ADRENAL SECRETION IN STRONG EMOTIONS AND PAIN
If the secretion of adrenin is increased in strong emotional states
and in pain, that constitutes a fact of considerable significance,
for, as already mentioned, adrenin is capable of producing many
of the bodily changes which are characteristically manifested in
emotional and painful experiences. It is a matter of prime importance
for further discussion to determine whether the adrenal glands are
in fact roused to special activity in times of stress.
The Evidence that Adrenal Secretion Is Increased in
Emotional Excitement
That blood from the adrenal veins causes the relaxation of intestinal
muscle characteristic of adrenal extract or adrenin is shown in
Fig. 3. The muscle was originally beating in blood which contained
no demonstrable amount of adrenal secretion; this inactive blood
was replaced by blood from the adrenal veins, obtained after quick
etherization. Etherization, it will be recalled, is accompanied by
a “stage of excitement.” Relaxation occurred almost immediately (at
_b_). Then the rhythm was renewed in the former blood, and thereupon
the muscle was surrounded with blood from the vein leading away
from the left kidney, i. e., blood obtained from the same animal
and under the same conditions as the adrenal blood, but from a
neighboring vein. No relaxation occurred. By this and other similar
tests the reliability of the method was proved.
[Illustration: Figure 3.--Intestinal muscle beating in inactive
blood, which was withdrawn from the chamber at _a_. Blood from the
_adrenal_ vein of an animal excited by etherization was substituted
at _b_, and withdrawn at _c_. Contractions were restored in the
original inactive blood which was removed at _d_. Blood from the
_renal_ vein (same animal) was added at _e_.
In this and subsequent records time is marked in half minutes.]
In no instance did blood from the inferior vena cava of the quiet
normal animal produce relaxation. On the other hand, blood from the
animal after emotional excitement showed more or less promptly the
typical relaxation. In Fig. 4 is represented the record of intestinal
muscle which was beating regularly in Ringer’s solution. At _a_ the
Ringer’s solution was removed, and at _b_ “excited” blood was added;
after the preliminary shortening, which, as already stated, occurs
at the first immersion in blood, the muscle lengthened gradually
into complete inhibition. At _c_ the “excited” blood was removed,
and at _d_ “quiet” blood was added in its place. The muscle at
once began fairly regular rhythmic beats. At _e_ the “quiet” blood
was removed, and at _f_ the “excited” blood was again applied. The
muscle lengthened almost immediately into an inhibited state. In
this instance the “excited” blood was taken after the cat had been
barked at for about fifteen minutes.
[Illustration: Figure 4.--Alternate application of “excited” blood
(at _b_ and _f_) and “quiet” blood (at _d_), from the same animal,
to intestinal muscle initially beating in Ringer’s solution.]
The increase of effect with prolongation of the period of excitement
is shown in Fig. 5. _A_ is the record of contractions after the
muscle was surrounded with “quiet” blood serum. _B_ shows the
gradual inhibition which occurred when the muscle was surrounded
with defibrinated blood taken when the animal had been excited
eleven minutes. And _C_ is the record of rapid inhibition after
fifteen minutes of excitement. In other instances the effect was
manifested merely by a lowering of the tonus of the muscle, and a
notable slowing of the beats, without, however, a total abolition
of them.
[Illustration: Figure 5.--The effect of prolonging the
excitement. _A_, the record in “quiet” serum; _B_, in defibrinated
blood after eleven minutes of excitement; and _C_, in serum after
fifteen minutes of excitement.]
The inference that this inhibition of contraction of the intestinal
muscle is due to an increased amount of adrenal secretion in the
“excited” blood de la Paz and I justified on several grounds:
(1) The inhibition was produced by “excited” blood from the inferior
vena cava anterior to the mouths of the adrenal veins, when blood
from the femoral vein, taken at the same time, had no inhibitory
influence. Since blood from the femoral vein is typical of the
cava blood below the entrance of the kidney veins, the conclusion
is warranted that the difference of effect of the two samples of
blood is not due to any agent below the kidneys. But that blood
from the kidneys does not cause the relaxation is shown in Fig. 3.
The only other structures which could alter the blood between the
two points at which it was taken are the adrenal glands, and the
material secreted by them would produce precisely the inhibition
of contraction which was in fact produced.
(2) If in ether anesthesia the blood vessels leading to and from the
adrenal glands are first carefully tied, and then the glands are
removed, excitement four or five hours later, before the weakness
that follows the removal has become prominent, does not alter the
blood so that the typical inhibition occurs (see Fig. 6). Thus,
although the animal shows all the characteristic signs of sympathetic
stimulation, the blood, in the absence of the adrenals, remains
unchanged.
