Bodily Changes in Pain, Hunger, Fear and Rage

(1) Normal threshold stimulus. (2) Threshold five minutes after an intraven- ous injection of 0.1 cubic centimeter of ad- renin (1:100,000) without previous fatigue. (4) Threshold five minutes after an injec- tion of 0.2 cubic centimeter of adrenin (1:100,000) without previous fatigue. (5) Threshold after one hour's fatigue. The muscle contracted 120 times per minute against a spring having an initial tension of 120 grams. (6) Threshold five minutes after an injection (0.1 cubic centimeter) of adrenin (1:100,000). (7) Threshold five minutes after another injection of adrenin (0.5 cubic centimeter of a 1:100,000 solu- tion).

of the muscle remained unaltered — 26 per cent above its normal threshold. In Fig. 20 the threshold (at 5) was taken five mimites after an injection of 0.1 cubic centimeter of adrenin. The drop here was as large as that shown in Fig. 19. The threshold taken from the Figure 20. — A record plotted from the data of one experiment. The time intervals in hours and minutes are registered on the abscissa; the values of the threshold in units are registered on the ordinate. The continuous line is the record of the muscle, the broken line that of the nerve-muscle. The record of the nerve- muscle is magnified ten times; that of the muscle is normal.

(1) Normal threshold. (2) The threshold after one hour's fatigue. The muscle contracted 120 times per minute against a spring having an initial tension of 120 grams. (3 and 4) Thresh- olds after rest; after 60 minutes (3), and after 90 minutes (4). (5) Threshold five minutes after an injection of adrenin (0.1 cubic centimeter of a 1:100,000 solution). (6 and 7) Thresholds after rest; after 60 minutes (6), and after 90 minutes (7). muscle directly was lowered from 30.6 to 18 units, a recovery of 61 per cent; the nerve-muscle from 1.08 to 0.87 units, a recovery of 51 per cent. That this sudden decrease cannot be due«to rest is shown in the same Figure (at 3 and 4). These readings were made after 60 and 90 minutes' rest respective- ly. The sharp decline in the record (at 5) indi- cates distinctly the remarkable restorative influ-

enee of adrenin in promptly lowering tlie high fatigue threshold of neuro-muscular irritability. The Evidence that the Eestorative Action op Adrenin is Specific As stated in describing the effects of arterial blood pressure, an increase of pressure is capable of causing a decided loweriug of the neuro-muscu- lar threshold after fatigue. Is it not possible that adrenin produces its beneficial effects by better- ing the circulation 1 Nice and I had argued that the higher contrac- tions of fatigued muscle, that follow stimulation or injection of adrenin, could not be wholly due to improved blood flow through the muscle, for when by traction on the aorta or compression of the thorax arterial pressure in the hind legs was pre- vented from rising, splanchnic stimulation still caused a distinct improvement, the initial appear- ance of which coincided with the point in the blood- pressure curve at which evidence of adrenal secre- tion appeared. And, furthermore, the improve- ment was seen also when adrenin was given intra- venously in such weak solution (1:100,000) as to produce a fall instead of a rise of arterial pressure. Lyman and I had shown that this fall of pressure was due to a dilator effect of adrenin. Since the blood vessels of the fatigued muscle were dilated by severance of their nerves when the nerve trunk was

cut, and, besides, as previously stated (see p. 86), were being stimulated through, their nerves at a rate favorable to relaxation, it seemed hardly prob- FiGtTRB 21. — Top record, blood pressure with mercury manometer. Middle record, contractions of the tibialis anticus muscle 240 times per minute against a spring with an initial tension of 120 grams. Bottom record (zero blood pressure), injection of 0.4 cubic centimeter of adrenin (1:100,- 000). Time in half minutes.

able that adrenin could produce its beneficial effect by further dilation of the vessels and by consequent flushing of the muscle with an extra supply of blood.^ The lowering of blood pressure had been proved to have no other effect than to impair the action of the muscle ( see p. 103 ) . Although the chances were thus against an interpretation of the beneficial influence of adrenin through action on the circulation, it was thought desirable to test the possibility by comparing its effect with that of another vasodilator — amyl nitrite.

