Bodily Changes in Pain, Hunger, Fear and Rage

In order that these reactions may be iiseful they must be prompt. Such is the case. Some observations made by one of my students, Mr. H. Osgood, show that the latent period of adrenal secretion, when the splanchnic nerve is stimulated below the diaphragm, is not longer than 16 sec- onds ; and Macleod ^ states that within a few min- utes after splanchnic stimulation the sugar in the blood rises between 10 and 30 per cent. The two secretions are, therefore, almost instantly ready for service.

Conceivably the two secretions might act in con- junction, or each might have its own function alone. Thus adrenin might serve in cooperation with nervous excitement to produce increase of blood sugar, or it might have that function and other functions quite apart from that. Before these possibilities are considered, however, the value of the increased blood sugar itself will be discussed. The Utility of the Increased Blood Sugar as a Source of Muscular Energy

When we were working on emotional glycosuria a clue to the significance of the increase of sugar in the blood was found in McDougall's suggestion of a relation between "flight instinct" and "fear emotion," and "pugnacity instinct" and "anger emotion." And the point was made that, since the fear emotion and the anger emotion are, in wild life, likely to be followed by activities (run- ning or fighting) which require contraction of great muscular masses in supreme and prolonged strug- gle, a mobilization of sugar in the blood might be of signal service to the laboring muscles. Pain — and fighting is almost certain to involve pain — would, if possible, call forth even greater muscular effort. "In the agony of pain almost every muscle of the body is brought into strong action," Dar- win ^ wrote, for "great pain urges all animals, and has urged them during endless generations, to make the most violent and diversified efforts to escape from the cause of suffering."*

* It is recognized that both pain and the major emotions may have at times depressive rather than stimulating effects. For example, Martin and Lacey have shown (American Jour- nal of Physiology, 1914, xxxiii, p. 212) that such stimuli as vpould induce pain may cause a fall of blood pressure, and they suggest that the rise of blood pressure commonly report- ed at times of painful experience is due to the psychic dis- turbance that is simultaneously aroused. Conceivably there is a relation between recognizing the possibility of escape (with the psychic consequences of that possibility) and the degree of stimulating effect. Thus pains originating from the interior of the body, or from injuries sure to be made more painful by action, would not likely lead to action. On the other hand, the whip and spur illustrate the well-known excitant effect of painful stimuli.

Similarly in the case of the strong emotions, the effect may be paralyzing until there is a definite deed to perform. Thus terror may be the most depressing of all emotions, but, as Dar- win pointed out (Loc. cit., p. 81), "a man or animal driven through terror to desperation is endowed with wonderful strength, and is notoriously dangerous in the highest degree." That muscular work is performed by energy supplied in carbonaceous material is shown by the great increase of carbon-dioxide output in severe muscular work, which may exceed twenty times the output during rest. Furthermore, the storage of glycogen in muscle, and the disappearance of this glycogen deposit from excised muscle stimu- lated to activity,'^ or its reduction after excessive contractions produced by strychnine,^ and the lessened ability of muscles to work if their glyco- gen store has been reduced,® and the simple chemical relation between sugar and the lactic acid which appears when muscles are repeatedly made to contract, are all indications that carbohydrate (sugar and glycogen) is the elective source of en- ergy for contraction. This conclusion is sup- ported in recent careful studies by Benedict and Cathcart,^" who have shown that a small but distinct increase in the ratio between the carbon- dioxide breathed out and the oxygen breathed in during a given period (the respiratory quotient) occurs during muscular work, and that a decrease in the quotient follows, thus pointing to a larger proportion of carbohydrate burned during mus- cular work than before or after — i. e., a call on the carbohydrate deposits of the body.

Whether circulating sugar can be immediately utilized by active muscles has been a subject of dis- pute. The claim of Chauveau and Kaufmann^^ that a muscle uses about three and a half times as much blood sugar when active as when rest- ing, although supported by Quinquaud/^ and by Morat and Dufourt/^ has been denied by Pavy,i* who failed to find any difference be- tween the sugar content of arterial and venous blood when the muscle was contracting ; and also by Magnus-Levy/® who has estimated that the amount of change ia sugar content of the blood passing through a muscle must be so slight as to be within the limits of the error of analysis. On the other hand, when blood or Ringer's solution is repeatedly perfused through contracting heart muscle, the evidence is clear that the contained sugar may more or less completely disappear. Thus Locke and Eosenheim ^^ found that from 5 to 10 centigrams of dextrose disappeared from Ringer's solution repeatedly circulated through the rabbit heart for eight or nine hours. And recently Patterson and Starling ^'' have shown that if blood is perfused repeatedly through a heart-lung preparation for three or four hours, and the heart is continually stimulated by adrenin added to the blood, the sugar in the blood wholly vanishes ; or if the supply of sugar is maintauied, the consumption may rise as high as 8 milligrams per gram of heart muscle per hour — about four times the usual consumption. "When an animal is eviscerated it may be regarded as a preparation

