This section is from the book "A Text-Book Of Pharmacology, Therapeutics And Materia Medica", by T. Lauder Brunton. Also available from Amazon: A text-book of pharmacology, therapeutics and materia medica.
The reflex action of the cord is greatly increased by certain drugs, more especially by ammonia and by strychnine. The action of strychnine was first investigated by Magendie, and his research is not only the first example of the systematic investigation of the physiological action of a drug leading to its therapeutical employment, but is such a model of this method of research that it is worth giving in detail.
He first introduced a little of the upas poison, of which strychnine was the essential ingredient, under the skin of the thigh of a dog, and found that for the first three minutes no symptoms at all were produced. Then the action of the poison began to manifest itself by general malaise, succeeded by marked symptoms. The animal took shelter in a corner of the laboratory; and almost immediately afterwards convulsive contraction of all the muscles of the body occurred, the fore-feet quitting the ground for a moment on account of the sudden extension of the spine. This contraction was only momentary, and almost immediately afterwards ceased; the animal remained calm for several seconds, and was then seized with a second convulsion, more marked and prolonged than the first. These convulsions succeeded each other at short intervals, gradually becoming more severe. The respiration was hurried, the pulse quick, and it was observed that each time the animal was touched a convulsion immediately followed. Finally, death occurred at an interval increasing with the age and strength of the animal.
These symptoms suggested to Magendie the following explanation of the action of the poison.
It was, he thought, absorbed from the wound into the blood, by which it was carried to the heart, and thence to all the organs of the body. On arriving at the spinal cord, it acted upon it as a violent excitant, producing the same symptoms as mechanical irritation or the application of electricity. Magendie was not content until he had tested his theory by experiment. The first question to be settled was whether the poison was absorbed or not.
To test this supposition he applied the poison first to the serous membranes, the peritoneum and pleura, from which, as he had learned by previous experience, absorption takes place with extreme rapidity. The result showed that his supposition was correct. The symptoms appeared almost immediately after the injection of the poison into the pleura, and within twenty seconds after it had been injected into the peritoneum. In order to ascertain whether absorption took place from mucous as well as from serous surfaces, he isolated a loop of small intestine by means of two ligatures, and injected a little of the poison into the part between them. In six minutes, symptoms of poisoning appeared, showing that absorption had occurred, but they were less intense than when the poison was applied to the serous surface.
Further experiments showed that absorption took place from the large intestine, from the bladder, and from the vagina; but that it was comparatively feeble and slow. When introduced into the stomach along with food, upas invariably caused death; but the symptoms did not appear until half an hour after it had been taken. This delay might have been due either to absorption from the stomach having taken place very slowly or not at all, so that the drug had passed on to the small intestine, and thence been absorbed into the blood. To determine this point, he isolated the stomach by ligatures applied to its cardiac and pyloric orifices, and then injected a little poison into its cavity.
Under such conditions, symptoms of poisoning were only observed after the lapse of an hour. This showed that while absorption from the stomach did occur, it was much slower than from the small intestine.
The second question was, Does the poison act through the circulation? If so, reasoned Magendie, the first symptoms of the action of the poison will come on more slowly when it has far to travel to the spinal cord from the point of introduction, and vice versa. On testing this by experiment, he found that when the poison was injected into the jugular vein, tetanus occurred almost instantaneously, and death took place in less than three minutes, for the upas had only to pass through the pulmonary circulation and heart to the arteries of the cord. When injected into the femoral artery (at D, Fig. 66) the distance to be travelled before reaching the cord would be greatly increased, for the poison must first pass through the artery itself, through the capillaries, and along the vena cava, traversing the whole distance marked D A B in Fig. 66 before it reached the point where it entered the circulation when it was injected into the jugular. Under these conditions the action should be slow, and experiment showed this to be actually the case, for no symptoms appeared until seven minutes after the injection. Although these experiments of Magendie's appear to prove completely that the upas poison acts through the circulation, a number of persons nevertheless considered that the symptoms were produced through the nervous system by means of so-called sympathy. In order to remove their doubts, Magendie narcotised a dog by means of opium, and then divided all the structures of one leg with the exception of the artery and vein. Into this almost isolated limb he then introduced a little of the poison. This was followed by the usual symptoms almost exactly as if the limb had been intact. By pressing upon the vein which passed from the limb to the body when the symptoms of tetanus appeared he was able to arrest their further development, and by releasing the vessel and allowing the circulation to have free course the symptoms reappeared. Lest by any chance the poison might have acted through nerves or lymphatics contained in the walls of the artery and vein, he divided these structures also, connecting their several ends by means of quills through which circulation then took place. When the poison was applied to the severed limb connected with the body only by these quills, the same succession of phenomena occurred as when the limb was uninjured. The possibility of the action being due to sympathy between the nervous system and the point of application of the poison was thus completely excluded, and the operation of the poison through the circulation triumphantly demonstrated.