Figs. 21 and 22 are curves obtained from the left tibialis anticus muscle. The rate of stimulation was 240 times a minute. The muscle in Fig. 21 contracted against a spring having an initial tension of 120 grams, and that in Fig. 22 against an initial tension of 100 grams. In Fig. 21, at the point indicated on the base line, 0.4 cubic centimeter of adrenin (1:100,000) was in- jected into the left external jugular vein. There resulted a fall of 25 millimeters of mercury in the arterial pressure and a concurrent betterment of 15 per cent in the height of contraction, requiring two minutes and fifteen seconds of fatigue (about 540 contractions) before it returned to the former level. In Fig. 22, at the point indicated by the arrow, a solution of amyl nitrite was injected into the right external jugular vein. There resulted a fall of 70 millimeters of mercury in arterial pres- sure and a betterment of 4.1 per cent in the height of muscular contraction, requiring fifteen seconds of fatigue (about 60 contractions) to decrease the height of contraction to its former level. In

Figure 22. — Top record, blood pressure with mercury manometer. Middle record, con- tractions of tibialis anlicus mus- cle 240 per minute against a spring with an initial tension of 100 grams direct load. Bottom record (zero blood pressure), time in half minutes. The arrow indi- cates the point at which a solu- tion of amyl nitrite was injected. neither case did the blood pressure fall below the critical region (see p. 104).* Although the fall in arterial pressure caused by dilation of the vessels due to amyl nitrite was al- most three times as great as that produced by the adrenin, yet the resultant betterment was only about one-fourth the percentage height and lasted but one-ninth the time. In all cases in which these solutions caused an equal fall in arterial pressure, adrenin caused higher contractions, whereas amyl nitrite caused no appreciable change.

From the evidence presented in the foregoing pages it is clear that adrenin somehow is able to bring about a rapid recovery of normal irritability of muscle after the irritability has been much less- ened by fatigue, and that the higher contractions of a fatigued muscle after an injection of adrenin are due, certainly in part, to some specific action of this substance and not wholly to its influence~o5~ tlie circulation. Some of the earlier investigators

* In some cases after injection of amyl nitrite the normal blood pressure, which was high, dropped sharply to a point below the critical region. There resulted a primary increase in muscular contraction due to the betterment in circulation caused by the dilation of the vessels before the critical region was reached. During the time that the pressure was below the critical region the muscle contraction fell. As the blood pressure again rose to normal the muscle contraction in- creased coincidently.

of adrenal function, notably Albanese,* and also Abelous and Langlois,^ inferred from experi- ments on tbe removal of the glands that the role they played in the bodily economy was that of neu- tralizing, destroying or transforming toxic sub- stances produced in the organism as a result of muscular or nervous work. It seemed possible that the metabolites might have a checking or blocking influence at the junction of the nerve fibres with the muscle: fibres, and might thus, like curare, lessen the efficiency of the nerve impulses. Eadwanska's ob- servation ® that the beneficial action of adrenin is far greater when the muscle is stimulated through its nerve than when stimulated directly, and Panel- la's discovery ^ that adrenin antagonizes the ef- fect of curare, were favorable to the view that adrenin improves the contraction of fatigued mus- cle by lessening or removing a block established by accumulated metabolites.