[Illustration: Figure 6.--Failure of the cava blood (added at
_a_) to produce inhibition when excitement has occurred after
removal of the adrenal glands. The muscle later proved sensitive
to adrenin in blood in the ratio 1:1,000,000.]
(3) As already shown, sometimes the effect produced by the “excited”
blood was prompt inhibition, sometimes the inhibition followed only
after several beats, and sometimes a slowing and shortening of
contractions, with a lower tone, were the sole signs of the action
of adrenin. All these degrees of relaxation can be duplicated by
adding to inactive blood varying amounts of adrenin. Fig. 7 shows
the effects, on a somewhat insensitive muscle preparation, of adding
adrenin, 1:1,000,000 (A), 1:2,000,000 (B), and 1:3,000,000 (C), to
different samples of blood previously without inhibitory influence.
These effects of adrenin and the effects produced by blood taken
near the opening of the adrenal veins are strikingly analogous.
[Illustration: Figure 7.--Effect of adding adrenin 1:1,000,000 (A),
1:2,000,000 (B), and 1:3,000,000 (C), to formerly inactive blood.
In each case _a_ marks the moment when the quiet blood was removed,
and _b_, the time when the blood with adrenin was added.]
(4) Embden and v. Furth[43] have reported that 0.1 gram of suprarenin
chloride disappears almost completely in two hours if added to
200 cubic centimeters of defibrinated beef blood, and the mixture
constantly aerated at body temperature. “Excited” blood which
produces inhibition loses that power on standing in the cold for
twenty-four hours, or on being kept warm and agitated with bubbling
oxygen. This change is illustrated in Fig. 8; the power of the
“excited” blood to inhibit the contractions of the intestinal muscle
when record _A_ was written was destroyed after three hours of
exposure to bubbling oxygen, as shown by record _B_. The destruction
of adrenin and the disappearance of the effect which adrenin would
produce are thus closely parallel.
[Illustration: Figure 8.--The effect of bubbling oxygen through
active blood. A, relaxation after active blood applied at _a_; B,
failure of relaxation when the same blood, oxygenated three hours,
was applied to a fresh strip at _b_.]
All these considerations, taken with the proof that sympathetic
impulses increase secretion of the adrenal glands, and taken also
with the evidence that, during such emotional excitement as was
employed in these experiments, signs of sympathetic discharges
appeared throughout the animal from the dilated pupil of the eye to
the standing hairs of the tail-tip, led us to the conclusions that
the characteristic action of adrenin on intestinal muscle was in
fact, in our experiments, due to secretion of the adrenal glands,
and that that secretion is increased in great emotion.
The Evidence that Adrenal Secretion is Increased by
“Painful” Stimulation
As mentioned in the first chapter, stimulation of sensory fibres in
one of the larger nerve trunks is known to result in such nervous
discharges along sympathetic paths as to produce marked inhibition
of digestive processes. Other manifestations of sympathetic
innervations--e. g., contraction of arterioles, dilation of pupils,
erection of hairs--are also demonstrable. And since the adrenal
glands are stimulated to activity by sympathetic impulses, it
was possible that they would be affected as are other structures
supplied with sympathetic fibres, and that they would secrete in
greater abundance when sensory nerves were irritated.
The testing of this possibility was undertaken by Hoskins and
myself in 1911. Since bodily changes from “painful” stimulation can
in large degree be produced in an anesthetized animal, without,
however, an experience of pain by the animal, it was possible to
make the test quite simply. The sensory stimulus was a rapidly
interrupted induced current applied to the sciatic nerve. The current
was increased in strength as time passed, and thus the intensity
of the effect, indicated by continuous dilation of the pupils, was
maintained. There was no doubt that such stimulation would have
caused very severe pain if the animal had not been anesthetized.
Indeed, the stimulus used was probably much stronger than would
be necessary to obtain a positive result in the absence of the
anesthetic (urethane), which markedly lessens the irritability of
visceral nerve fibres.[44] In different instances the stimulation
lasted from three to six minutes. Throughout the period there was
markedly increased rapidity and depth of breathing.
As Fig. 9 shows, the normal blood, removed from the vena cava before
stimulation, caused no inhibition of the beating segment, whereas
that removed afterwards produced a deep relaxation. Hoskins and I
showed that the increased respiration which accompanies “painful”
stimulation does not augment adrenal activity. We concluded,
therefore, that when a sensory trunk is strongly excited the adrenal
glands are reflexly stimulated, and that they pour into the blood
stream an increased amount of adrenin.
