Bodily Changes in Pain, Hunger, Fear and Rage

More direct evidence of the favorable influence of adrenal extract on skeletal muscle was brought forward by Oliver and Schafer.^ After inject- ing the extract subcutaneously into a frog they found that the excised gastrocnemius muscle regis- tered 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 Urandis,* who studied the phenomenon in a salamander.* Further evidence leading to the same conclusion was offered in a discriminat-

* 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: Am- erican 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.

ing paper I)y Panella.^ He found that in cold- blooded animals the active principle of the adre- nal medulla notably reinforced skeletal muscle, prolonging its ability to do work, and improv- ing 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. The foregoing evidence indicates that removal of the adrenals has a debilitating effect on muscu- lar power, and that injection of extracts of the glands has an invigorating effect. It seemed pos- sible, 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 dyna- mogenic factor in the performance of muscular work. With this possibility in mind L. B. Nice and I ^ 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 rhyth- mically and uniformly excited with break induc- tion 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 con- tinue 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 perform- ance, 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 qual- ity of the blood supplied to the laboring muscle. Cats were used for most experiments, but re- sults obtained with cats were confirmed on rab- bits 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 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 em- ployed. The anterior tibial nerve which supplies these muscles was bared for about two centimeters, severed toward the body, and set in shielded elec- trodes, 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 con- nected with its proper blood supply. The prepa- ration 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 tri- pod. 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 sup- port 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 be- tween 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. Constric- tion of the blood vessels would be likely to pro- duce the most serious disturbance, by lessening the blood flow to the muscle. The observations of Bowditch and Warren,'^ 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 onr 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 rea- sonably be attributed to a diminished circulation. The Splanchnic Preparation The splanchnic nerves were stimulated in vari- ous ways. At first only the left splanchnics in the abdomen were prepared. The nerves, sepa- rated from the spinal cord, were placed upon shielded electrodes. The form of electrodes which was found most satisfactory was that illustrated

FiGTjKB 10. — The shielded electrodes used in stimulating the splanchnic nerves. For description see text. 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 sur- face. 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 down- ward.

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 con- ductivity 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 milli- meters 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. Ab- sorbent 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 per- mitting 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 abdo- men.

The current delivered to the splanchnic nerves was a rapidly interrupted induced current of such strength that no effects of spreading were notice- able. That splanchnic stimulation causes secre- tion of the adrenal glands has been proved in many different ways whicH have already been de- scribed (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 splanch- nic 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

FiGtTBB 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. while contracting lifted a weight of 125 grams. The rate of stimulation was 80 per minute. 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 maxi- mum 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 in- termediate betterment of its efficiency.

The brief first elevation in the muscle record when registered simultaneously with arterial blood pressure is observed to occur at the same time Figure 12. — Top record, arterial blood pressure with membrane manometer. Mid- dle record, contractions of tibialis anticus loaded with 125 grams and stimulated 80 times a minute. Bottom record, splanchnic stimulation (two minutes). Time, half min- utes. 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 prob- ably due directly to the better blood supply result- ing 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.

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 Elli- ott,^ and as Lyman and I " have shown, this sharp drop after the first rise, and also the subse- quent elevation of blood pressure, are the conse- quences of liberation of adrenal secretion into the circulation. Fig. 12 demonstrates that the pro- longed rise of the muscle record begins soon after this characteristic drop in blood pressure.

If after clips have been placed on the adre- nal veins so that no blood passes from them, the splanchnic nerves are stimulated, and later the clips are removed, a slight bnt distinct improve- ment in the muscular contraction occurs. As in the experiments of Young and Lehmann,^" 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 ac- count 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 ap- pear 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 in- creased height of the record. In some instances the height of contraction was doubled — a better- ment by 100 per cent ; in other instances the con- traction after splanchnic stimulation was only a small fraction higher than that preceding the stim- ulation; 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 ia degree as in- dicated by persistence of effect. In some in- stances 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 effi- ciency for fifteen or twenty minutes after the stim- ulation.

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 pres- sure and it also causes a discharge of adrenin from the adrenal glands. The questions now arise — Does splanchnic stimulation produce the improve- ment 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 con- traction? Or may the two factors cooperate? These questions will be dealt with in the next two chapters.

^ Panella : Archives Italiennes de Biologie, 1907, xlviii, p. ^° Young and Lehmann : Journal of Physiology, 1908, xxxvii, p. liv. That great excitement is accompanied by sym- pathetic innervations which increase the contrac- tion of the small arteries, render unusually forc- ible the heart beat, and consequently raise arterial pressure, has already been pointed out (see p. 26). Indeed, the counsel to avoid circumstances likely to lead to such excitement, which is given to per- sons with hardened arteries or with weak hearts, is based on the liability of serious consequences, either in the heart or in the vessels, that might arise from an emotional increase of pressure in these pathological conditions. That great muscu- lar effort also is accompanied by heightened arte- rial pressure is equally well known, and is avoided by persons likely to be injured by it. Both in ex- citement and in strong exertion the blood is forced in large degree from the capacious vessels of the abdomen into other parts of the body. In excite-

ment the abdominal arteries and veins are con- tracted by impulses from the splanchnic nerves. In violent effort the diaphragm and the muscles of the belly wall are voluntarily and antagonistic- ally contracted in order to stiffen the trunk as a support for the arms ; and the increased abdominal pressure which results forces blood out of that region and does not permit reaccumulation. The general arterial pressure in man, as McCurdy ^ has shown, may suddenly rise during extreme physical effort, from approximately 110 millime- ters to 180 millimeters of mercury.