The high threshold of fatigued denervated mus- cle, however, Gruber found was quite as promptly lowered by adrenin as was that of normal muscles stimulated through their nerves. Fig. 23 shows that the height of contraction, also, of the fatigued muscle is increased when adrenin is administered. In this experiment the left tibialis anticus muscle was stimulated directly by thrusting platinum needle electrodes into it. The peroneus communis nerve supplying the muscle had been cut and two

centiineters of it removed nine days previous to the experiment. The rate of stimulation was 120 times per minute and the initial tension of the spring about 120 grams. At the point indicated Figure 23. — Top record, blood pressure with mercury manometer. Middle record, contractions of a denervated muscle {tibialis anticus) 240 per per minute against a spring having an initial ten- sion of 120 grams {peroneus communis nerve was cut nine days before this record was taken). Bot- tom record (zero blood pressure), time in half min- utes. At the point indicated by an arrow 0.1 cubic centimeter of adrenin (1:100,000) was injected intravenously.

by the arrow an injection of 0.1 cubic centimeter of adrenin (1:100,000) was made into a jugular vein. A fall in arterial pressure from 110 to 86 millimeters of mercury and a simultaneous better- ment of 20 per cent in the height of contraction were obtained. It required four minutes of fatigue (about 480 contractions) to restore the muscle curve to its former level. Eesults similar to this were obtained from animals in which the nerve had been cut 7, 9, 12, 14, and 21 days. In all instances the nerve was inexcitable to strong f aradic stimula- tion.

In Eadwanska's experiments, mentioned above, the muscle was stimulated directly when the nerve endings were intact. It seems reasonable to sup- pose, therefore, that in all cases he was stimulat- ing nerve tissue. Since a muscle is more irritable when stimulated through its nerve than when stimulated directly (nerve and muscle), a slight change in the irritability of the muscle by adrenin would naturally result in a greater contraction when the nerve was stimulated. Panella's results also are not inconsistent with the interpretation that the effect of adrenin is on the muscle substance rather than on the nerve endings. A method which has long been used to separate muscle from nerve is that of blocking the nervous impulses by the drug curare. Gruber found that when curare is in- jected the threshold of the normal muscle is in- creased as was to be expected from the removal of the highly efficient nervous stimulations. And also, as was to be expected on that basis, curare did not increase the threshold in a muscle in which the nerve endings had degenerated. Adrenin antago-

nizes curare with great promptness, decreasing the heightened threshold of a curarized muscle, in five minutes or less, in some cases to normal. From this observation it might be supposed that curare and fatigue had the same effect, and that adrenin had the single action of opposing that effect. But fatigue raises the threshold of a curarized muscle, and adrenin then antagonizes this fatigue. Lang- ley ^ has argued that curare acts upon a hypo- thetical "receptive substance" in muscle. If so, probably curare acts upon a substance, or at a point, different from that upon which fatigue acts ; for, as the foregoing evidence shows, fatigue in- creases the threshold of a muscle whether deprived of its nerve supply by nerve section and degenera- tion or by curare, whereas curare affects only the threshold of a muscle in which the nerve endings are normal.^ And since adrenin can oppose the effects of both curare and fatigue, it may be said to have two actions, or to act on two different substances or at two different points in the muscle. The evidence adduced in the last chapter indi- cated that the greater "head" of arterial pressure produced by the more rapid heart beat and the stronger contraction of many arterioles in times of great excitement would be highly serviceable to the organism in any extensive muscular activity which the excitement might involve. By assuring an abundant flow of blood through the enlarged ves-

sels of the working muscle, the waste products resulting from the wear and tear in contraction would be promptly swept away and thus would be prevented from impairing the muscular effi- ciency. The adrenin discharge at such times would, as was pointed out, probably reinforce the effects of sympathetic impulses. The evidence presented in this chapter shows that adrenin has also another action, a very remarkable action, that of restor- ing to a muscle its original ability to respond to stimulation, after that has been largely lost by continued activity through a long period. What rest will do only after an hour or more, adrenin will do in five minutes or less. The bearing of this striking phenomenon on the functions of the or- ganism in times of great need for muscular activ- , ity will be considered in a later discussion.

