two or three hours. And whenever the animals showed any indications of being uncomfortable or distressed, the contractions were inhibited and the discharge of contents from the stomach checked.

Like the peristaltic waves in the stomach, the peristalsis and the kneading movements (segmentation) in the small intestine, and the reversed peristalsis in the large intestine all cease whenever the observed animal shows signs of emotional excitement.

There is no doubt that just as the secretory activity of the stomach is affected in a similar fashion in man and in lower animals, so likewise gastric and intestinal peristaltic waves are stopped in man as they are stopped in lower animals, by worry and anxiety and the stronger affective states. The conditions of mental discord may thus give rise to a sense of gastric inertia. For example, a patient described by Müller[16] testified that anxiety was always accompanied by a feeling of weight, as if the food remained in the stomach. Every addition of food caused an increase of the trouble. Strong emotional states in this instance led almost always to gastric distress, which persisted, according to the grade and the duration of the psychic disturbance, between a half-hour and several days. The patient was not hysterical or neurasthenic, but was a very sensitive woman deeply affected by moods.

The feeling of heaviness in the stomach, mentioned in the foregoing case, is not uncommonly complained of by nervous persons, and may be due to stagnation of the contents. That such stagnation occurs is shown by the following instance. A refined and sensitive woman, who had had digestive difficulties, came with her husband to Boston to be examined. They went to a hotel for the night. The next morning the woman appeared at the consultant’s office an hour after having eaten a test meal. An examination of the gastric contents revealed no free acid, no digestion of the test breakfast, and the presence of a considerable amount of the supper of the previous evening. The explanation of this stagnation of the food in the stomach came from the family doctor, who reported that the husband had made the visit to the city an occasion for becoming uncontrollably drunk, and that he had by his escapades given his wife a night of turbulent anxiety. The second morning, after the woman had had a good rest, the gastric contents were again examined; the proper acidity was found, and the test breakfast had been normally digested and discharged.

These cases are merely illustrative and doubtless can be many times duplicated in the experience of any physician concerned largely with digestive disorders. Indeed, the opinion has been expressed that a great majority of the cases of gastric indigestion that come for treatment are functional in character and of nervous origin. It is the emotional element that seems most characteristic of these cases. To so great an extent is this true that Rosenbach has suggested that as a term to characterize the cause of the disturbances, “emotional” dyspepsia is better than “nervous” dyspepsia.[17]

The Disturbing Effect of Pain on Digestion

The advocates of the theory of organic evolution early pointed out the similarity between the bodily disturbances in pain and in the major emotions. The alterations of function of internal organs they could not know about. The general statement, however, that pain evokes the same changes that are evoked by emotion, is true also of these deep-lying structures. Wertheimer[18] proved many years since that stimulation of a sensory nerve in an anesthetized animal—such stimulation as in a conscious animal would induce pain—quickly abolished the contractions of the stomach. And Netschaiev, working in Pawlow’s[19] laboratory, showed that excitation of the sensory fibres in the sciatic nerve for two or three minutes resulted in an inhibition of the secretion of gastric juice that lasted for several hours. Similar effects from painful experience have been not uncommonly noted in human beings. Mantegazza,[20] in his account of the physiology of pain, has cited a number of such examples, and from them he has concluded that pain interferes with digestion by lessening appetite and by producing various forms of dyspepsia, with arrest of gastric digestion, and with vomiting and diarrhea. The expression, “sickening pain” is testimony to the power of strong sensory stimulation to upset the digestive processes profoundly. Vomiting is as likely to follow violent pain as it is to follow strong emotion. A “sick headache” may be, indeed, a sequence of events in which the pain from the headache is primary, and the nausea and other evidences of digestive disorder are secondary.

As the foregoing account has shown, emotional conditions or “feelings” may be accompanied by quite opposite effects in the alimentary canal, some highly favorable to good digestion, some highly disturbing. It is an interesting fact that the feelings having these antagonistic actions are typically expressed through nerve supplies which are correspondingly opposed in their influence on the digestive organs. The antagonism between these nerve supplies is of fundamental importance in understanding not only the operation of conditions favorable or unfavorable to digestion but also in obtaining insight into the conflicts of emotional states. Since a consideration of the arrangement and mode of action of these nerves will establish a firm basis for later analysis and conclusions, they will next be considered.

REFERENCES

[1] Pawlow: The Work of the Digestive Glands, London, 1902.

[2] Bidder and Schmidt: Die Verdauungssäfte und der Stoffwechsel, Leipzig, 1852, p. 35.

[3] Richet: Journal de l’Anatomie et de la Physiologie, 1878, xiv, p. 170.

[4] See Hornborg: Skandinavisches Archiv für Physiologie, 1904, xv, p. 248. Cade and Latarjet: Journal de Physiologie et Pathologie Générale, 1905, vii, p. 221. Bogen: Archiv für die gesammte Physiologie, 1907, cxvii, p. 156. Lavenson: Archives of Internal Medicine, 1909, iv, p. 271.

[5] Lea: Superstition and Force, Philadelphia, 1892, p. 344.

[6] Le Conte: La Cellule, 1900, xvii, p. 291.

[7] Bickel and Sasaki: Deutsche medizinische Wochenschrift, 1905, xxxi, p. 1829.

[8] Bickel: Berliner klinische Wochenschrift, 1906, xliii, p. 845.

[9] Oechsler: Internationelle Beiträge zur Pathologie und Therapie der Ernährungstörungen, 1914, v, p. 1.

[10] Cannon: The Mechanical Factors of Digestion, London and New York, 1911, p. 200.

[11] Cannon and Washburn: American Journal of Physiology, 1912, xxix, p. 441.

[12] Cannon: The American Journal of Physiology, 1898, i, p. 38.

[13] Cannon: American Journal of Physiology, 1902, vii, p. xxii.

[14] Auer: American Journal of Physiology, 1907, xviii, p. 356.

[15] Lommel: Münchener medizinische Wochenschrift, 1903, i, p. 1634.

[16] Müller: Deutsches Archiv für klinische Medicin, 1907, lxxxix, p. 434.

[17] Rosenbach: Berliner klinische Wochenschrift, 1897, xxxiv, p. 71.

[18] Wertheimer: Archives de Physiologie, 1892, xxiv, p. 379.

[19] Pawlow: Loc. cit., p. 56.

[20] Mantegazza: Fisiologia del Dolore, Florence, 1880, p. 123.

CHAPTER II

THE GENERAL ORGANIZATION OF THE VISCERAL NERVES CONCERNED IN EMOTIONS

The structures of the alimentary canal which are brought into activity during the satisfactions of appetite or are checked in their activity during pain and emotional excitement are either the secreting digestive glands or the smooth muscle which surrounds the canal. Both the gland cells and the smooth-muscle cells differ from other cells which are subject to nervous influence—those of striated, or skeletal, muscle—in not being directly under voluntary control and in being slower in their response. The muscle connected with the skeleton responds to stimulation within two or three thousandths of a second; the delay with gland cells and with smooth muscle is more likely to be measured in seconds than in fractions of a second.

The Outlying Neurones

The skeletal muscles receive their nerve supply direct from the central nervous system, i. e., the nerve fibres distributed to these muscles are parts of neurones whose cell bodies lie within the brain or spinal cord. The glands and smooth muscles of the viscera, on the contrary, are, so far as is now known, never innervated directly from the central nervous system.[*] The neurones reaching out from the brain or spinal cord never come into immediate relation with the gland or smooth-muscle cells; there are always interposed between the cerebrospinal neurones and the viscera extra neurones whose bodies and processes lie wholly outside the central nervous system. They are represented in dotted lines in [Fig. 1]. I have suggested that possibly these outlying neurones act as “transformers,” modifying the impulses received from the central source (impulses suited to call forth the quick responses of skeletal muscle), and adapting these impulses to the peculiar, more slowly-acting tissues, the secreting cells and visceral muscle, to which they are distributed.[1]

[*]The special case of the adrenal glands will be considered later.

The outlying neurones typically have their cell bodies grouped in ganglia (G’s, [Fig. 1]) which, in the trunk region, lie along either side of the spinal cord and in the head region and in the pelvic part of the abdominal cavity are disposed near the organs which the neurones supply. In some instances these neurones lie wholly within the structure which they innervate (see e. g., the heart and the stomach, [Fig. 1]). In other instances the fibres passing out from the ganglia—the so-called “postganglionic fibres”—may traverse long distances before reaching their destination. The innervation of blood vessels in the foot by neurones whose cell bodies are in the lower trunk region is an example of this extensive distribution of the fibres.

Figure 1.—Diagram of the more important distributions of the autonomic nervous system. The brain and spinal cord are represented at the left. The nerves to skeletal muscles are not represented. The preganglionic fibres of the autonomic system are in solid lines, the postganglionic in dash-lines. The nerves of the cranial and sacral divisions are distinguished from those of the thoracico-lumbar or “sympathetic” division by broader lines. A + mark indicates an augmenting effect on the activity of the organ; a - mark, a depressive or inhibitory effect. For further description see text.

The Three Divisions of the Outlying Neurones

As suggested above, the outlying neurones are connected with the brain and spinal cord by neurones whose cell bodies lie within the central nervous organs. These connecting neurones, represented in continuous lines in [Fig. 1], do not pass out in a continuous series all along the cerebrospinal axis. Where the nerves pass out from the spinal cord to the fore and hind limbs, fibres are not given off to the ganglia. Thus these connecting or “preganglionic” fibres are separated into three divisions. In front of the nerve roots for the fore limbs is the head or cranial division, between the nerve roots for the fore limbs and those for the hind limbs is the trunk division (or thoracico-lumbar division, or, in the older terminology, the “sympathetic system”); and after the nerve roots for the hind limbs the sacral division.

