Bodily Changes in Pain, Hunger, Fear and Rage

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 respira- tion 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 in- creased amount of adrenin.

The foregoing experiments and conclusions were reported in 1911. In 1912, Elliott * brought con- firmatory evidence by use of a method quite differ- ent 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 B-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 pro- longed 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,* working in Crile's laboratory in Cleveland. They used the same method which we had used to ob- tain 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 connec- tions 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 probabil- ity, therefore, that these glands are stimulated to extra secretion at such times. Both by an ex- ceedingly delicate biological test (intestinal mus- cle) and by an examination of the glands them- selves, 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 sig- nificance of these changes, occurring when condi- tions 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 indi- cated 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 ren- ders more rapid the coagulation of the blood. There may be other activities of adrenin not yet discovered — it may co-operate 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 emo- tional excitement produced or helped to produce

nin. Our later researches were concerned with an- swers to this question. ' Embden and v. Eurtli : Hofmeister's Beitrage zur chemischen Physiologie und Pathologie, 1904, iv, p. 423. Sugar is the form in which carbohydrate mate- rial is transported in organisms ; starch is the stor- age 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 neighbor- hood 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 prop- erly be considered, in certain circumstances, as evidence of increased sugar in the blood. The in- jection of adrenin can liberate sugar from the

liver to sucli an extent that glycosuria results. Does the adrenal secretion discharged in pain and strong emotional excitement play a role in pro- ducing glycosuria under such conditions? In clinical literature scattered suggestions are to be found that conditions giving rise to emo- tional states may be the occasion also of more or less permanent glycosuria. Great grief and pro- longed 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 ^ 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;^ 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^ has reported that in these cases the amount of glycosuria is de- pendent on the degree of depression, and that the greatest excretion of sugar occurs in the fear- psychoses. Eaimann * 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,^ and by Folin and Denis.« The latter investiga- tors found glycosuria in 12 per cent of 192 insane patients, most of whom suffered from depression, apprehension, or excitement. And Arndt '' 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 * and Hirschfeld, although mentioning instances of diabetes apparently due to an emo- tional experience, urge a skeptical attitude to- ward such statements. It is desirable, therefore, that the question of an emotional glycosuria be tested under simpler and more controllable con- ditions. "Emotional glycosuria" in experimental animals has indeed been referred to by Water- man and Smit * and more recently by Hender- son and Underhill.i" Both these references, how- ever, are based on the work of Bohm and Hoff- mann,^^ reported in 1878.

Bohm 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 ap- pearing in the urine, but returned to "normal" as the glycosuria disappeared. Since they were able to produce the phenomenon by simply bind- ing animals to the holder, they called it "Fes- selungsdiabetes."

As possible causes af 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 con- cluded that painful confinement was itself a suffi- cient cause. Other factors, however, such as cool- ing and circulatory disturbances, probably co- operated with pain, they believed, to produce the result. Their observations on cats have been proved true also of rabbits ;i2 and recently it has been shown that an operation involving some pain increases blood sugar in dogs.^^ Temporary gly-

cosuria has likewise been noted in association with intense pain in human beings. Inasmuch as Bohm and Hoffmann did not men- tion the emotional element in discussing their re- sults, and inasmuch as they admitted that they could not obviate from their experimental pro- cedure pain, which they themselves proved was effective in causing glycosuria, desig-nating what they called "Fesselungsdiabetes" as "emotional glycosuria" is not justified. The discovery that during strong emotion adre- nal secretion is increased, and the fact that injec- tion 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 Bohm 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 Bohm 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 obser- vations on the movements of ttie 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 beginniag 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 metab- olism 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 confine- ment 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 eases no sugar was found in the urine passed on the day after the excitement.

The promptness with which the glycosuria de- veloped 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 tem- perature was observed from time to time, and it was found to vary so slightly that in these experi- ments 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 ex- citement was obtained from three cats which gave negative results when bound in the holder for varying periods up to four hours. It was note- worthy 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 ex- hibited no glycosuria, now had sugar in the urine. Pain, cooling, and bondage were not factors in these experiments. The animal was either fright- ened or enraged by the barking dog, and that ex- citement was attended by glycosuria.

The sugar excreted in the twenty-four hours which included the period of excitement was de- termined by the Bertrand method.^* 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 imtil 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 ^^ has concluded a thorough in-

vestigation 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-lib- erating mechanism that all the early determina- tions 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 per- centage (0.069, Scott; 0.088, Pavy) is much less than when the blood is drawn without anesthesia (0.15, Bohm and Hoffmann), or after light nar- cosis (0.282, Bona and Takahashi").

Our observations on eats have since been found valid for rabbits. EoUy and Oppermann, Jacob- sen, and Hirseh and Eeinbach ^'^ have recently recorded that the mere handling of a rabbit pre- paratory to operating on it will increase the per- centage 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 funda- mental 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 sym- pathetic 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.^^ The results noted in these lower animals have been confirmed in human beings. One of my for- mer students, W. G. Smillie, found that four of nine medical students, all normally without sugar in their urine, had glycosuria after a hard exami- nation, 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 exam- ination. Furthermore, 0. H. Fiske and I ex- amined the urine of twenty-five members of the Harvard University football squad immedi- ately 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 Har-

* Since the foregoing sentences were written Hirsch and Eeinbach have reported (Zeitschrift fiir 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. vard 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 pub- lished by Folin, Denis and Smillie.i" Qf thirty- four second-year medical students tested, one had sugar before the examination as well as after- wards. 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 stu- dents 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 examina- tion.

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 tem- porary increase of blood sugar. Since artificial stimulation of the splanchnic nerves produces glycosuria,^** and since major emotions, such as rage and fright, are attended by nervous discharges along splanchnic pathways, glycosuria as an accompaniment of emotional ex- citement 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,^^ 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, Wert- heimer and Battez ^* have stated that removal of the glands does not abolish the effects of sugar puncture in the cat. It was questionable, there- fore, 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 ex- ' cited on being bound to the holder, and had mani- fested glycosuria after about an hour of confine- ment. In the operation, to avoid' discharge of adrenin by handling, the adrenal veins were first tied, and then the glands freed from their attach- ments 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 througli 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. Al- though 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 ex- cited after removal of the adrenals than before. That the animals might not be excessively cooled they were kept warm with coverings or an elec- tric 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, there- fore, to support the view that the adrenal glands perform an important contributory role in the glycosuria resulting from splanchnic stimula- tion.

Possibly the emotional element is in part ac- countable for the glycosuria observed after pain- ful 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 re- - suiting from painful stimulation, as well as in emo- tional glycosuria, the adrenal glands may be es- sential factors.

Later the evidence will be given that sugar is the optimum source of muscular energy. In pass- ing, 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. ^ Schultze : Verhandlungen der Gesellschaft deutscher Naturforscher und Aerzte, Cologne, 1908, ii, p. 358. 11 Bohm and Hoffmann : Archiv fiir experimentelle Pa- thologie und Pharmakologie, 1878, viii, p. 295.

-" See Macleod : American Journal of Physiology, 1907, xix, p. 405, also for other references to literature. ^^ Gautrelet and Thomas : Comptes rendus de la So- ciete de Biologie, 1909, Ixvii, p. 233 ; and Macleod : Pro- ceedings of the Society for Experimental Biology and Medi- cine, 1911, viii, p. 110 (true for left adrenal and left splanch- nic). ^^ Wertheimer and Battez : Archives Internationales de Physiologic, 1910, ix, p. 392. 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,^ 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 Boi- net 2 reported, in 1895, that rats recently deprived of their adrenals were much, more quickly ex- hausted in a revolving cage than were normal animals.