in whicli the muscles are perfused with their proper blood, pumped by the heart and oxygenated by the lungs. Under these circumstances, the per- centage of sugar in the blood steadily falls,^* because the utilization by the tissues is not com- pensated for by further supply from the liver. Thus, although there may be doubt that analyses of sugar in the blood flowing into and out from an active muscle during a brief period can be accu- rate enough to prove a clear difference, the evi- dence from the experiments above cited shows that when the supply of sugar is limited it disappears to a greater or less degree when passed repeatedly through muscular organs.

The argument may be advanced, of course, that the sugar which thus disappears is not directly utilized, but must first be changed to glycogen. There is little basis for this assumption. There is, on the other hand, considerable evidence that increasing the blood sugar does, in fact, directly increase muscular efficiency. Thus Locke ^^ proved that if oxygenated salt solution is perfused through the isolated rabbit heart, the beats begin to weaken after one or two hours ; but if now 0.1 per cent dextrose is added to the perfusing liquid, the beats at once become markedly stronger and may continue with very slow lessening of strength as long as seven hours. And Schumberg ^" noted that when he performed a large amount of gen-

eral bodily work (thus using up blood sugar) and then tested flexion of the middle finger in an ergograph, the ability of the muscle was greater if he drank a sugar solution than if he drank an equally sweet solution of "dulcin." He did not know during the experiment which solution he was drinking. These observations have been confirmed by Prantner and Stowasser, and by Frentzel.^^ In experiments on cats, Lee and Harrold ^^ found that when sugar is removed from the animal by means of phlorhizin the tibialis anticus is quick- ly fatigued ; but if, after the phlorhizin treatment, the animal is given an abundance of sugar and then submitted to the test, the muscle shows a much larger capacity for work. All this evidence is, of course, favorable to the view that circulating sugar may be quickly utilized by contracting muscles.

From the experimental results presented above it is clear that muscles work preferably by utilizing the energy stored in sugar, that great muscular labor is capable of considerably reducing the quan- tity of stored glycogen and of circulating sugar, and that under circumstances of a lessened sugar content the increase of blood sugar considerably augments the ability of muscles to continue con- tracting. The conclusion seems justified, there- fore, that the increased blood sugar attendant on the major emotions and pain would be of direct

benefit to the organism in the strenuous muscular efforts involved in flight or conflict or struggle to be free. The function which the discharged adrenin itself might have in favoring vigorous muscular con- traction has already been suggested in the chapter on the effect of adrenin in restoring the irritability of fatigued muscle. Some of the earliest evidence proved that removal of the adrenal glands has a debilitating effect on muscular power, and that injection of adrenal extract has an invigorating effect. For these reasons it seemed possible that increased adrenal secretion, as a reflex result of pain or the major emotions, might act in itself as a dynamogenic factor in the performance of mus- cular work. It was on the basis of that possibility that Nice and I tested the effect of stimulating the splanchnic nerves (thus causing adrenal secre- tion), or injecting adrenin, on the contraction of the fatigued tibialis anticus. We found, as already described, that when arterial pressure was of nor- mal height, and was prevented from rising in the legs while the splanchnic was being stimulated, there was a distinct rise in the height of contrac- tion of the fatigued muscle. And we drew the inference that adrenin set free in the blood may

operate favorably to the organism by preparing fatigued muscles for better response to the nervous discbarges sent forth in great excitement. This inference led to the experiments by Gruber, who examined the effects of minute amounts of adrenin (0.1 or 0.5 cubic centimeter, 1:100,000), and also of splanchnic stimulation, on the thresh- old stimulus of fatigued neuro-muscular and mus- cular apparatus. Fatigue, the reader will recall, raises the threshold not uncommonly 100 or 200 per cent, and in some instances as much as 600 per cent. Eest will restore the normal threshold in periods varying from fifteen minutes to two hours, according to the length of previous stimulation. If a small dose of adrenin is given, however, the normal threshold may be restored in three to five minutes.