This system of outlying neurones, with postganglionic fibres innervating the viscera, and with preganglionic fibres reaching out to them from the cerebrospinal system, has been called by Langley, to whom we are indebted for most of our knowledge of its organization, the autonomic nervous system.[2] This term indicates that the structures which the system supplies are not subject to voluntary control, but operate to a large degree independently. As we have seen, a highly potent mode of influencing these structures is through conditions of pain and emotional excitement. The parts of the autonomic system—the cranial, the sympathetic, and the sacral—have a number of peculiarities which are of prime importance in accounting for the bodily manifestations of such affective states.

The Extensive Distribution of Neurones of the “Sympathetic” Division and Their Arrangement for Diffuse Action

The fibres of the sympathetic division differ from those of the other two divisions in being distributed through the body very widely. They go to the eyes, causing dilation of the pupils. They go to the heart and, when stimulated, they cause it to beat rapidly. They carry impulses to arteries and arterioles of the skin, the abdominal viscera, and other parts, keeping the smooth muscles of the vessel walls in a state of slight contraction or tone, and thus serving to maintain an arterial pressure sufficiently high to meet sudden demands in any special region; or, in times of special discharge of impulses, to increase the tone and thus also the arterial pressure. They are distributed extensively to the smooth muscle attached to the hairs; and when they cause this muscle to contract, the hairs are erected. They go to sweat glands, causing the outpouring of sweat. These fibres pass also to the entire length of the gastro-intestinal canal. And the inhibition of digestive activity which, as we have learned, occurs in pain and emotional states, is due to impulses which are conducted outward by the splanchnic nerves—the preganglionic fibres that reach to the great ganglia in the upper abdomen (see [Fig. 1])—and thence are spread by postganglionic fibres all along the gut.[3] They innervate likewise the genito-urinary tracts, causing contraction of the smooth muscle of the internal genital organs, and usually relaxation of the bladder. Finally they affect the liver, releasing the storage of material there in a manner which may be of great service to the body in time of need. The extensiveness of the distribution of the fibres of the sympathetic division is one of its most prominent characteristics.

Another typical feature of the sympathetic division is an arrangement of neurones for diffuse discharge of the nerve impulses. As shown diagrammatically in [Fig. 1], the preganglionic fibres from the central nervous system may extend through several of the sympathetic ganglia and give off in each of them connections to cell bodies of the outlying neurones. Although the neurones which transmit sensory impulses from the skin into spinal cord have similar relations to nerve cells lying at different levels of the cord, the operation in the two cases is quite different. In the spinal cord the sensory impulse produces directed and closely limited effects, as, for example, when reflexes are being evoked in a “spinal” animal (i. e., an animal with the spinal cord isolated from the rest of the central nervous system), the left hind limb is nicely lifted, in response to a harmful stimulus applied to the left foot, without widespread marked involvement of the rest of the body in the response.[4] In the action of the sympathetic division, on the contrary, the connection of single preganglionic fibres with numerous outlying neurones seems to be not at all arranged for specific effects in this or that particular region. There are, to be sure, in different circumstances variations in the degree of activity of different parts; for example, it is probable that dilation of the pupil in the cat occurs more readily than erection of the hairs. It may be in this instance, however, that specially direct pathways to the eye are present for common use in non-emotional states (in dim light, e. g.), and that only slight general disturbance in the central nervous system, therefore, would be necessary to send impulses by these well-worn courses. Thus for local reasons (dust, e. g.) tears might flow from excitation of the tear glands by sympathetic impulses, although other parts innervated by this same division might be but little disturbed. We have no means of voluntarily wearing these pathways, however, and both from anatomical and physiological evidence the neurone relations in the sympathetic division of the autonomic system seem devised for widespread diffusion of nervous impulses.

The Arrangement of Neurones of the Cranial and Sacral Divisions for Specific Action

The cranial and sacral autonomic divisions differ from the sympathetic in having only restricted distribution (see [Fig. 1]). The third cranial nerves deliver impulses from the brain to ganglia in which lie the cell bodies of neurones innervating smooth muscle only in the front of the eyes. The vagus nerves are distributed to the lungs, heart, stomach, and small intestine. As shown diagrammatically in [Fig. 1], the outlying neurones in the last three of these organs lie within the organs themselves. By this arrangement, although the preganglionic fibres of the vagi are extended in various directions to structures of quite diverse functions, singleness and separateness of connection of the peripheral organs with the central nervous system is assured. The same specific relation between efferent fibres and the viscera is seen in the sacral autonomic. In this division the preganglionic fibres pass out from the spinal cord to ganglia lying in close proximity to the distal colon, the bladder, and the external genitals. And the postganglionic fibres deliver the nerve impulses only to the nearby organs. Besides these innervations the cranial and sacral divisions supply individual arteries with “dilator nerves”—nerves causing relaxation of the particular vessels. Quite typically, therefore, the efferent fibres of the two terminal divisions of the autonomic differ from those of the mid-division in having few of the distributed connections characteristic of the mid-division, and in innervating distinctively the organs to which they are distributed. The cranial and sacral preganglionic fibres resemble thus the nerves to skeletal muscles, and their arrangement provides similar possibilities of specific and separate action in any part, without action in other parts.

The Cranial Division a Conserver of Bodily Resources

The cranial autonomic, represented by the vagus nerves, is the part of the visceral nervous system concerned in the psychic secretion of the gastric juice. Pawlow showed that when these nerves are severed psychic secretion is abolished. The cranial nerves to the salivary glands are similarly the agents for psychic secretion in these organs, and are known to cause also dilation of the arteries supplying the glands, so that during activity the glands receive a more abundant flow of blood. As previously stated (see [p. 13]), the evidence for a psychic tonus of the gastro-intestinal musculature rests on a failure of the normal contractions if the vagi are severed before food is taken, in contrast to the continuance of the contractions if the nerves are severed just afterwards. The vagi artificially excited are well known as stimulators of increased tone in the smooth muscle of the alimentary canal. Aside from these positive effects on the muscles of the digestive tract and its accessory glands, cranial autonomic fibres cause contraction of the pupil of the eye, and slowing of the heart rate.

A glance at these various functions of the cranial division reveals at once that they serve for bodily conservation. By narrowing the pupil of the eye they shield the retina from excessive light. By slowing the heart rate, they give the cardiac muscle longer periods for rest and invigoration. And by providing for the flow of saliva and gastric juice and by supplying the muscular tone necessary for contraction of the alimentary canal, they prove fundamentally essential to the processes of proper digestion and absorption by which energy-yielding material is taken into the body and stored. To the cranial division of the visceral nerves, therefore, belongs the quiet service of building up reserves and fortifying the body against times of need or stress.

The Sacral Division a Group of Mechanisms for Emptying

Sacral autonomic fibres cause contraction of the rectum and distal colon and also contraction of the bladder. In both instances the effects result reflexly from stretching of the tonically contracted viscera by their accumulating contents. No affective states precede this normal action of the sacral division and even those which accompany or follow are only mildly positive; a feeling of relief rather than of elation usually attends the completion of the act of defecation or micturition—though there is testimony to the contrary.

The sacral autonomic fibres also include, however, the nervi erigentes which bring about engorgement of erectile tissue in the external genitals. According to Langley and Anderson[5] the sacral nerves have no effect on the internal generative organs. The vasa deferentia and the seminal vesicles whose rhythmic contractions mark the acme of sexual excitement in the male, and the uterus whose contractions in the female are probably analogous, are supplied only by lumbar branches—part of the sympathetic division. These branches also act in opposition to the nervi erigentes and cause constriction of the blood vessels of the external genitals. The sexual orgasm involves a high degree of emotional excitement; but it can be rightly considered as essentially a reflex mechanism; and, again in this instance, distention of tubules, vesicles, and blood vessels can be found at the beginning of the incident, and relief from this distention at the end.

Although distention is the commonest occasion for bringing the sacral division into activity it is not the only occasion. Great emotion, such as is accompanied by nervous discharges via the sympathetic division, may also be accompanied by discharges via the sacral fibres. The involuntary voiding of the bladder and lower gut at times of violent mental stress is well known. Veterans of wars testify that just before the beginning of a battle many of the men have to retire temporarily from the firing line. And the power of sights and smells and libidinous thoughts to disturb the regions controlled by the nervi erigentes proves that this part of the autonomic system also has its peculiar affective states. The fact that one part of the sacral division, e. g., the distribution to the bladder, may be in abeyance, while another part, e. g., the distribution to the rectum, is active, illustrates again the directive discharge of impulses which has been previously described as characteristic of the cranial and sacral portions of the autonomic system.

Like the cranial division, the sacral is engaged in internal service to the body, in the performance of acts leading immediately to greater comfort.

The Sympathetic Division Antagonistic To Both The Cranial and the Sacral

As indicated in the foregoing description many of the viscera are innervated both by the cranial or sacral part of the autonomic and by the sympathetic. When the mid-part meets either end-part in any viscus their effects are antagonistic. Thus the cranial supply to the eye contracts the pupil, the sympathetic dilates it; the cranial slows the heart, the sympathetic accelerates it; the sacral contracts the lower part of the large intestine, the sympathetic relaxes it; the sacral relaxes the exit from the bladder, the sympathetic contracts it. These opposed effects are indicated in [Fig. 1] by + for contraction, acceleration or increased tone; and by - for inhibition, relaxation, or decreased tone.[*]

[*] The vagus nerve, when artificially stimulated, has a primary, brief inhibitory effect on the stomach and small intestine; its main function, however, as already stated, is to produce increased tone and contraction in these organs. This double action of the vagus is marked thus, ∓, in [Fig. 1].

