THE EMERGENCY FUNCTION OF THE ADRENAL MEDULLA IN PAIN AND THE MAJOR EMOTIONS The aim of this composition

is to discuss W.B. Cannons paper The emergency of the adrenal medulla in pain and the mayor emotions, which he wrote in 1914. In the paper, as the title mentions, Dr. Cannon checks and studies the role of the adrenals- which are secretory glands- in the response to pain, asphyxia, and emotional excitement; in other words, the changes that its secretions produce in the body in order to face up to these stressing situations. In addition to this, it is interesting to say that, in spite of the fact that he wrote the paper in the early 20thcentury, his resolutions and conclusions are valid today. In fact, his works serve as a point of reference to all people who want to know about how our body operates under different physiological conditions. After this short introduction, I will start the discussion proper, in which I will express my opinion and go deeply, including extra information, into those subjects I find more relevant and appropriate. I will also use different fragments of the text as supports of my comments. First and foremost, I would like to remark that the adrenals are endosecretary glands, located just above the kidneys, which are divided into 2 portions, one internal and the other external: the adrenal medulla and the adrenal cortex, respectively. I will focus on the first. The adrenal medulla contains specific cells that have not got the typical structure of a neuron, but which are deeply relationed with sympathetic pathways. In fact, these cells, which are called Chromaffin cells, respond to stimulation by preganglionic sympathetic nerves, which secrete acetylcholine. Nevertheless, Chromaffin cells lack axons and they release adrenalin (or epinephrine) and norepinephrine into the blood, which serve as hormones. In the paper, Dr. Walter Cannon explains: Artificial stimulation of the splanchnic nerves will induce secretory activity in the adrenal medulla, and in consequence adrenalin is increased in the blood. As Dr. Cannon points out, the splanchnic nerves are the paired nerves which make the adrenal medulla discharge their products, as they carry sympathetic fibers. Therefore, we can assume that the adrenals are stimulated by nerve impulses and are submitted to the control of the Nervous System. As we said above, adrenalin is released at times of great emergency, such us asphyxia, pain and great emotions. But, what is its purpose? The role of adrenalin is to facilitate the ability of the animal to cope with various stresses, including an acute stress. The typical acute stress situation, which gave adrenalin the name the hormone of fight or flight, is the encounter of predator and prey. This extreme situation can be simulated experimentally: We found that when a cat was frightened by a barking dog the blood in the cats vena cava close in front of the opening of the adrenal veins gave definite evidence of the presence of adrenalin The pain led the adrenal medulla of the cat to secrete adrenalin, which was detected in the vena cava. The suprarenal veins received blood from the adrenal glands and the right one, 1

in other words, the right suprarenal vein, drains into the inferior vena cava. Therefore, the outpouring of adrenalin can be easily detected in this vessel.

Having said that, I will go on to explain the mechanism of action of the adrenalin. Furthermore, I will present the effects it produces in the body. Once into the blood, the adrenalin (or epinephrine) and norepinephrine act via the same series of adrenergic receptors, although their relative effectiveness on the various receptors is not the same. All receptors are of the G-protein-coupled receptor (GPCR) type, which cross the plasma membrane seven times. Consequently, it possible to state that adrenalin carries out its functions trough its receptors. Otherwise, the cells could not understand the hormonal sign and could not respond to it. But, what are the changes adrenalin produce at the cell level? Dr. Cannon, his colleagues and other investigators discovered that the levels of sugar in blood go up at moments of fear, rage, asphyxia, pain, etc. The increase in sugar leads to what is called hyperglycaemia due to adrenalin. Nowadays, it is known that in the liver, adrenalin activates 2 receptors, thus increasing cyclic AMP production. The increase in the AMP levels activates protein kinase A (PKA). Then, PKA phosphorylates, and thus activates, phosphorylase kinase, which, as a result of its activation, phosphorylates glycogen phosphorylase, the enzyme which breaks down glycogen. After that, the liver releases glucose to the blood, increasing the levels of it in the bloodstream. The hyperglycaemia can lead to glycosuria which is the excretion of glucose into the urine. Nevertheless, the hyperglycaemia due to adrenalin does not appear if the adrenals are removed: In our studies we observed that animals which had glycosuria when bound for about an hour, failed to have it after careful adrenalectomy, although bound between two and three times as long as before, and although still manifesting the same degree of excitement which they had manifested previous to the operation. This result harmonizes with that already reported that the presence of the adrenals is necessary when hyperglycaemia is to be produced by splanchnic stimulation.