[Illustration: Figure 9.--Intestinal muscle beating in normal
vena cava blood, removed at 1 and renewed at 2. At 3 normal blood
removed. At 4 contraction inhibited by vena cava blood drawn
after sensory stimulation; at 5 removed. At 6 Ringer’s solution
substituted.]
Confirmation of Our Results by Other Observers
The foregoing experiments and conclusions were reported in 1911.
In 1912, Elliott[45] brought confirmatory evidence by use of a
method quite different from ours. As previously stated, he studied
the effects of experimental procedures on adrenal secretion by a
careful comparative quantitative assay of the adrenin content of the
glands when one gland was isolated from the central nervous system
and the other left connected. He took advantage of the action of
morphia and of the substance Β-tetrahydronaphthylamine in evoking
in cats all the appearances of great fright. After the animals
had thus been “frightened,” he found that the adrenal gland which
was still connected with the spinal cord was much depleted of its
adrenin content compared with the other, isolated gland. And he
observed, further, that animals newly brought to the laboratory,
and evidently disturbed by the strangeness of their surroundings,
had a considerably smaller amount of adrenin in their glands than
other animals grown accustomed to the situation. Elliott also
observed that prolonged excitation of a sensory nerve, such as the
great sciatic, may cause the adrenin largely to disappear from the
gland still connected with the central nervous system and subjected,
therefore, to reflex influences.
Our conclusions have also been confirmed more recently (1913) by
Hitchings, Sloan and Austin,[46] working in Crile’s laboratory in
Cleveland. They used the same method which we had used to obtain
blood and to test for adrenin, and found that after great fear and
rage had been induced in a cat by the attempt of a muzzled dog to
fight it, the adrenin reaction was clearly demonstrable. And just
as we had noted that the reaction did not occur if the adrenal
glands had been removed, they showed that it did not occur if the
nervous connections with the spinal cord were previously severed.
The logic of all these experiments may be briefly summed up. That
the adrenal glands are subject to splanchnic influence has been
demonstrated anatomically and by the physiological effects of their
secretion after artificial stimulation of the splanchnic nerves.
Impulses are normally sent along these nerves, in the natural
conditions of life, when animals become greatly excited, as in
fear and rage and pain. There is every probability, therefore, that
these glands are stimulated to extra secretion at such times. Both
by an exceedingly delicate biological test (intestinal muscle) and
by an examination of the glands themselves, clear evidence has been
secured that in pain and deep emotion the glands do, in fact, pour
out an excess of adrenin into the circulating blood.
Here, then, is a remarkable group of phenomena--a pair of glands
stimulated to activity in times of strong excitement and by such
nerve impulses as themselves produce at such times profound changes
in the viscera; and a secretion given forth into the blood stream
by these glands, which is capable of inducing by itself, or of
augmenting, the nervous influences which induce the very changes in
the viscera which accompany suffering and the major emotions. What
may be the significance of these changes, occurring when conditions
of pain and great excitement--experiences common to animals of
most diverse types and probably known to their ancestors for ages
past--lay hold of the bodily functions and determine the instinctive
responses?
Certain remarkable effects of injecting adrenin into the blood have
for many years been more or less well recognized. For example, when
injected it causes liberation of sugar from the liver into the
blood stream. It relaxes the smooth muscle of the bronchioles. Some
old experiments indicated that it acts as an antidote for muscular
fatigue. It alters the distribution of the blood in the body, driving
it from the abdominal viscera into the heart, lungs, central nervous
system and limbs. And there was some evidence that it renders more
rapid the coagulation of the blood. There may be other activities
of adrenin not yet discovered--it may coöperate with the products
of other glands of internal secretion. And other glands of internal
secretion may be stimulated by sympathetic impulses. But we were
not concerned with these possibilities. We wished to know whether
the adrenin poured out in pain and emotional excitement produced
or helped to produce the same effects that follow the injection of
adrenin. Our later researches were concerned with answers to this
question.
REFERENCES
[Footnote 43: Embden and v. Furth: Hofmeister’s Beiträge zur
chemischen Physiologie und Pathologie, 1904, iv, p. 423.]
[Footnote 44: Elliott: Journal of Physiology, 1905, xxxii, p. 448.]
[Footnote 45: Elliott: Journal of Physiology, 1912, xliv, p. 409.]
[Footnote 46: Hitchings, Sloan and Austin: Cleveland Medical Journal,
1913, xii, p. 686; see also Crile and Lower: Anoci-association,
Philadelphia, 1914, p. 56.]