Irritability: A Physiological Analysis of the General Effect of Stimuli in Living Substance

by Max Verworn

Fig. 63.

Rhizoplasma Kaiseri. Effect of chloroform.

In the face of all this evidence there can be indeed no further barrier to the assumption that the symptoms in narcosis are a result of a suppression of the oxydative processes. Nevertheless, I would not at present venture to maintain that the entrance of the narcotic into living substance produces no alterations whatever, except just this oxydative suppression. For the present it seems to me that the possibility is in no way precluded that the same process, which is expressed in the oxydative suppression, is connected with other alterations in the living substance, of which we are as yet ignorant. As far as the effects of larger doses of narcotics are concerned, the assumption that other alterations take place in the living substance can in any case hardly be avoided. An application of larger quantities of narcotics brings about destruction of the living system with great rapidity. Here the alterations in the optical properties of the cell are of such magnitude that the changes are directly perceptible under the microscope. Binz[222] has observed such alterations in the nerve cell and looked upon them as coagulation. In unicellular organisms these optical alterations can readily be followed. If amœbæ, sea rhizopods or infusoria are narcotized with stronger doses of ether or chloroform, the protoplasm becomes opaque and granulated, it appears darker than formerly and in many cases displays a yellowish brown color in transmitted light. Cells altered in this way no longer recover after removal of the narcotic. These intense and rapidly appearing alterations of protoplasm resulting from the application of stronger doses of the narcotic can scarcely be explained as simply the result of a mere decrease of the oxydative processes. They would seem to consist rather, as suggested by Binz, as coagulation, in an alteration of the state of certain components of living substance. Whether these alterations are already present in a correspondingly slight amount in those degrees of narcosis after which complete recovery can take place and further whether in this case they are in any way concerned in bringing about the individual symptoms of the former, are questions the decision of which must be left to future investigations. Höber[223] indeed makes such an alteration of the colloidal state of the lipoid the basis of a theory of narcosis. But such assumptions are scarcely more than speculations. This is one of the points in which our present knowledge is lacking.

Even if we restrict ourselves to the actually established alterations produced by the narcotic in living substance, new problems present themselves, the investigation of which requires further effort. Above all, the question arises as to the finer mechanism of oxydative depression. In what manner does the narcotic molecule, entering into the living substance, suppress the oxydative processes? Here there are very different possibilities to be taken into consideration and up to the present in our investigations of a suppression of the oxydative processes resulting from narcosis, we have stood on the firm ground of assured facts. However, the discussion of the nature of this suppression leads us into the domain of hypothesis. But without hypothesis there can be no progress in knowledge. In all branches of scientific research, working hypotheses are required for the obtainment of new facts.

On closer reflection, there are chiefly three possibilities, which, considered from the standpoint of our present knowledge of the processes in living substance, offer an explanation of the oxydative suppression as a result of narcosis.

One of these possibilities is, that the narcotic itself consumes the oxygen which activates living substance and uses it for its individual oxydation, so that the specific oxydable material of living substance receives less oxygen from the oxygen carriers. Based on a series of interesting experiments this view has been recently maintained by Bürker.[224] He observed that with the electrolysis of acidulated water, to which a small per cent. of ether was added, a much less amount of oxygen was at the anode than in one used as means of control, containing acidulated water without ether. The oxygen was replaced at the anode by oxydation products of the ether, such as carbonic oxide, carbon dioxide, acetate aldehyde and acetic acid. In experiments with various narcotics he likewise found that the stronger the effect produced by narcosis, the greater the oxygen amount required for the oxydation taking place of electrolysis. Bürker applies these results obtained for electrolysis to the processes in living substance and takes the view that the narcotic seizes on the active oxygen, and so withdraws it from the masses of living substance possessing a great oxygen requirement. It cannot be denied that this conception of the nature of certain narcotics deserves careful investigation. It seems to me, however, that before considering it in the light of a serious probability a grave difficulty would first have to be removed. In living substance the narcotic would occur under conditions essentially different from those existing during the experiment in the voltameter. In the former case there would be the struggle for oxygen of the specific oxydable cell masses to be met with. Considering the small amount of chemical activity of the greater number of narcotics it would appear at least doubtful if in this battle for supremacy the latter would achieve a victory. For some narcotics, as, for instance, carbon dioxide, this method of a depression of the oxydative processes would have no bearing whatever. This is rather to be looked for in the effects of oxydative suppression of the aldehydes, which Warburg[225] has recently observed and investigated. Here, however, it is not a true narcosis which is concerned.

A second possibility of a suppression of oxydation would be the fixation of the molecules of the oxydable substances by chemical or physical combinations in that they would lose their capability of oxydative disintegration. Such a supposition would, however, likewise contain but few elements of probability. As has been shown, an anoxydative breaking down continues during narcosis, which, and this we may assume with certainty, furnishes very different products in great variety. These anoxydative disintegration products, as recovery on the cessation of narcosis shows, are removed during recovery by oxydation. If the effect of the narcotic consisted in the prevention in spite of the presence of oxygen of the oxydation by combination, it would be necessary to assume that the narcotic was bound to a mass of completely heterogeneous substances, a conclusion we should find difficult to entertain.

If, however, depression of the oxydative processes is founded neither on the seizure of oxygen by the narcotic nor the fixation of oxydable substances by the former, there remains the possibility that the narcotic suppresses the transmission of oxygen to these points of consumption. We assume that the oxygen transmission to those points where its consumption takes place is carried out by special substances, the existence of which has been established in the most varied vegetable and animal cell forms. Unfortunately we only know these oxygen-carrying substances by their effects. Of their chemical constitution we have no knowledge, but we usually assume that the transmission of oxygen occurs in the same manner as in catalytic processes. On another occasion I have previously expressed the suggestion,[226] that the narcotic suppresses oxydation by producing incapability of the groups acting as oxygen carriers to carry out this function. If we assume that the substances possessing the character of oxygen carriers, which activate the molecular oxygen and so render it capable of attacking the oxydable substances, lose this capability under the influence of narcotics, this supposition would not only make all of the facts of suppression of oxygen exchange in narcosis comprehensible, considered from one point, but likewise, as careful investigation has shown, be in complete harmony with all knowledge obtained up to the present of the process of narcosis.

Here is the point where the interesting observations of Hans Meyers[227] and Overton[228] on the relations of the depressing influence of narcotics to their solubility of fat and water may be connected with the facts of the suppression of oxydation. Meyer and Overton have quite independently of each other made the same observation, that the depressing effect of a narcotic is the greater, the larger the coefficient of distribution between substances of a fatty nature and water. Those narcotics produce the strongest effects which are readily soluble in substances of a fatty nature, but not easily so in water, that is, in which the coefficient distribution between fat and water is very great. This law, which has been demonstrated by Meyer and Overton for a large number of narcotic processes, is in itself not a theory of narcosis, as has been often erroneously assumed. It shows us, however, an important condition, which must be considered in every theory of narcosis. It demonstrates that it is the ease with which transmission in the lipoid occurs which allows a substance to develop narcotic effects. These facts would seem to indicate that the lipoids of the cell are connected in some way or other with the exchange of oxygen. If we assume that the oxygen carriers, the chemical constitution of which is so far not known, bear the character of lipoids and belong, say, to the generally extended group of phosphatides, there results at once an apparent connection of the law established by Meyer and Overton with the nature of narcosis.