Sherrington has demonstrated that the setting of skeletal muscles in opposed groups about a joint or system of joints—as in flexors and extensors—is associated with an internal organization of the central nervous system that provides for relaxation of one group of the opposed muscles when the other group is made to contract. This “reciprocal innervation of antagonistic muscles,” as Sherrington has called it,[6] is thus a device for orderly action in the body. As the above description has shown, there are peripheral oppositions in the viscera corresponding to the oppositions between flexor and extensor muscles. In all probability these opposed innervations of the viscera have counterparts in the organization of neurones in the central nervous system. Sherrington has noticed, and I can confirm the observation, that even though the sympathetic supply to the eye is severed and is therefore incapable of causing dilation of the pupil, nevertheless the pupil dilates in a paroxysm of anger—due, no doubt (because the response is too rapid to be mediated by the blood stream), to central inhibition of the cranial nerve supply to the constrictor muscles—i. e., an inhibition of the muscles which naturally oppose the dilator action of the sympathetic. Pain, the major emotions—fear and rage—and also intense excitement, are manifested in the activities of the sympathetic division. When in these states impulses rush out over the neurones of this division they produce all the changes typical of sympathetic excitation, such as dilating the pupils, inhibiting digestion, causing pallor, accelerating the heart, and various other well-known effects. The impulses of the sympathetic neurones, as indicated by their dominance over the digestive process, are capable of readily overwhelming the conditions established by neurones of the cranial division of the autonomic system.

Neurones of the Sympathetic Division and Adrenal Secretion Have the Same Action

Lying anterior to each kidney is a small body—the adrenal gland. It is composed of an external portion or cortex, and a central portion or medulla. From the medulla can be extracted a substance, called variously suprarenin, adrenin, epinephrin or “adrenalin,”[*] which, in extraordinarily minute amounts, affects the structures innervated by the sympathetic division of the autonomic system precisely as if they were receiving nervous impulses. For example, when adrenin is injected into the blood, it will cause pupils to dilate, hairs to stand erect, blood vessels to be constricted, the activities of the alimentary canal to be inhibited, and sugar to be liberated from the liver. These effects are not produced by action of the substance on the central nervous system, but by direct action on the organ itself.[7] And the effects occur even after the structures have been removed from the body and kept alive artificially.

[*] The name “adrenalin” is proprietary. “Epinephrin” and “adrenin” have been suggested as terms free from commercial suggestions. As adrenin is shorter and more clearly related to the common adjectival form, adrenal, I have followed Schäfer in using adrenin to designate the substance produced physiologically by the adrenal glands.

The adrenals are glands of internal secretion, i. e., like the thyroid, parathyroid, and pituitary glands, for example; they have no connection with the surface of the body, and they give out into the blood the material which they elaborate. The blood is carried away from each of them by the lumbo-adrenal vein which empties either into the renal vein or directly into the inferior vena cava just anterior to the openings of the renal veins. The adrenal glands are supplied by preganglionic fibres of the autonomic group,[8] shown in solid line in [Fig. 1]. This seems an exception to the general rule that gland cells have an outlying neurone between them and the neurones of the central nervous system. The medulla of the adrenal gland, however, is composed of modified nerve cells, and may therefore be regarded as offering exceptional conditions.

The foregoing brief sketch of the organization of the autonomic system brings out a number of points that should be of importance as bearing on the nature of the emotions which manifest themselves in the operations of this system. Thus it is highly probable that the sympathetic division, because arranged for diffuse discharge, is likely to be brought into activity as a whole, whereas the sacral and cranial divisions, arranged for particular action on separate organs, may operate in parts. Also, because antagonisms exist between the middle and either end division of the autonomic, affective states may be classified according to their expression in the middle or an end division and these states would be, like the nerves, antagonistic in character. And finally, since the adrenal glands are innervated by autonomic fibres of the mid-division, and since adrenal secretion stimulates the same activities that are stimulated nervously by this division, it is possible that disturbances in the realm of the sympathetic, although initiated by nervous discharge, are automatically augmented and prolonged through chemical effects of the adrenal secretion.

REFERENCES

[1] Cannon: The American Journal of Psychology, 1914, xxv, p. 257.

[2] For a summary of his studies of the organization of the autonomic system, see Langley: Ergebnisse der Physiologie, Wiesbaden, 1903, ii², p. 818.

[3] See Cannon: American Journal of Physiology, 1905, xiii, p. xxii.

[4] See Sherrington: The Integrative Action of the Nervous System, New York, 1909, p. 19.

[5] Langley and Anderson: Journal of Physiology, 1895, xix, see pp. 85, 122.

[6] Sherrington: Loc. cit., p. 90.

[7] Elliott: Journal of Physiology, 1905, xxxii, p. 426.

[8] See Elliott: Journal of Physiology, 1913, xlvi, p. 289 ff.

CHAPTER III

METHODS OF DEMONSTRATING ADRENAL SECRETION AND ITS NERVOUS CONTROL

As stated in the first chapter, the inhibition of gastric secretion produced by great excitement long outlasts the presence of the object which evokes the excitement. The dog that was enraged by seeing a cat for five minutes secreted only a few drops of gastric juice during the next fifteen minutes. Why did the state of excitation persist so long after the period of stimulation had ended? This question, which presented itself to me while reading Bickel and Sasaki’s paper, furnished the suggestion expressed at the close of the last chapter, that the excitement might provoke a flow of adrenal secretion, and that the changes originally induced in the digestive organs by nervous impulses might be continued by circulating adrenin. The prolongation of the effect might be thus explained. Whether that idea is correct or not has not been tested. Its chief service was in leading to an enquiry as to whether the adrenal glands are in fact stimulated to action in emotional excitement. The preganglionic fibres passing to the glands are contained in the splanchnic nerves. What is the effect of splanchnic stimulation?

The Evidence that Splanchnic Stimulation Induces Adrenal Secretion

It was in 1891 that Jacobi[1] described nerve fibres derived from the splanchnic trunks which were distributed to the adrenal glands. Six years later Biedl[2] found that these nerves conveyed vasodilator impulses to the glands, and he suggested that they probably conveyed also secretory impulses. Evidence in support of this suggestion was presented the following year by Dreyer,[3] who demonstrated that electrical excitation of the splanchnic nerves produced in the blood taken from the adrenal veins an increased amount of a substance having the power of raising arterial blood pressure, and that this result was independent of accompanying changes in the blood supply to the glands. The conclusion drawn by Dreyer that this substance was adrenin has been confirmed in various ways by later observers. Tscheboksaroff[4] repeated Dreyer’s procedure and found in blood taken from the veins after splanchnic stimulation evidences of the presence of adrenin that were previously absent. Asher[5] observed a rise of blood pressure when the glands were stimulated in such a manner as not to cause constriction of the arteries—the rise was therefore assumed to be due to secreted adrenin. Dilation of the pupil was used by Meltzer and Joseph[6] to prove secretory action of the splanchnics on the adrenal glands; they found that stimulation of the distal portion of the cut splanchnic nerve caused the pupil to enlarge—an effect characteristic of adrenin circulating in the blood. Elliott[7] repeated this procedure, but made it a more rigorous proof of internal secretion of the adrenals by noting that the effect failed to appear if the gland on the stimulated side was removed. Additional proof was brought by myself and Lyman[8] when we found that the typical drop in arterial pressure produced in cats by injecting small amounts of adrenin could be exactly reproduced by stimulating the splanchnic nerves after the abdominal blood vessels, which contract when these nerves are excited, were tied so that no changes in them could occur to influence the rest of the circulation.

The problem of splanchnic influence on the adrenal glands Elliott attacked by a still different method. Using, as a measure, the graded effects of graded amounts of adrenin on blood pressure, he was able to assay the quantity of adrenin in adrenal glands after various conditions had been allowed to prevail. The tests were made on cats. In these animals each adrenal gland is supplied only by the splanchnic fibres of its own side, and the two glands normally contain almost exactly the same amount of adrenin. Elliott[9] found that when the gland on one side was isolated by cutting its splanchnic supply, and then impulses were sent along the intact nerves of the other side, either by disturbing the animal or by artificial excitation of the nerves, the gland to which these fibres reached invariably contained less adrenin, often very much less, than the isolated gland. Results obtained by the method employed by Elliott have been confirmed with remarkable exactness in results obtained by Folin, Denis and myself,[10] using a highly sensitive color test after adding the gland extract to a solution of phosphotungstic acid.

All these observations, with a variety of methods, and by a respectable number of reliable investigators, are harmonious in bringing proof that artificial stimulation of the nerves leading to the adrenal glands will induce secretory activity in the adrenal medulla, and that in consequence adrenin will be increased in the blood. The fact is therefore securely established that in the body a mechanism exists by which these glands can be made to discharge this peculiar substance promptly into the circulation.

The Question of Adrenal Secretion in Emotional Excitement

As we have already seen, the phenomena of a great emotional disturbance in an animal indicate that sympathetic impulses dominate the viscera. When, for example, a cat becomes frightened, the pupils dilate, the activities of the stomach and intestines are inhibited, the heart beats rapidly, the hairs of the back and tail stand erect—from one end of the animal to the other there are abundant signs of nervous discharges along sympathetic courses. Do not the adrenal glands share in this widespread subjugation of the viscera to sympathetic control?

This question, whether the common excitements of an animal’s life might be capable of evoking a discharge of adrenin, was taken up by D. de la Paz and myself in 1910. We made use of the natural enmity between two laboratory animals, the dog and the cat, to pursue our experiments. In these experiments the cat, fastened in a comfortable holder (the holder already mentioned as being used in X-ray studies of the movements of the alimentary canal), was placed near a barking dog. Some cats when thus treated showed almost no signs of fear; others, with scarcely a movement of defense, presented the typical picture. In favorable cases the excitement was allowed to prevail for five or ten minutes, and in a few cases longer. Samples of blood were taken within a few minutes before and after the period.