From the foregoing evidence the conclusion is warranted that adrejiin,. when freely liberated in the blood, not only aids in bringing out sugar from the liver's store of glycogen, but also has a remark- able influence in quickly restoring to fatigued mus- cles, which have lost their original irritability, the same readiness for response which they had when fresh. Thus the adrenin set free iu pain and in fear and rage would put the muscles of the body unqualifiedly at the disposal of the nervous sys- tem; the difficulty which nerve impulses might have in calling the muscles into full activity would

be practically abolished ; and this provision, along with the abundance of energy-supplying sugar newly flushed into the circulation, would give to the animal in which these mechanisms are most efficient the best possible conditions for putting forth supreme muscular efforts.* The Question Whether Adrenin Normally Secreted Inhibits the Use of Sugar in the Body The only evidence opposed to the conclusion which has just been drawn is that which may be found in results recently reported by Wilenko. He injected adrenin into urethanized rabbits, usually one milligram per kilo body weight, and then found that the animals did not oxidize any part of an intravenous injection of glucose. Rabbits supplied with glucose in a similar manner, but not given adrenin, have an increased respiratory quotient. Wilenko ^^ concluded, therefore, that adrenin les- sens the capacity of the organism to burn carbo- hydrates. In a later paper he reported that adren- in, when added, with glucose, to physiological salt solution (Locke's), and perfused through the iso- lated rabbit heart, notably increases the use of sugar by the heart (from 2.2-2.8 to 2.9-4.3 milli-

* If these results of emotion and pain are not "worked ofE" by action, it is conceivable that the excessive adrenin and sugar in the blood may have pathological effects. (Cf. Can- non : Journal of the American Medical Association, 1911, Ivi, p. 742.) grams of glucose per gram of heart muscle per hour), but that the heart removed after the animal has received a subcutaneous injection of adrenin uses much less sugar, only 0.5-1.2 milligrams per gram per hour. From these results Wilen- ko ^* concludes that the glycosuria following in- jection of adrenin is the result of disturbance of the use of sugar — an effect which is not direct on the sugar-consuming organ, but indirect through action on some other organ.

Wilenko's conclusion fails to account readily for the disappearance of glycogen from the liver in adrenin glycosuria. Furthermore, Lusk^® has recently reported that the subcutaneous adminis- tration of adrenin (one milligram per kilo body weight) to dogs, simultaneously with 50 grams of glucose by mouth, interferes not at all with the use of the sugar — the respiratory quotient remains for several hours at 1.0 ; i. e., at the figure which glucose alone would have given. In other words, Lusk's results with dogs are directly contradictory to Wilenko's results with rabbits. Nevertheless, Wilenko's conclusion might be quite true for the glycosuria produced by adrenin alone (which must be excessive), and yet have no bearing whatever on the glycosuria produced physiologically by splanchnic stimulation, even though some adrenin is thereby simultaneously liberated.

adrenin glycosuria is enormous. Osgood lias stud- ied in the Harvard Physiological Laboratory the effects on blood pressure of alternately stimulating the left splanchnic nerves (with the splanchnic vessels eliminated) and injecting adrenin, and by this method of comparison ^^ has shown that the amount secreted after five seconds of stimula- tion varies betweet 0.0015 and 0.007 milligram. If 0.005 milligram is taken as a rather high average figure, and doubled (for two glands), the amount would be 0.01 milligram. To produce adrenin gly- cosuria, an animal weighing two kilos would be injected with two hundred times this amount. It is granted that more adrenin would be secreted if the nerves were stimulated longer than five sec- onds, and that with injection under the skin or into the abdominal cavity (to produce glycosuria), the' amount of adrenin in the blood at one time would not be so great as if the injection were into a vein ; but even with these concessions the amount of ad- renin in the blood, when it has been injected to produce glycosuria, is probably very much above the amount following physiological stimulation of the glands.

Other evidence that the amount of adrenin dis- charged when the glands are stimulated is not so great as the amount needed to produce glycosuria when acting alone is presented in experiments by Macleod.^'^ He found that if the nerve fibres to the liver were destroyed, stimulation of the splanchnic, which would cause increased adrenal secretion, did not increase the blood sugar. The increased blood sugar due to splanchnic stimula- tion, therefore, is a nervous effect, dependent, to be sure, on the presence of adrenin in the blood, but the amount of adrenin present is not in itself capable of evoking increase.