The primary value of blood to the body must have been one of the earliest observations of rea- soning beings. When we consider the variety of fundamental services which this circulating fluid performs — the conveyance of food and oxygen to all the tissues, the removal of waste, the delivery of the internal secretions, the protection of the body against toxins and bacterial invasion, and the dis- tribution of heat from active to inactive regions — the view of the ancient Hebrews that the "life of the flesh is in the blood" is well justified. It is naturally of the utmost importance that this pre- cious fluid shall be safeguarded against loss. And its property of turning to a jelly soon after escap- ing from its natural channels assures a closure of the opening through which the escape occurred, and thus protection of the body from further bleeding. The slight evidence that adrenin hastens the clot- ting process has already been hinted at. When we

found that adrenin is set free in pain and intense emotion, it seemed possible that there might exist in the body an arrangement for making doubly sure the assurance against loss of blood, a proc- ess that might nicely play its role precisely when the greatest need for it would be likely to arise. It was in 1903, while tracing in dogs the rise and fall of sugar in the blood after administering adrenin, that Vosburgh and Richards ^ first noted that simultaneously with the increase of blood sugar there occurred more rapid coagulation. In some cases the diminution was as much as four- fifths the coagulation time of the control. Since this result was obtained by painting "adrenalin" on the pancreas, as well as by injecting it into the abdominal cavity, they concluded that "the phe- nomenon appears to be due to the application of adrenalin to the pancreas." Six years later, dur- ing a study of the effect of adrenalin on internal hemorrhage, Wiggers ^ examined incidentally the evidence presented by Vosburgh and Eichards, and after many tests on five dogs found "never the slightest indication that adrenalin, either when injected or added to the blood, appreciably hast- ened the coagulation process." In 1911 von den Velden^ reported that adrenin (about 0.007 mil- ligram per kilo of body weight) decreased the coagulation time in man about one-half — an effect appearing 11 minutes after administration by

mouth, and 85 miniites after subcutaneous injec- tion. He affirmed also, but without describing the conditions or giving figures, that adrenin de- creases coagulation time in vitro. He did not at- tribute the coagulative effect of adrenin in patients to this direct action on the blood, however, but to vasoconstriction disturbing the normal circulation and thereby the normal equilibrium between blood and tissue. In consequence, the tissue juices with their coagulative properties enter the blood, so he assumed. In support of this theory he offered his observation that coagulation time is decreased after the nasal mucosa has been rendered anemic by adrenin pledgets. Von den Velden's claim ^ for adrenin given by mouth was subjected to a single test on man by Dale and Laidlaw,* but their re- sult was completely negative.

The importance of Vosburgh and Richards' ob- servation, the thoroughly discordant testimony of later investigators, as well as the meager and inci- dental nature of all the evidence that has been ad- duced either for or against the acceleration of clot- ting by adrenin, made desirable a further study of this matter. Especially was this further study de- sirable because of the discharge of adrenin into the blood in pain and emotional excitement. Ac- cordingly, in 1914, H. Gray and I ^ undertook an investigation of the question. In doing so we em- ployed cats as subjects. Usually they were quickly

decerebrated under etlier, and tlien continuance of the drug became unnecessary. Body temperature was maintained by means of an electric heating pad. Eespiration proceeded normally except in a few instances (in which, presumably, there was hemorrhage into the medulla), when artificial res- piration had to be given. In order to avoid, so far as possible, the personal element in determining when the blood was clotted. Figure 24. — Diagram of the graphic coagulometer. The can- nula at the right rests in a water bath not shown in this diagram. For further description see text.

the blood was made to record its own clotting. The instrument by means of which this was done was the graphic coagulometer devised by W. L. Men- denhall and myself,® and illustrated diagram- matically in Fig. 24. It consists essentially of a light aluminum lever with the long arm nearly counterpoised by a weight W. The long arm is prevented from falling by a support 8, and is pre- vented from rising by a horizontal right-angled rod reaching over the lever at R^ and fixed into the block B which turns on the axis A. Into the same block is fixed the vertical rod R^. When this rod is moved from the post P^, against which it is held by the weight of the horizontal rod iJ^ towards the other post P^, the check on the long arm of the lever is lifted, and if the short arm is heavier, the long arm will then rise.