The Method of Securing Blood from Near the Adrenal Veins

The blood was obtained from the inferior vena cava anterior to the opening of the adrenal veins, i. e., at a point inside the body near the level of the notch at the lower end of the sternum. To get the blood so far from the surface without disturbing the animal was at first a difficult problem. We found, however, that by making anesthetic with ethyl chloride the skin directly over the femoral vein high in the groin, the vein could be quickly bared, cleared of connective tissue, tied, and opened without causing any general disturbance whatever. A long, fine, flexible catheter (2.4 millimeters in diameter) which had previously been coated with vaseline inside and out, to lubricate it and to delay the clotting of blood within it, was now introduced into the opening in the femoral vein, thence through the iliac and on into the inferior cava to a point near the level of the sternal notch. A thread tied around this tube where, after being inserted to the proper distance, it disappeared into the femoral vein, marked the extent of insertion, and permitted a later introduction to the same extent. This slight operation—a venesection, commonly practised on our ancestors—consumed only a few minutes, and as the only possibility of causing pain was guarded against by local anesthesia, the animal remained tranquil throughout. Occasionally it was necessary to stroke the cat’s head gently to keep her quiet on the holder, and under such circumstances I have known her to purr during all the preparations for obtaining the blood, and while the blood was being taken.

The blood (3 or 4 cubic centimeters) was slowly drawn through the catheter into a clean glass syringe. Care was taken to avoid any marked suction such as might cause collapse of the vein near the inner opening of the tube. As soon as the blood was secured, the catheter was removed and the vein tied loosely, to prevent bleeding. The blood was at once emptied into a beaker, and the fibrin whipped from it by means of fringed rubber tubing fitted over a glass rod. Since this defibrinated blood was obtained while the animal was undisturbed, it was labelled “quiet blood.”

The animal was then exposed to the barking dog, as already described, and immediately thereafter blood was again removed, from precisely the same region as before. This sample, after being defibrinated, was labelled “excited blood.” The two samples, the “quiet” and the “excited,” both obtained in the same manner and subsequently treated in the same manner, were now tested for their content of adrenin.

The Method of Testing the Blood for Adrenin

It was desirable to use as a test tissues to which the blood was naturally related. As will be recalled, adrenin affects viscera even after they have been removed from the body, just as if they were receiving impulses via sympathetic fibres, and further, that sympathetic fibres normally deliver impulses which cause contraction of the internal genitals and relaxation of the stomach and intestines. The uterus has long been employed as a test for adrenin, the presence of which it indicates by increased contraction. That isolated strips of the longitudinal muscle of the intestine, which are contracting rhythmically, are characteristically inhibited by adrenin in dilutions of 1 part in 20 millions, had been shown by Magnus in 1905. Although, previous to our investigation in 1910, this extremely delicate reaction had not been used as a biological signal for adrenin, it possesses noteworthy advantages over other methods. The intestine is found in all animals and not in only half of them, as is the uterus; it is ready for the test within a few minutes, instead of the several hours said to be required for the best use of the uterus preparation;[11] and it responds by relaxing. This last characteristic is especially important, for in defibrinated blood there are, besides adrenin, other substances capable of causing contraction of smooth muscle,[12] and liable therefore to lead to erroneous conclusions when a structure which responds by contracting, such as uterus or artery, is used to prove whether adrenin is present. On the other hand, substances producing relaxation of smooth muscle are few, and are unusual in blood.[13]

We used, therefore, the strip of intestinal muscle as an indicator. Later Hoskins[14] modified our procedure by taking, instead of the strip, a short segment of the rabbit intestine. The segment is not subjected to danger of injury during its preparation, and when fresh it is almost incredibly sensitive. It may be noticeably inhibited by adrenin, 1 part in 200 millions!

The strip, or the intestinal segment, was suspended between minute wire pincers (serres fines) in a cylindrical chamber 8 millimeters in diameter and 5 centimeters deep. By a thread attached to the lower serre fine the preparation was drawn into the chamber, and was held firmly; by the upper one it was attached to the short end of a writing lever (see [Fig. 2]). When not exposed to blood, the strip was immersed in a normal solution of the blood salts (Ringer’s). The blood or the salt solution could be quickly withdrawn from or introduced into the chamber, without disturbing the muscle, by means of a fine pipette passed down along the inner surface. The chamber and its contents, the stock of Ringer’s solution, and the samples of “quiet” and “excited” blood were all surrounded by a large volume of water kept approximately at body temperature (37° C.). Through the blood or the salt solution in the chamber oxygen was passed in a slow but steady stream of bubbles. Under these circumstances the strip will live for hours, and will contract and relax in a beautifully regular rhythm, which may be recorded graphically by the writing lever.

Figure 2.—Diagram of the arrangements for recording contractions of the intestinal muscle.

The first effect of surrounding the muscle with blood, whether “quiet” or “excited,” was to send it into a strong contraction which might persist, sometimes with slight oscillations, for a minute or two (see [Figs. 4] and [5]). After the initial shortening, the strip, if in quiet blood soon began to contract and relax rhythmically and with each relaxation to lengthen more, until a fairly even base line appeared in the written record. At this stage the addition of fresh “quiet” blood usually had no effect, even though the strip were washed once with Ringer’s solution before the second portion of the blood was added. For comparison of the effects of “quiet” and “excited” blood on the contracting strip, the two samples were each added to the muscle immediately after the Ringer’s solution had been removed, or they were applied to the muscle alternately and the differences in effect then noted. The results obtained by these methods are next to be presented.

REFERENCES

[1] Jacobi: Archiv für experimentelle Pathologie und Pharmakologie, 1891, xxix, p. 185.

[2] Biedl: Archiv für die gesammte Physiologie, 1897, lxvii, pp. 456, 481.

[3] Dreyer: American Journal of Physiology, 1898–99, ii, p. 219.

[4] Tscheboksaroff: Archiv für die gesammte Physiologie, 1910, cxxxvii, p. 103.

[5] Zeitschrift für Biologie, 1912, lviii, p. 274.

[6] Meltzer and Joseph: American Journal of Physiology, 1912, xxix, p. xxxiv.

[7] Elliott: Journal of Physiology, 1912, xliv, p. 400.

[8] Cannon and Lyman: American Journal of Physiology, 1913, xxxi, p. 377.

[9] Elliott: Journal of Physiology, 1912, xliv, p. 400.

[10] Folin, Cannon and Denis: Journal of Biological Chemistry, 1913, xiii, p. 477.

[11] Fraenkel: Archiv für experimentelle Pathologie und Pharmakologie, 1909, lx, p. 399.

[12] See O’Connor: Archiv für die experimentelle Pathologie und Pharmakologie, 1912, lxvii, p. 206.

[13] Grutzner: Ergebnisse der Physiologie, 1904, iii², p. 66; Magnus: Loc. cit., p. 69.

[14] Hoskins: Journal of Pharmacology and Experimental Therapeutics, 1911, iii, p. 95.

CHAPTER IV

ADRENAL SECRETION IN STRONG EMOTIONS AND PAIN

If the secretion of adrenin is increased in strong emotional states and in pain, that constitutes a fact of considerable significance, for, as already mentioned, adrenin is capable of producing many of the bodily changes which are characteristically manifested in emotional and painful experiences. It is a matter of prime importance for further discussion to determine whether the adrenal glands are in fact roused to special activity in times of stress.

The Evidence that Adrenal Secretion Is Increased in Emotional Excitement

That blood from the adrenal veins causes the relaxation of intestinal muscle characteristic of adrenal extract or adrenin is shown in [Fig. 3]. The muscle was originally beating in blood which contained no demonstrable amount of adrenal secretion; this inactive blood was replaced by blood from the adrenal veins, obtained after quick etherization. Etherization, it will be recalled, is accompanied by a “stage of excitement.” Relaxation occurred almost immediately (at b). Then the rhythm was renewed in the former blood, and thereupon the muscle was surrounded with blood from the vein leading away from the left kidney, i. e., blood obtained from the same animal and under the same conditions as the adrenal blood, but from a neighboring vein. No relaxation occurred. By this and other similar tests the reliability of the method was proved.

Figure 3.—Intestinal muscle beating in inactive blood, which was withdrawn from the chamber at a. Blood from the adrenal vein of an animal excited by etherization was substituted at b, and withdrawn at c. Contractions were restored in the original inactive blood which was removed at d. Blood from the renal vein (same animal) was added at e.

In this and subsequent records time is marked in half minutes.

In no instance did blood from the inferior vena cava of the quiet normal animal produce relaxation. On the other hand, blood from the animal after emotional excitement showed more or less promptly the typical relaxation. In [Fig. 4] is represented the record of intestinal muscle which was beating regularly in Ringer’s solution. At a the Ringer’s solution was removed, and at b “excited” blood was added; after the preliminary shortening, which, as already stated, occurs at the first immersion in blood, the muscle lengthened gradually into complete inhibition. At c the “excited” blood was removed, and at d “quiet” blood was added in its place. The muscle at once began fairly regular rhythmic beats. At e the “quiet” blood was removed, and at f the “excited” blood was again applied. The muscle lengthened almost immediately into an inhibited state. In this instance the “excited” blood was taken after the cat had been barked at for about fifteen minutes.

Figure 4.—Alternate application of “excited” blood (at b and f) and “quiet” blood (at d), from the same animal, to intestinal muscle initially beating in Ringer’s solution.

The increase of effect with prolongation of the period of excitement is shown in [Fig. 5]. A is the record of contractions after the muscle was surrounded with “quiet” blood serum. B shows the gradual inhibition which occurred when the muscle was surrounded with defibrinated blood taken when the animal had been excited eleven minutes. And C is the record of rapid inhibition after fifteen minutes of excitement. In other instances the effect was manifested merely by a lowering of the tonus of the muscle, and a notable slowing of the beats, without, however, a total abolition of them.

Figure 5.—The effect of prolonging the excitement. A, the record in “quiet” serum; B, in defibrinated blood after eleven minutes of excitement; and C, in serum after fifteen minutes of excitement.