Furthermore, the increased blood sugar follow- ing splanchnic stimulation may long outlast the stimulation period. The adrenals, however, as has been demonstrated by Osgood, are soon fatigued, and fail to respond to repeated stimulation. They seem to be incapable of prolonged action. Again, as Macleod ^^ has shown, a rise in the sugar content of the blood can be induced, if the adrenals are intact, merely by stimulating the nerves going to the liver. The increased blood sugar of splanchnic origin, therefore, is not due to a disturbance of the use of sugar in the body, as Wilenko claims for the increase after adrenin in- jection, but is a result of a breaking down of the stored glycogen in the liver and is of nervous origin.

We may conclude, therefore, that since the condi- tions of Wilenko' s observations are not compar- able with emotional conditions, his inferences are not pertinent to the present discussion ; that when both adrenin and sugar are increased in the blood as a result of excitement, the higlier percentage of sugar is not due to adrenin inhibiting the use of sugar by the tissues, and that there is no evi- dence at present to show that the brief augmenta- tion of adrenal discharge, following excitement or splanchnic stimulation, affects in any deleterious manner the utilization of sugar as a source of en- ergy. [ Indeed, the observation of Wilenko and of Patterson and Starling, above mentioned, that ad- renin increases the use of sugar by the heart, may signify that a physiological discharge of the ad- renals can have a favorable rather than an unfa- vorable effect on the employment of sugar by the tissues. , ^

The Vascular Changes Produced by Adrenin Eavorable to Supreme Muscular Exertion Quite in harmony with the foregoing argument that sugar and adrenin, which are poured into the blood during emotional excitement, render the or- ganism more efficient in the physical struggle for existence, are the vascular changes wrought by increased adrenin, probably in cooperation with sympathetic innervations. The studies of volume changes of parts of the body, made by Oliver and Schafer, have already been mentioned. Their ob- servations, it will be remembered, showed that injected adrenin drove the blood from the abdom- inal viscera into the organs called upon in emer-

gencies — ^into the central nervous system, the lungs, the heart, and the active skeletal muscles. The absence of effective vasoconstrictor nerves in the brain and the lungs, and the dilation of vessels in the heart and skeletal muscles during times of increased activity, make the blood supply to these parts dependent on the height of general arterial pressure. In pain and great excitement, as we have already noted, this pressure is likely to be much elevated, and consequently the blood flow through the unconstrieted or actually dilated vessels of the body will be all the more abundant. Adreniu has a well-known stimulating effect on the isolated heart — causing an increase both in the rate and the amplitude of cardiac contraction. This effect accords with the general rule that adrenin simulates the action of sympathetic impulses. It is commonly stated, however, that if the heart holds its normal relations in the body, adrenin causes slowing of the beat.^" This view is doubt- less due to the massive doses that have been employed, which are quite beyond physiological limits and which induce such enormous increases of arterial pressure that the natural influence of adrenin on heart muscle is overcome by mechanical obstacles to quick contractions and by inhibitory impulses from the central nervous system. Hos- kins and Lovellette have recently shown that when the precaution, is taken to inject adrenin into a vein

in a manner resembling the discharge from the adrenal glands, not only is there increased blood pressure, but generally, also, an acceleration of the pulse.^" At the same time, therefore, that a greater amount of work, from increased arterial pressure, is demanded of the heart, blood is de- livered to the heart in greater abundance, and the muscle is excited to more rapid and vigorous pul- sations. The augmentation of the heart beat is thus coordinate with the other adaptive functions of^the adrenal glands in great emergencies.