The cannula C, into which the blood is received, is two centimeters in total length and slightly more than two millimeters in internal diameter. It is attached by a short piece of rubber tubing to the tapered glass tube T, five centimeters long and five millimeters in internal diameter. The upper end of this tube is surrounded by another piece of rub- ber which supports the tube when it is slid into the U-shaped support U, fixed directly below the end of the short arm of the lever.

By drawing the cannulas from a single piece of glass tubing and by making the distance from shoulder to upper end about twelve millimeters, receptacles of fairly uniform capacity are assured. All the dimensions, the reach of the rubber con- nection over the top of the cannula (2-3 milli- meters), the distance of the upper rubber ring from the lower end of the glass chamber (4 centi- meters), etc., were as nearly standard as possible. A copper wire D, eiglit centimeters long and 0.6 millimeters ia diameter, bent above into a hook and below into a small ring slightly less than two millimeters in diameter, is hung in a depression at the end of the short arm of the lever. The small ring then rests in the upper part of the cannula (see Fig. 24). The weight of the copper wire makes the short arm of the lever heavier than the long arm by 30 milligrams, when the delicate writ- ing point is moving over a lightly smoked drum. Half a dozen of these standard wires are needed.

For accurate determination of the coagulation time Addis '^ has defined the following conditions as essential: 1. The blood must always be obtained under the same conditions. 3. The blood must always come in contact with the same amount and kind of foreign material. 4. The end point must be clear and definite and must always indicate the same degree of coagula- tion. The precautions taken to fulfill these conditions were as follows: 1. Drawing the blood. — The blood was taken from the femoral artery. The artery (usually the right) was laid bare in the groin and freed from surrounding tissue. A narrow artery clip, with

each limb enclosed in soft rubber tubing (to pre- vent injury of the tissues), and with its spring ex- erting gentle pressure, was placed on the artery immediately below the deep femoral branch, thus allowing no blood to stagnate above the clip. Be- tween the clip and a ligature applied about 1.5 centimeters below, an opening was made. The blood was carefully milked out of the vessels be- tween a blunt dissector moved beneath, and a small forceps, twisted into a pinch of absorbent cotton, moved above.

The cannula, cleaned in water, alcohol, and ether, was set in the rubber connection of the glass tube ; the point of the cannula was then lubricated with vaseline and slipped into the artery. The pres- sure of the clip on the artery was next very slightly released and blood was allowed to flow into the cannula up to the lower border of the rubber con- nection. Only a good-sized drop of blood was needed. Sometimes the blood ran one or two milli- meters above or below, but without appreciably changing the result. Since the clip was situated on the femoral immediately below a branch in which the circulation persisted, the blood received in the cannula was always fresh from the moving stream. As soon as the clip gripped the artery again, the cannula was slipped out. A helper then promptly milked the vessel in the manner described above, and covered it with a pad of absorbent cotton

smeared with, vaseline to prevent drying. There- by blood was not permitted to stagnate ; and when a new sample was to be taken, the vessel was clean and ready for use. The tip of the cannula was at once plugged by plunging it into a flat mound of plasticine about three millimeters high. It was drawn off sidewise lest the plasticine plug be pulled out again. One of the copper wires D was now slid into the tube and cannula, the tube slipped into the U-support, and the wire lifted and hung on the lever. This procedure, from the moment blood began to flow until the wire was hung, consumed usually about twenty seconds.

2. Uniform temperature. — Under the U-support was placed a large water bath, in which the can- nula and the tapering part of the tube were sub- merged. A thermometer was fixed to the U-sup- port so that the bulb came near the cannula in the bath. The water was kept within a degree of 25° C. This temperature was chosen for several rea- sons : (a) The cannula has room temperature and rapidly cools the small volume of blood that enters it. To heat blood and cannula to body tempera- ture would take time. A bath near room tempera- ture, therefore, seems preferable to one near body temperature, (b) The test of clotting was conveni- ently made at intervals of a half -minute, and if the clotting process were hastened by higher tempera-