The inference that this inhibition of contraction of the intestinal muscle is due to an increased amount of adrenal secretion in the “excited” blood de la Paz and I justified on several grounds:

(1) The inhibition was produced by “excited” blood from the inferior vena cava anterior to the mouths of the adrenal veins, when blood from the femoral vein, taken at the same time, had no inhibitory influence. Since blood from the femoral vein is typical of the cava blood below the entrance of the kidney veins, the conclusion is warranted that the difference of effect of the two samples of blood is not due to any agent below the kidneys. But that blood from the kidneys does not cause the relaxation is shown in [Fig. 3]. The only other structures which could alter the blood between the two points at which it was taken are the adrenal glands, and the material secreted by them would produce precisely the inhibition of contraction which was in fact produced.

(2) If in ether anesthesia the blood vessels leading to and from the adrenal glands are first carefully tied, and then the glands are removed, excitement four or five hours later, before the weakness that follows the removal has become prominent, does not alter the blood so that the typical inhibition occurs (see [Fig. 6]). Thus, although the animal shows all the characteristic signs of sympathetic stimulation, the blood, in the absence of the adrenals, remains unchanged.

Figure 6.—Failure of the cava blood (added at a) to produce inhibition when excitement has occurred after removal of the adrenal glands. The muscle later proved sensitive to adrenin in blood in the ratio 1:1,000,000.

(3) As already shown, sometimes the effect produced by the “excited” blood was prompt inhibition, sometimes the inhibition followed only after several beats, and sometimes a slowing and shortening of contractions, with a lower tone, were the sole signs of the action of adrenin. All these degrees of relaxation can be duplicated by adding to inactive blood varying amounts of adrenin. [Fig. 7] shows the effects, on a somewhat insensitive muscle preparation, of adding adrenin, 1:1,000,000 (A), 1:2,000,000 (B), and 1:3,000,000 (C), to different samples of blood previously without inhibitory influence. These effects of adrenin and the effects produced by blood taken near the opening of the adrenal veins are strikingly analogous.

Figure 7.—Effect of adding adrenin 1:1,000,000 (A), 1:2,000,000 (B), and 1:3,000,000 (C), to formerly inactive blood. In each case a marks the moment when the quiet blood was removed, and b, the time when the blood with adrenin was added.

(4) Embden and v. Furth[1] have reported that 0.1 gram of suprarenin chloride disappears almost completely in two hours if added to 200 cubic centimeters of defibrinated beef blood, and the mixture constantly aerated at body temperature. “Excited” blood which produces inhibition loses that power on standing in the cold for twenty-four hours, or on being kept warm and agitated with bubbling oxygen. This change is illustrated in [Fig. 8]; the power of the “excited” blood to inhibit the contractions of the intestinal muscle when record A was written was destroyed after three hours of exposure to bubbling oxygen, as shown by record B. The destruction of adrenin and the disappearance of the effect which adrenin would produce are thus closely parallel.

Figure 8.—The effect of bubbling oxygen through active blood. A, relaxation after active blood applied at a; B, failure of relaxation when the same blood, oxygenated three hours, was applied to a fresh strip at b.

All these considerations, taken with the proof that sympathetic impulses increase secretion of the adrenal glands, and taken also with the evidence that, during such emotional excitement as was employed in these experiments, signs of sympathetic discharges appeared throughout the animal from the dilated pupil of the eye to the standing hairs of the tail-tip, led us to the conclusions that the characteristic action of adrenin on intestinal muscle was in fact, in our experiments, due to secretion of the adrenal glands, and that that secretion is increased in great emotion.

The Evidence that Adrenal Secretion is Increased by “Painful” Stimulation

As mentioned in the first chapter, stimulation of sensory fibres in one of the larger nerve trunks is known to result in such nervous discharges along sympathetic paths as to produce marked inhibition of digestive processes. Other manifestations of sympathetic innervations—e. g., contraction of arterioles, dilation of pupils, erection of hairs—are also demonstrable. And since the adrenal glands are stimulated to activity by sympathetic impulses, it was possible that they would be affected as are other structures supplied with sympathetic fibres, and that they would secrete in greater abundance when sensory nerves were irritated.

The testing of this possibility was undertaken by Hoskins and myself in 1911. Since bodily changes from “painful” stimulation can in large degree be produced in an anesthetized animal, without, however, an experience of pain by the animal, it was possible to make the test quite simply. The sensory stimulus was a rapidly interrupted induced current applied to the sciatic nerve. The current was increased in strength as time passed, and thus the intensity of the effect, indicated by continuous dilation of the pupils, was maintained. There was no doubt that such stimulation would have caused very severe pain if the animal had not been anesthetized. Indeed, the stimulus used was probably much stronger than would be necessary to obtain a positive result in the absence of the anesthetic (urethane), which markedly lessens the irritability of visceral nerve fibres.[2] In different instances the stimulation lasted from three to six minutes. Throughout the period there was markedly increased rapidity and depth of breathing.

As [Fig. 9] shows, the normal blood, removed from the vena cava before stimulation, caused no inhibition of the beating segment, whereas that removed afterwards produced a deep relaxation. Hoskins and I showed that the increased respiration which accompanies “painful” stimulation does not augment adrenal activity. We concluded, therefore, that when a sensory trunk is strongly excited the adrenal glands are reflexly stimulated, and that they pour into the blood stream an increased amount of adrenin.

Figure 9.—Intestinal muscle beating in normal vena cava blood, removed at 1 and renewed at 2. At 3 normal blood removed. At 4 contraction inhibited by vena cava blood drawn after sensory stimulation; at 5 removed. At 6 Ringer’s solution substituted.

Confirmation of Our Results by Other Observers

The foregoing experiments and conclusions were reported in 1911. In 1912, Elliott[3] brought confirmatory evidence by use of a method quite different from ours. As previously stated, he studied the effects of experimental procedures on adrenal secretion by a careful comparative quantitative assay of the adrenin content of the glands when one gland was isolated from the central nervous system and the other left connected. He took advantage of the action of morphia and of the substance Β-tetrahydronaphthylamine in evoking in cats all the appearances of great fright. After the animals had thus been “frightened,” he found that the adrenal gland which was still connected with the spinal cord was much depleted of its adrenin content compared with the other, isolated gland. And he observed, further, that animals newly brought to the laboratory, and evidently disturbed by the strangeness of their surroundings, had a considerably smaller amount of adrenin in their glands than other animals grown accustomed to the situation. Elliott also observed that prolonged excitation of a sensory nerve, such as the great sciatic, may cause the adrenin largely to disappear from the gland still connected with the central nervous system and subjected, therefore, to reflex influences.

Our conclusions have also been confirmed more recently (1913) by Hitchings, Sloan and Austin,[4] working in Crile’s laboratory in Cleveland. They used the same method which we had used to obtain blood and to test for adrenin, and found that after great fear and rage had been induced in a cat by the attempt of a muzzled dog to fight it, the adrenin reaction was clearly demonstrable. And just as we had noted that the reaction did not occur if the adrenal glands had been removed, they showed that it did not occur if the nervous connections with the spinal cord were previously severed.

The logic of all these experiments may be briefly summed up. That the adrenal glands are subject to splanchnic influence has been demonstrated anatomically and by the physiological effects of their secretion after artificial stimulation of the splanchnic nerves. Impulses are normally sent along these nerves, in the natural conditions of life, when animals become greatly excited, as in fear and rage and pain. There is every probability, therefore, that these glands are stimulated to extra secretion at such times. Both by an exceedingly delicate biological test (intestinal muscle) and by an examination of the glands themselves, clear evidence has been secured that in pain and deep emotion the glands do, in fact, pour out an excess of adrenin into the circulating blood.

Here, then, is a remarkable group of phenomena—a pair of glands stimulated to activity in times of strong excitement and by such nerve impulses as themselves produce at such times profound changes in the viscera; and a secretion given forth into the blood stream by these glands, which is capable of inducing by itself, or of augmenting, the nervous influences which induce the very changes in the viscera which accompany suffering and the major emotions. What may be the significance of these changes, occurring when conditions of pain and great excitement—experiences common to animals of most diverse types and probably known to their ancestors for ages past—lay hold of the bodily functions and determine the instinctive responses?

Certain remarkable effects of injecting adrenin into the blood have for many years been more or less well recognized. For example, when injected it causes liberation of sugar from the liver into the blood stream. It relaxes the smooth muscle of the bronchioles. Some old experiments indicated that it acts as an antidote for muscular fatigue. It alters the distribution of the blood in the body, driving it from the abdominal viscera into the heart, lungs, central nervous system and limbs. And there was some evidence that it renders more rapid the coagulation of the blood. There may be other activities of adrenin not yet discovered—it may coöperate with the products of other glands of internal secretion. And other glands of internal secretion may be stimulated by sympathetic impulses. But we were not concerned with these possibilities. We wished to know whether the adrenin poured out in pain and emotional excitement produced or helped to produce the same effects that follow the injection of adrenin. Our later researches were concerned with answers to this question.

REFERENCES

[1] Embden and v. Furth: Hofmeister’s Beiträge zur chemischen Physiologie und Pathologie, 1904, iv, p. 423.

[2] Elliott: Journal of Physiology, 1905, xxxii, p. 448.

[3] Elliott: Journal of Physiology, 1912, xliv, p. 409.

[4] Hitchings, Sloan and Austin: Cleveland Medical Journal, 1913, xii, p. 686; see also Crile and Lower: Anoci-association, Philadelphia, 1914, p. 56.