The Changes in Eespiratory Functon Also Favorable TO Great Effort The urgent need in struggle or flight is a gen- erous supply of oxygen to oxidize the metabolites of muscular contraction, and a quick riddance of the resultant carbon-dioxide from the body. The moment vigorous exercise is begun the breathing at once changes so as to bring about a more thor- ough ventilation of the lungs. And one of the most characteristic reactions of animals in pain and emotional excitement is deep and rapid respiration. Again the reflex response is precisely what would be most serviceable to the organism in the stren- uous efforts of fighting or escape that might accom- pany or follow distress or fear or rage. It is known that by such forced respirations the carbon- dioxide content of the blood can be so much re-

duced that the need for any breathing whatever may be deferred for as much as a minute or even longer.^^ And Douglas and Haldane ^^ have found that moderately forced breathing for three minutes previous to severe muscular exertion re- sults in greatly diminishing the subsequent res- piratory distress, as well as lessening the amount of air breathed and the amount of carbon-dioxide given off. Furthermore, the heart beats less rap- idly after the performance and returns more quickly from its increased rate to normal. The forced respirations in deeply emotional experi- ences can be interpreted, therefore, as an antici- patory reduction of the carbon-dioxide in the blood, a preparation for the augmented discharge of carbon-dioxide into the blood as soon as great muscular exertion begins.*

As the air moves to and fro in the lungs with each respiration, it must pass through the fine divisions of the air tubes or bronchioles. The bronchioles are provided with smooth muscle, which, in all probability, like smooth muscle else- where in the body, is normally held in a state of * The excessive production of heat in muscular work gives rise to sv^eating. The evaporation of sweat helps to keep the body temperature from rising unduly from the heat of exer- tion. Again in strong emotion and in pain the "cold sweat" that appears on the skin may be regarded as a reaction anticipatory of the strenuous muscular movements that are likely to ensue.

tonic contraction. When this tonic contraction is much increased, as in asthma, breathing becomes difficult, and even with the body at rest unusual effort is then required to maintain the minimal necessary ventilation of the lungs. During stren- uous exertion, with each breath the air must rush through the bronchioles in greatly increased vol- ume and speed. Thus in a well person "winded" with running, for example, the bronchioles might become relatively too small for the stream of air, just as they are too small in a person ill with asthma. And then some extra energy would have to be expended to force the air back and forth with sufficient rapidity to satisfy the bodily needs. It is probable that even under the most favorable con- ditions, the labored breathing in hard exercise in- volves to some degree the work of accelerating the tidal flow of the respiratory gases. This extra labor would obviously be reduced, if the tonic con- traction of the ring-muscles in the wall of the bronchioles was reduced, so that the tubules were enlarged. It has been shown by a number of in- vestigators, who have used various methods, that adrenin injected into the blood stream has as one of its precise actions the dilating of the bronchi- oles.^^ The adrenin discharged in emotional ex- citement goes to the lungs before entering into relation with any other organ except the right heart chamber ; it may, therefore, have as its first

effect the relaxation of the smooth muscles of the lungs. This would be another very direct means of rendering the organism more efficient when fierce struggle calls for a bounteous supply of fresh air and a speedy discharge of the carbonaceous waste. Effects Produced in Asphyxia Similar to those Produced IN Pain and Excitement All the bodily responses occurring in pain and emotional excitement have thus far been consid- ered as anticipatory of the instinctive acts which naturally follow. And as we have seen, these re- sponses can reasonably be interpreted as prepar- atory to the great exertions which may be de- manded of the organism. This interpretation of the facts is supported by the discovery that a mechanism exists whereby the changes initiated in an anticipatory manner by emotional excite- ment are continued or perhaps augumented by the exertion itself.

Great exertion, such as might attend flight or conflict, would result in an excessive production of carbon-dioxide. Then, although respiratory and circulatory changes of emotional origin may have prepared the body for struggle, the emotional pro- visions for keeping the working parts at a high level of efficiency may not continue to operate, or they may not be adequate. If there is painful gasp- ing for breath in the course of prolonged and vig- orous exertion, or for a considerable period after the work has ceased, a condition of partial asphyxia has evidently been induced. This condi- tion, as everyone knows, is distinctly unfavorable to further effort. But the asphyxia itself may act as a stimulus.^*

In our examination of the influence of various conditions on the secretion of the adrenal glands, Hoskins and I ^^ tested the effects of asphyxia. By use of the intestinal segment as an indicator we compared the action of blood, taken as nearly si- multaneously as possible from the vena cava above the adrenal vessels and from the femoral vein be- fore asphyxia, with blood taken from the same sources after asphyxia had been produced. The femoral venous blood after passing the capillaries of the leg thus acted as a standard for the same blood after receiving the contribution of the adrenal veins. Asphyxia was caused by covering the tracheal cannula until respiration became labored and slow, but capable of recovery when air was admitted. It may be regarded, therefore, as not extreme.