Logically, if the adrenals are removed, and after the great excitement cause in the animal (the animal was bound), the nerve impulses via splanchnic pathways cannot stimulate the chromaffin cells of these glands. As a result, adrenalin is not liberated to the blood and cannot break down the glycogen of the liver. Having reached to this point, it is convenient to say that the body reactions to great excitement caused by pain, fear or other great emotions are reflex responses. These reflex responses, which are not willed movements, have been developed and fit to each species through the course of evolution in order to favor the survival of the organism when they are exposed to extreme situations. For example, dogs uncover their teeth to show their opponents they are prepared to fight if necessary. In the text, these are the relations between several great emotions and reflex actions or instincts: 2

The emotion of fear is associated with the instinct for flight, and the emotion of anger or rage with the instinct for fighting or attack. Many of these useful reflex responses are possible thanks to the increase of adrenalin in the blood and the subsequent hyperglycaemia. Now, I will explain why the hyperglucaemia due to adrenalinaemia is important in moments of great excitement: Several of the great emotions, such as fear or anger, are likely to be followed by activities in which animals need to exert an intensive physical effort and to be capable of quick reactions. Among these activities, some of the most important are running and fighting, so the muscles have to be prepared to exert a great effort. In this sense, the muscles need to be supplied with a large quantity of sugar and adrenalin serves this necessary purpose. Apart from breaking down the glycogen stores of the liver (already discussed), adrenalin can also stimulate the breakdown of glycogen stores in the skeletal muscle and inhibit glycogen synthesis. The ultimate product of glycogen breakdown is glucose-6-phosphate (G-6-P). Since skeletal muscle (unlike the liver) does not express glucose-6-phosphatase, free glucose is not exported to the blood, but can be utilized by the muscle itself. According to Chauveau and Kaufmann, an active muscle uses sugar three and a half times as much as resting muscles. Many experiments confirm that active muscles use the energy stored in form of glycogen; when their own stores disappear, they are capable of lessening the quantity of circulating sugar in a greater or less degree, depending on the intensity of the exercise. These are some of them: When blood or Ringers solution 1 is repeatedly perfused through contracting heart muscle, the evidence is clear that the contained sugar may more or less completely disappear. Locke perfused a contracting heart of a rabbit with Ringers solution and he saw how the dextrose of the fluid was disappearing steadily. Schumberg [...] tested flexion of the middle finger in an ergograph2 [] the ability of the muscle was greater if he drank a sugar solution than if he drank an equally sweet solution of dulcin.

The experiment of Schumberg confirms that muscles use glucose as source of energy. Moreover, the efficiency of the muscular labor increases if the muscle is abundantly supplied with this carbohydrate. After all these examples, it has been clearly shown that a central role of adrenalin is to increase the availability of metabolites for the intensive physical activity involved in the acute stress situations.
1

Ringers solution: It is a solution used in physiological experiments with contains sodium, potassium, calcium, chloride and lactate. There are some variants; Lockes solutions or Ringer -Locke solution contains more glucose, and is particularly used for mammals. The solution is suitable to keep a heart beating outside the body. 2 Ergograph: A device for measuring the work capacity of a muscle or group of muscles during contraction.

Apart from helping to mobilize the metabolites, adrenalin also seems to favor the muscle labor in extreme situations by restoring the excitability of a fatigued muscular fiber. Numerous experiments show how injections of small doses of adrenalin lead to restore the threshold of stimulation of fatigued fibers. Consequently, the muscular fiber can response to a new stimulus as if it was completely fresh. Several experiments carried out by Wilenko led him to state that adrenalin, instead of increasing the capacity of using sugar by the muscular tissue, lessened this property of the tissue. He injected adrenalin into urethanized rabbits, usually I mgm. per kilo body weight, and then found that the animals did not oxidize any part of an intravenous injection of glucose. He also observed high levels of adrenalin glycosuria and concluded that adrenalin had altered the consumption of sugar by the different organs. However, Wilenko was wrong, at least, when talking about physiological conditions: Wilenko injected in his experiments much more adrenalin than that the one released after splanchnic stimulation. The excess of adrenalin led to glycosuria. Therefore, the physiological discharges, and the hyperglycemia subsequent, have positive benefits for the body. Regarding the effects adrenalin produce in the body at times of pain and other great emotions, we go on to talk about the changes this hormone produces in the cardiovascular system. The adrenalin contracts blood vessels which have -adrenergic receptors in their smooth muscle, for example in skin, kidney, and some other abdominal organs. This is what Oliver and Schfer proved in their experiment: The spleen, the kidneys and the intestines suffer a considerable diminution of volume when adrenalin is administered. Nevertheless, in the vessels of the heart, adrenalin has a vasodilator effect. In fact, intensive physical effort benefits from an increase in the volume of blood delivered by the heart per unit time, leading to more effective supply of oxygen and fuel metabolites. Adrenalin also increases the heart rate (number of beats per minute) and the contractile force of the heart muscle, thus increasing the cardiac output per heart beat. Both effects of adrenalin on the heart are mediated by 1 adrenergic receptors. Therefore, adrenalin causes a significant redistribution of blood flow, with preference given to organs (the tripod of life: the heart, the lungs and brain- we can include the skeletal muscles) directly involved in the response to the acute stress. Conclusion: In conclusion, adrenalin produces in the body a great number of changes which favor the survival of the organism in extreme situations, such as pain, fear or rage. Mainly, these changes are the mobilization of sugar from the liver to the bloodstream, the redistribution of

the blood flow from the less important organs to the Tripod of life, the quick restoring of the excitability of the skeletal muscle fibers and the increase of the heart rate.