CHAPTER V

THE INCREASE OF BLOOD SUGAR IN PAIN AND GREAT EMOTION

Sugar is the form in which carbohydrate material is transported in organisms; starch is the storage form. In the bodies of animals that have been well fed the liver contains an abundance of glycogen or “animal starch,” which may be called upon in times of need. At such times the glycogen is changed, and set free in the blood as sugar. Ordinarily there is a small percentage of sugar in the blood—from 0.06 to 0.1 per cent. When only this small amount is present the kidneys are capable of preventing its escape in any noteworthy amount. If the percentage rises to the neighborhood of 0.2–0.3 per cent, however, the sugar passes the obstacle set up by the kidneys, and is readily demonstrable in the urine by ordinary tests. The condition of “glycosuria,” therefore, may properly be considered, in certain circumstances, as evidence of increased sugar in the blood. The injection of adrenin can liberate sugar from the liver to such an extent that glycosuria results. Does the adrenal secretion discharged in pain and strong emotional excitement play a rôle in producing glycosuria under such conditions?

In clinical literature scattered suggestions are to be found that conditions giving rise to emotional states may be the occasion also of more or less permanent glycosuria. Great grief and prolonged anxiety during a momentous crisis have been regarded as causes of individual instances of diabetes, and anger or fright has been followed by an increase in the sugar excreted by persons who already have the disease. Kleen[1] cites the instance of a German officer whose diabetes and whose Iron Cross for valor both came from a stressful experience in the Franco-Prussian War. The onset of the disease in a man directly after his wife was discovered in adultery is described by Naunyn;[2] and this author also mentions two cases in his own practice—one started during the bombardment of Strassburg (1870), the other started a few days after a companion had shot himself. In cases of mental disease, also, states of depression have been described accompanied by sugar in the urine. Schultze[3] has reported that in these cases the amount of glycosuria is dependent on the degree of depression, and that the greatest excretion of sugar occurs in the fear-psychoses. Raimann[4] has reported that in both melancholia and mania the assimilation limit of sugar may be lowered. Similar results in the insane have recently been presented by Mita,[5] and by Folin and Denis.[6] The latter investigators found glycosuria in 12 per cent of 192 insane patients, most of whom suffered from depression, apprehension, or excitement. And Arndt[7] has observed glycosuria appearing and disappearing as alcoholic delirium appeared and disappeared in his patients.

Although clinical evidence thus indicates an emotional origin of some cases of diabetes and glycosuria, the intricacies of existence and the complications of disease in human beings throw some doubt on the value of that evidence. Both Naunyn[8] and Hirschfeld, although mentioning instances of diabetes apparently due to an emotional experience, urge a skeptical attitude toward such statements. It is desirable, therefore, that the question of an emotional glycosuria be tested under simpler and more controllable conditions. “Emotional glycosuria” in experimental animals has indeed been referred to by Waterman and Smit[9] and more recently by Henderson and Underhill.[10] Both these references, however, are based on the work of Böhm and Hoffmann,[11] reported in 1878.

Glycosuria From Pain

Böhm and Hoffmann found that cats, when bound to an operating board, a tube inserted into the trachea (without anesthesia), and in some instances a catheter inserted into the urethra through an opening above the pubis, had in about half an hour an abundance of sugar in the urine. In three determinations sugar in the blood proved slightly above “normal” so long as sugar was appearing in the urine, but returned to “normal” as the glycosuria disappeared. Since they were able to produce the phenomenon by simply binding animals to the holder, they called it “Fesselungsdiabetes.”

As possible causes of this glycosuria in bound animals, they considered opening the trachea, cooling, and pain. The first two they readily eliminated, and still they found sugar excreted. Pain they could not obviate, and since, without binding the animals, they caused glycosuria by merely stimulating the sciatic nerves, they concluded that painful confinement was itself a sufficient cause. Other factors, however, such as cooling and circulatory disturbances, probably coöperated with pain, they believed, to produce the result. Their observations on cats have been proved true also of rabbits;[12] and recently it has been shown that an operation involving some pain increases blood sugar in dogs.[13] Temporary glycosuria has likewise been noted in association with intense pain in human beings.

Inasmuch as Böhm and Hoffmann did not mention the emotional element in discussing their results, and inasmuch as they admitted that they could not obviate from their experimental procedure pain, which they themselves proved was effective in causing glycosuria, designating what they called “Fesselungsdiabetes” as “emotional glycosuria” is not justified.

Emotional Glycosuria

The discovery that during strong emotion adrenal secretion is increased, and the fact that injection of adrenin gives rise to glycosuria, suggested that glycosuria might be called forth by emotional excitement, and then that even without the painful element of Böhm and Hoffmann’s experiments, sugar might be found in the urine. The testing of this possibility was undertaken by A. T. Shohl, W. S. Wright and myself in 1911.

Our first procedure was a repetition of Böhm and Hoffmann’s experiments, freed from the factor of pain. The animals (cats) were bound to a comfortable holder, which left the head unfastened. This holder I had used hundreds of times in X-ray studies of digestion, with many different animals, without causing any signs of even so much as uneasiness. Just as in observations on the movements of the alimentary canal, however, so here, the animals reacted differently to the experience of being confined. Young males usually became quite frantic, and with eyes wide, pupils dilated, pulse accelerated, hairs of the tail more or less erect, they struggled, snarling and growling, to free themselves. Females, on the contrary, especially if elderly, were as a rule much more calm, and resignedly accepted the novel situation.

According to differences in reaction the animals were left in the holder for periods varying in length from thirty minutes to five hours. In order to insure prompt urination, considerable quantities of water were given by stomach tube at the beginning of the experiment and in some cases again later. Arrangements were made for draining the urine promptly, when the animal was on the holder or when afterwards in a metal metabolism cage, into a glass receiver containing a few drops of chloroform to prevent fermentation. The diet in all cases consisted of customary raw meat and milk. In every instance the urine was proved free from sugar before the animal was excited.

In our series of observations twelve cats were used, and in every one a well-marked glycosuria was developed. The shortest periods of confinement to the holder which were effective were thirty and forty minutes; the longest we employed, five hours. The average time required to bring about a glycosuria was less than an hour and a half; the average in seven of the twelve cases was less than forty minutes. In all cases no sugar was found in the urine passed on the day after the excitement.

The promptness with which the glycosuria developed was directly related to the emotional state of the animal. Sugar was found early in animals which early showed signs of being frightened or in a rage, and much later in animals which took the experience more calmly.

As cooling may result in increased sugar in the blood, and consequent glycosuria, the rectal temperature was observed from time to time, and it was found to vary so slightly that in these experiments it was a wholly negligible factor. In one cat the rectal temperature fell to 36° C. while the animal was bound and placed in a cold room (about 2° C.) for fifty minutes, but no sugar appeared in the urine.

Further evidence that the appearance of sugar in the urine may arise purely from emotional excitement was obtained from three cats which gave negative results when bound in the holder for varying periods up to four hours. It was noteworthy that these animals remained calm and passive in their confinement. When, however, they were placed, separately, in a small wire cage, and were barked at by an energetic little dog, that jumped at them and made signs of attack, the cats became much excited, they showed their teeth, humped their backs, and growled defiance. This sham fight was permitted to continue for a half hour in each of the three cases. In each case the animal, which after four hours of bondage had exhibited no glycosuria, now had sugar in the urine. Pain, cooling, and bondage were not factors in these experiments. The animal was either frightened or enraged by the barking dog, and that excitement was attended by glycosuria.

The sugar excreted in the twenty-four hours which included the period of excitement was determined by the Bertrand method.[14] It ranged from 0.024 gram to 1.93 grams, or from 0.008 gram to 0.62 gram per kilo body weight, for the twenty-four hours’ quantity.

The presence of sugar in the urine may be used as an indication of increased sugar in the blood, for unless injury has been done to the cells of the kidneys, they do not permit sugar to escape until the percentage in the blood has risen to a considerable degree. Thus, though testing the urine reveals the instances of a high content of blood sugar, it does not show the fine variations that appear when the blood itself is examined. Recently Scott[15] has concluded a thorough investigation of the variations of blood sugar in cats, and has found that merely incidental conditions, producing even mild excitement, as indicated by crying or otherwise, result in a noticeable rise in the amount. Indeed, so sensitive is the sugar-liberating mechanism that all the early determinations of the “normal” content of sugar in blood which has been drawn from an artery or vein in the absence of anesthesia, are of very doubtful value. Certainly when care is taken to obtain blood suddenly from a tranquil animal, the percentage (0.069, Scott; 0.088, Pavy) is much less than when the blood is drawn without anesthesia (0.15, Böhm and Hoffmann), or after light narcosis (0.282, Rona and Takahashi[16]).

Our observations on cats have since been found valid for rabbits. Rolly and Oppermann, Jacobsen, and Hirsch and Reinbach[17] have recently recorded that the mere handling of a rabbit preparatory to operating on it will increase the percentage of blood sugar (in some cases from 0.10 to 0.23 and 0.27 per cent). Dogs are said to be much less likely to be disturbed by the nature of their surroundings than are rabbits and cats. Nevertheless, pain and excitement are such fundamental experiences in animals that without much doubt the same mechanism is operative in all when these experiences occur. Probably, just as the digestion of dogs is disturbed by strong emotion, the blood sugar likewise is increased, for sympathetic impulses occasion both changes.[*] Gib has given an account of a bitch that became much agitated when shut up, and after such enforced seclusion, but never otherwise, she excreted small quantities of sugar in the urine.[18]

[*] Since the foregoing sentences were written Hirsch and Reinbach have reported (Zeitschrift für physiologische Chemie, 1914, xci, p. 292) a “psychic hyperglycemia” in dogs, that resulted from fastening the animals to a table. The blood sugar rose in one instance from 0.11 to 0.14 per cent, and in another from 0.09 to 0.16 per cent.

The results noted in these lower animals have been confirmed in human beings. One of my former students, W. G. Smillie, found that four of nine medical students, all normally without sugar in their urine, had glycosuria after a hard examination, and only one of the nine had glycosuria after an easier examination. The tests, which were positive with Fehling’s solution, Nylander’s reagent, and also with phenyl-hydrazine, were made on the first urine passed after the examination. Furthermore, C. H. Fiske and I examined the urine of twenty-five members of the Harvard University football squad immediately after the final and most exciting contest of the season of 1913, and found sugar in twelve cases. Five of these positive cases were among substitutes not called upon to enter the game. The only excited spectator of the Harvard victory whose urine was examined also had a marked glycosuria, which on the following day had disappeared.