What effect the increase of arterial pressure, re- sulting from excitement or physical strain, may have on muscular efficiency, has received only slight consideration. Nice and I found there was need of careful study of the relations between arterial pressure and muscular ability, and, in 1913, one of my students, 0. M. Gruber, under- took to make clearer these relations. The methods of anesthesia and stimulation used by Gruber were similar to those described in the last chapter. The arterial blood pressure was registered from the right carotid or the femoral artery by means of a mercury manometer. A time marker indicating half -minute intervals was placed at the atmospheric pressure level of the

manometer. And since the blood-pressure style, the writing point of the muscle lever, and the time signal were all set in a vertical line on the surface of the recording drum, at any given muscular con- traction the height of blood pressure was simul- taneously registered. To increase general arterial pressure two meth- ods were used: the spinal cord was stimulated in the cervical region through platinum electrodes, or the left splanchnic nerves were stimulated after the left adrenal gland had been excluded from the circulation. This was done in order to avoid any influence which adrenal secretion might exert. It is assumed in these experiments that vessels sup- plying active muscles would be actively dilated, as Kaufmann ^ has shown, and would, therefore, in case of a general increase of blood pressure, de- liver a larger volume of blood to the area they supply. The effects of increased arterial pressure are illustrated in Figs. 13, 14 and 15. In the ex- periment represented in Fig. 13, the rise of blood pressure was produced by stimulation of the cer- vical cord, and in Figs. 14 and 15 by stimulation of the left splanchnic nerves after the left adre- nal gland had been tied off.

The original blood pressure in Fig. 13 was 120 millimeters of mercury. This was increased by 62 millimeters, with a rise of only 8.4 per cent in the height of contraction of the fatigued muscle. Figure 13. — In this and the following records, the upper curve indicates the blood pressure, the middle Mne muscu- lar contraction, and the lower line the time in 30 seconds (also zero blood pressure.) Between the arrows the exposed cervical spinal cord was stimulated.

In Fig. 14 the original blood pressure was 100 millimeters of mercury. By increasing this pres- sure 32 millimeters there resulted simultaneous betterment of 9.8 per cent in the height of muscu- lar contraction. In Fig. 14 B the arterial pres- sure was raised 26 millimeters and the height of FiGTJRB 14. — Stimulation of the left splanchnic nerves (left adrenal gland tied off) during the periods indicated by the arrows. contraction increased correspondingly 7 per cent. In Fig. 14 C no appreciable betterment can be seen although the blood pressure rose 18 millimeters. In Fig. 15 the original blood pressure was low — 68 millimeters of mercury. This was increased in Fig. 15 A by 18 millimeters (the same as in

Fig. 14 C without effect), and there resulted an in- crease of 20 per cent in the height of contraction. In Fig. 15 B the pressure was raised 24 millime- Figure 15. — During the periods indicated in the time line the left splanchnic nerves were stimulated. The vessels of the left adrenal gland were tied off. ters with a corresponding increase of 90 per cent in the muscular contraction ; and in Fig. 15 C 30 millimeters with a betterment of 125 per cent.

Comparison of Figs. 13, 14 and 15 reveals that the improvement of contraction of fatigued mus- cle is much greater when the blood pressure is raised, even slightly, from a low level, than when it is raised, perhaps to a very marked degree, from a high level. In one of the experiments per- formed by Nice and myself the arterial pressure was increased by splanchnic stimulation from the low level of 48 millimeters of mercury to 110 milli- meters, and the height of the muscular contrac- tions was increased about sixfold (see Fig. 16).

Figure 16. — The bottom record (zero of blood pressure) shows stimulation of left splanchnics; between the arrows the pressure was kept from rising by compression of heart. Results confirming those described above were obtained by Gruber in a study of the effects of splanchnic stimulation on the irritability of mus- cle when fatigued. In a series of eleven observa- tions the average value of the barely effective stimulus (the "threshold" stimulus) had to be in- creased as the condition of fatigue developed. It

was increased for the nerve-muscle by 25 per cent and for the muscle by 75 per cent. The left splanchnic nerves, disconnected from the left adre- nal gland, were now stimulated. The arterial pres- sure, which had varied between 90 and 100 milli- meters of mercury, was raised at least 40 milli- meters. As a result of splanchnic stimulation there was an average recovery of 42 per cent in the nerve-muscle and of 46 per cent in the muscle. The increased general blood pressure was effec- tive, therefore, quite apart from any possible action of adrenal secretion, in largely restoring to the fatigued structures their normal irritability.

Inasmuch as an increase in arterial pressure produces an increase in the height of contraction of fatigued muscle, it is readily supposable that a decrease in the pressure would have the oppo- site effect. Such is the case only when the blood pressure falls below the region of 90 to 100 milli- meters of mercury. Thus if the arterial pressure stands at 150 millimeters of mercury, it has to fall approximately 55 to 65 millimeters before causing a decrease in the height of contraction. Fig. 17 is the record of an experiment in which the blood pressure was lowered by lessening the output of blood from the heart by compressing the thorax. The record shows that when the pressure