Other tests made on students before and after important scholastic examinations have been published by Folin, Denis and Smillie.[19] Of thirty-four second-year medical students tested, one had sugar before the examination as well as afterwards. Of the remaining thirty-three, six, or 18 per cent, had small but unmistakable traces of sugar in the urine passed directly following the ordeal. A similar study was made on second-year students at a women’s college. Of thirty-six students who had no sugar in the urine on the day before, six, or 17 per cent, eliminated sugar with the urine passed immediately after the examination.

From the foregoing results it is reasonable to conclude that just as in the cat, dog, and rabbit, so also in man, emotional excitement produces temporary increase of blood sugar.

The Rôle of the Adrenal Glands in Emotional Glycosuria

Since artificial stimulation of the splanchnic nerves produces glycosuria,[20] and since major emotions, such as rage and fright, are attended by nervous discharges along splanchnic pathways, glycosuria as an accompaniment of emotional excitement would naturally be expected to occur. To what extent the adrenal glands which, as already mentioned, are stimulated to increased secretion by excitement, might play a part in this process, has been in dispute. Removal of these glands or cutting of the nerve fibres supplying them, according to some observers,[21] prevents glycosuria after puncture of the fourth ventricle of the brain (the “sugar puncture,” which typically induces glycosuria) and also after stimulation of the splanchnics.[22] On the other hand, Wertheimer and Battez[23] have stated that removal of the glands does not abolish the effects of sugar puncture in the cat. It was questionable, therefore, whether removal of the adrenal glands would affect emotional glycosuria.

Evidence on this point I secured with Shohl and Wright in observations on three animals in which the adrenals were removed aseptically under ether. The animals selected had all become quickly excited on being bound to the holder, and had manifested glycosuria after about an hour of confinement. In the operation, to avoid discharge of adrenin by handling, the adrenal veins were first tied, and then the glands freed from their attachments and removed as quickly and with as little manipulation as possible. In one cat the entire operation was finished in twenty minutes. In two of the cats a small catheter was introduced into the urethra through an incision, so that the bladder could be emptied at any time.

In all three cases urine that was free from sugar was obtained soon after the operation. Although the animals deprived of their adrenals manifested a general lessening of muscular tone, they still displayed much of their former rage or excitement when bound. Indeed, one was more excited after removal of the adrenals than before. That the animals might not be excessively cooled they were kept warm with coverings or an electric heating pad. Although they were now bound for periods from two to three times as long as the periods required formerly to cause glycosuria, no trace of sugar was found in the urine in any instance. The evidence thus secured tends, therefore, to support the view that the adrenal glands perform an important contributory rôle in the glycosuria resulting from splanchnic stimulation.

Possibly the emotional element is in part accountable for the glycosuria observed after painful stimulation, but conditions causing pain alone will reasonably explain it. As we have already seen, strong stimulation of sensory fibres causes the discharge of impulses along the splanchnic nerves, and incidentally calls forth an increased secretion of the adrenal glands. In glycosuria resulting from painful stimulation, as well as in emotional glycosuria, the adrenal glands may be essential factors.

Later the evidence will be given that sugar is the optimum source of muscular energy. In passing, we may note that the liberation of sugar at a time when great muscular exertion is likely to be demanded of the organism may be interpreted as a highly interesting instance of biological adaptation.

REFERENCES

[1] Kleen: On Diabetes Mellitus and Glycosuria, Philadelphia, 1900, pp. 22, 37–39.

[2] Naunyn: Der Diabetes Mellitus, Vienna, 1898, p. 72.

[3] Schultze: Verhandlungen der Gesellschaft deutscher Naturforscher und Aerzte, Cologne, 1908, ii, p. 358.

[4] Zeitschrift für Heilkunde, 1902, xxiii, Abtheilung iii, pp. 14, 19.

[5] Mita: Monatshefte für Psychiatrie und Neurologie, 1912, xxxii, p. 159.

[6] Folin, Denis and Smillie: Journal of Biological Chemistry, 1914, xvii, p. 519.

[7] Arndt: Zeitschrift für Nervenheilkunde, 1897, x, p. 436.

[8] Naunyn: Loc. cit., p. 73; Hirschfeld: Die Zuckerkrankheit, Leipzig, 1902, p. 45.

[9] Waterman and Smit: Archiv für die gesammte Physiologie, 1908, cxxiv, p. 205.

[10] Henderson and Underhill: American Journal of Physiology, 1911, xxviii, p. 276.

[11] Böhm and Hoffmann: Archiv für experimentelle Pathologie und Pharmakologie, 1878, viii, p. 295.

[12] Eckhard: Zeitschrift für Biologie, 1903, xliv, p. 408.

[13] Loewy and Rosenberg: Biochemische Zeitschrift, 1913, lvi, p. 114.

[14] See Abderhalden: Handbuch der biochemischen Arbeitsmethoden, Berlin, 1910, ii, p. 181.

[15] Scott: American Journal of Physiology, 1914, xxxiv, p. 283.

[16] Cited by Scott: Loc. cit., p. 296.

[17] Rolly and Oppermann: Biochemische Zeitschrift, 1913, xlix, p. 201. Jacobsen: Ibid., 1913, li, p. 449. Hirsch and Reinbach: Zeitschrift für physiologische Chemie, 1913, lxxxvii, p. 122.

[18] Cited by Kleen: Loc. cit., p. 37.

[19] Folin, Denis and Smillie: Loc. cit., p. 520.

[20] See Macleod: American Journal of Physiology, 1907, xix, p. 405, also for other references to literature.

[21] See Meyer: Comptes rendus de la Société de Biologie, 1906, lviii, p. 1123; Nishi: Archiv für experimentelle Pathologie und Pharmakologie, 1909, lxi, p. 416.

[22] Gautrelet and Thomas: Comptes rendus de la Société de Biologie, 1909, lxvii, p. 233; and Macleod: Proceedings of the Society for Experimental Biology and Medicine, 1911, viii, p. 110 (true for left adrenal and left splanchnic).

[23] Wertheimer and Battez: Archives Internationales de Physiologie, 1910, ix, p. 392.

CHAPTER VI

IMPROVED CONTRACTION OF FATIGUED MUSCLE AFTER SPLANCHNIC STIMULATION OF THE ADRENAL GLAND

In the older literature on the adrenal glands the deleterious effect of their absence, or the beneficial effect of injected extracts, on the contraction of skeletal muscle was not infrequently noted. As evidence accumulated, however, tending to prove an important relation between the extract of the adrenal medulla (adrenin) and the sympathetic nervous system, the relations with the efficiency of skeletal muscle began to receive less consideration.

The muscular weakness of persons suffering from diseased adrenals (Addison’s disease) was well recognized before experimental work on the glands was begun. Experiments on rabbits were reported in 1892 by Albanese,[1] who showed that muscles which were stimulated after removal of the glands were much more exhausted than when stimulated the same length of time in the same animal before the removal. Similarly Boinet[2] reported, in 1895, that rats recently deprived of their adrenals were much more quickly exhausted in a revolving cage than were normal animals.

More direct evidence of the favorable influence of adrenal extract on skeletal muscle was brought forward by Oliver and Schäfer.[3] After injecting the extract subcutaneously into a frog they found that the excised gastrocnemius muscle registered a curve of contraction about 33 per cent higher and about 66 per cent longer than the corresponding muscle not exposed to the action of the extract. Similar prolongation of the muscle curve was observed after injecting the extract intravenously into a dog. A beneficial effect of adrenal extract on fatigued muscle, even when applied to the solution in which the isolated muscle was contracting, was claimed by Dessy and Grandis,[4] who studied the phenomenon in a salamander.[*] Further evidence leading to the same conclusion was offered in a discriminating paper by Panella.[5] He found that in cold-blooded animals the active principle of the adrenal medulla notably reënforced skeletal muscle, prolonging its ability to do work, and improving its contraction when fatigued. In warm-blooded animals the same effects were observed, but only after certain experimental procedures, such as anesthesia and section of the bulb, had changed them to a condition resembling the cold-blooded.

[*] These earlier investigations, in which an extract of the entire gland was used, made no distinction between the action of the medulla and that of the cortex. It may be that the weakness following removal or disease of the adrenals is due to absence of the cortex (see Hoskins and Wheelon: American Journal of Physiology, 1914, xxxiv, p. 184). Such a possible effect, however, should not be confused with the demonstrable influence of injected adrenin (derived from the adrenal medulla alone) and the similar effects from adrenal secretion caused by splanchnic stimulation.

The foregoing evidence indicates that removal of the adrenals has a debilitating effect on muscular power, and that injection of extracts of the glands has an invigorating effect. It seemed possible, therefore, that increased secretion of the adrenal glands, whether from direct stimulation of the splanchnic nerves or as a reflex result of pain or the major emotions, might act as a dynamogenic factor in the performance of muscular work. With this possibility in mind L. B. Nice and I[6] first concerned ourselves in a research which we conducted in 1912.

The general plan of the investigation consisted primarily in observing the effect of stimulating the splanchnic nerves, isolated from the spinal cord, on the contraction of a muscle whose nerve, also isolated from the spinal cord, was rhythmically and uniformly excited with break induction shocks. When a muscle is thus stimulated it at first responds by strong contractions, but as time passes the contractions become weaker, the degree of shortening of the muscle becomes less, and in this state of lessened efficiency it may continue for a long period to do work. The tired muscle which is showing continuously and evenly its inability to respond as it did at first, is said to have reached the “fatigue level.” This level serves as an excellent basis for testing influences that may have a beneficial effect on muscular performance, for the benefit is at once manifested in greater contraction.

In the experimental arrangement which we used, only a connection through the circulating blood existed between the splanchnic region and the muscle—all nervous relations were severed. Any change in muscular ability, therefore, occurring when the splanchnic nerve is stimulated, must be due to an alteration in the quantity or quality of the blood supplied to the laboring muscle.

Cats were used for most experiments, but results obtained with cats were confirmed on rabbits and dogs. To produce anesthesia in the cats and rabbits, and at the same time to avoid the fluctuating effects of ether, urethane (2 grams per kilo body weight) was given by a stomach tube. The animals were fastened back downward, over an electric warming pad, to an animal holder. Care was taken to maintain the body temperature at its normal level throughout each experiment.

The Nerve-muscle Preparation

The muscle selected to be fatigued was usually the extensor of the right hind foot (the tibialis anticus), though at times the common extensor muscle of the digits of the same foot was employed. The anterior tibial nerve which supplies these muscles was bared for about two centimeters, severed toward the body, and set in shielded electrodes, around which the skin was fastened by spring clips. Thus the nerve could be protected, kept moist, and stimulated without stimulation of neighboring structures. By a small slit in the skin the tendon of the muscle was uncovered, and after a strong thread was tied tightly about it, it was separated from its insertion. A nerve-muscle preparation was thereby made which was still connected with its proper blood supply. The preparation was fixed firmly to the animal holder by thongs looped around the hock and the foot, i. e., on either side of the slit through which the tendon emerged.

The thread tied to the tendon was passed over a pulley and down to a pivoted steel bar which bore a writing point. Both the pulley and this steel writing lever were supported in a rigid tripod. In the earliest experiments the contracting muscle was made to lift weights (125 to 175 grams); in all the later observations, however, the muscle pulled against a spring attached below the steel bar. The tension of the spring as the muscle began to lift the lever away from the support was, in most of the experiments, 110 grams, with an increase of 10 grams as the writing point was raised 4.5 millimeters. The magnification of the lever was 3.8.

The stimuli delivered to the anterior tibial nerve were, in most experiments, single break shocks of a value barely maximal when applied to the fresh preparation. The rate of stimulation varied between 60 and 300 per minute, but was uniform in any single observation. A rate which was found generally serviceable was 180 per minute.

Since the anterior tibial nerve contains fibres affecting blood vessels, as well as fibres causing contraction of skeletal muscle, the possibility had to be considered that stimuli applied to it might disturb the blood supply of the region. Constriction of the blood vessels would be likely to produce the most serious disturbance, by lessening the blood flow to the muscle. The observations of Bowditch and Warren,[7] that vasodilator rather than vasoconstrictor effects are produced by single induction shocks repeated at intervals of not more than five per second, reassured us as to the danger of diminishing the blood supply, for the rate of stimulation in our experiments never exceeded five per second and was usually two or three. Furthermore, in using these different rates we have never noted any result which could reasonably be attributed to a diminished circulation.

The Splanchnic Preparation

The splanchnic nerves were stimulated in various ways. At first only the left splanchnics in the abdomen were prepared. The nerves, separated from the spinal cord, were placed upon shielded electrodes. The form of electrodes which was found most satisfactory was that illustrated in [Fig. 10]. The instrument was made of a round rod of hard wood, bevelled to a point at one end, and grooved on the two sides. Into the grooves were pressed insulated wires ending in platinum hooks, which projected beyond the bevelled surface. Around the rod was placed an insulating rubber tube which was cut out so as to leave the hooks uncovered when the tube was slipped downward.

Figure 10.—The shielded electrodes used in stimulating the splanchnic nerves. For description see text.

In applying the electrodes the left splanchnic nerves were first freed from their surroundings and tightly ligatured as close as possible to their origin. By means of strong compression the conductivity of the nerves was destroyed central to the ligature. The electrodes were now fixed in place by thrusting the sharp end of the wooden rod into the muscles of the back. This was so done as to bring the platinum hooks a few millimeters above the nerves. With a small seeker the nerves were next gently lifted over the hooks, and then the rubber tube was slipped downward until it came in contact with the body wall. Absorbent cotton was packed about the lower end of the electrodes, to take up any fluid that might appear; and finally the belly wall was closed with spring clips. The rubber tube served to keep the platinum hooks from contact with the muscles of the back and the movable viscera, while still permitting access to the nerves which were to be stimulated. This stimulating apparatus could be quickly applied, and, once in place, needed no further attention. In some of the experiments both splanchnic nerves were stimulated in the thorax. The rubber-covered electrode proved quite as serviceable there as in the abdomen.

The current delivered to the splanchnic nerves was a rapidly interrupted induced current of such strength that no effects of spreading were noticeable. That splanchnic stimulation causes secretion of the adrenal glands has been proved in many different ways which have already been described (see [p. 41]).

The Effects of Splanchnic Stimulation on the Contraction of Fatigued Muscle

When skeletal muscle is repeatedly stimulated by a long series of rapidly recurring electric shocks, its strong contractions gradually grow weaker until a fairly constant condition is reached. The record then has an even top—the muscle has reached the “fatigue level.” The effect of splanchnic stimulation was tried when the muscle had been fatigued to this stage. The effect which was often obtained by stimulating the left splanchnic nerves is shown in [Fig. 11]. In this instance the muscle while relaxed supported no weight, and while contracting lifted a weight of 125 grams. The rate of stimulation was 80 per minute.

Figure 11.—Upper record, contraction of the tibialis anticus, 80 times a minute, lifting a weight of 125 grams. Lower record, stimulation of the left splanchnic nerves, two minutes. Time, half minutes.

The muscle record shows a brief initial rise from the fatigue level, followed by a drop, and that in turn by another, prolonged rise. The maximum height of the record is 13.5 millimeters, an increase of 6 millimeters over the height recorded before splanchnic stimulation. Thus the muscle was performing for a short period 80 per cent more work than before splanchnic stimulation, and for a considerably longer period exhibited an intermediate betterment of its efficiency.

The First Rise in the Muscle Record

The brief first elevation in the muscle record when registered simultaneously with arterial blood pressure is observed to occur at the same time with the sharp initial rise in the blood-pressure curve (see [Fig. 12]). The first sharp rise in blood pressure is due to contraction of the vessels in the area of distribution of the splanchnic nerves, for it does not appear if the alimentary canal is removed, or if the celiac axis and the superior and inferior mesenteric arteries are ligated. The betterment of the muscular contraction is probably due directly to the better blood supply resulting from the increased pressure, for if the adrenal veins are clipped and the splanchnic nerves are stimulated, the blood pressure rises as before and at the same time there may be registered a higher contraction of the muscle.

Figure 12.—Top record, arterial blood pressure with membrane manometer. Middle record, contractions of tibialis anticus loaded with 125 grams and stimulated 80 times a minute. Bottom record, splanchnic stimulation (two minutes). Time, half minutes.

The Prolonged Rise in the Muscle Record

As [Fig. 12] shows, the initial quick uplift in the blood-pressure record is quickly checked by a drop. This rapid drop does not appear when the adrenal veins are obstructed. A similar difference in blood-pressure records has been noted before and after excision of the adrenal glands. As Elliott,[8] and as Lyman and I[9] have shown, this sharp drop after the first rise, and also the subsequent elevation of blood pressure, are the consequences of liberation of adrenal secretion into the circulation. [Fig. 12] demonstrates that the prolonged rise of the muscle record begins soon after this characteristic drop in blood pressure.

If after clips have been placed on the adrenal veins so that no blood passes from them, the splanchnic nerves are stimulated, and later the clips are removed, a slight but distinct improvement in the muscular contraction occurs. As in the experiments of Young and Lehmann,[10] in which the adrenal veins were tied for a time and then released, the release of the blood which had been pent in these veins was quickly followed by a rise of blood pressure. The volume of blood thus restored to circulation was too slight to account for the rise of pressure. In conjunction with the evidence that splanchnic stimulation calls forth adrenal secretion, the rise may reasonably be attributed to that secretion. The fact should be noted, however, that in this instance the prolonged improvement in muscular contraction did not appear until the adrenal secretion had been admitted to the general circulation.

Many variations in the improvement of activity in fatigued muscle after splanchnic stimulation were noted in the course of our investigation. The improvement varied in degree, as indicated by increased height of the record. In some instances the height of contraction was doubled—a betterment by 100 per cent; in other instances the contraction after splanchnic stimulation was only a small fraction higher than that preceding the stimulation; and in still other instances there was no betterment whatever. Never, in our experience, were the augmented contractions equal to the original strong contractions of the fresh muscle.

The improvement also varied in degree as indicated by persistence of effect. In some instances the muscle returned to its former working level within four or five minutes after splanchnic stimulation ceased (see [Fig. 11]); and in other cases the muscle continued working with greater efficiency for fifteen or twenty minutes after the stimulation.

The Two Factors: Arterial Pressure and Adrenal Secretion

The evidence just presented has shown that splanchnic stimulation improves the contraction of fatigued muscle. Splanchnic stimulation, however, has two effects—it increases general arterial pressure and it also causes a discharge of adrenin from the adrenal glands. The questions now arise—Does splanchnic stimulation produce the improvement in muscular contraction by increasing the arterial blood pressure and thereby flushing the laboring muscles with fresh blood? Or does the adrenin liberated by splanchnic stimulation act itself, specifically, to improve the muscular contraction? Or may the two factors coöperate? These questions will be dealt with in the next two chapters.

REFERENCES

[1] Albanese: Archives Italiennes de Biologie, 1892, xvii, p. 243.

[2] Boinet: Comptes rendus, Société de Biologie, 1895, xlvii, pp. 273, 498.

[3] Oliver and Schäfer: Journal of Physiology, 1895, xviii, p. 263. See also Radwánska, Anzeiger der Akademie, Krakau, 1910, pp. 728–736. Reviewed in Zentralblatt für Biochemie und Biophysik, 1911, xi, p. 467.