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SCIENCE 



[N. S. Vol. XXXVII. No. 959 



solution, and also its permeability-increasing 

 action as indicated by loss of pigment. A 

 corresponding anti-cytolytic or anti-toxic ac- 

 tion is invariably found to be associated with 

 these effects. 



The following anesthetics have been used in 

 these experiments: alcohols: methyl, ethyl, n- 

 propyl, isopropyl, n-butyl, n-amyl, n-capryl; 

 esters: ethyl acetate, propionate, butyrate, 

 valerianate, nitrate; ureihanes: methyl, ethyl, 

 phenyl ; chloroform, carbon tetrachloride, nitro- 

 methane, acetonitrile, benzol, toluol, xylol, 

 phenanthrene, naphthalene; ethyl ether, 

 ehloretone, chloral hydrate, chloralose, paral- 

 dehyde, phenyl urea, acetanilide, phenacetin, 

 methacetin. 



Almost all of these substances have also been 

 used by Overton in his investigations of an- 

 esthesia in tadpoles. In the case of Arenicola 

 larvse the concentrations requisite for neuro- 

 muscular anesthesia are in all cases higher 

 (usually from three to five times higher) than 

 for the neuromuscular system of Vertebrata. 

 Otherwise the relations observed in these ex- 

 periments are closely similar to those found by 

 Overton and other experimenters in this field. 

 For homologous series (alcohols, esters) the 

 anesthetic action increases regularly with the 

 molecular weight — i. e., with the lipoid-water 

 partition coefficient. The anti-cytolytic or 

 protective action always runs closely parallel 

 with the anti-stimulating action. A well- 

 marked protective efPect is however often seen 

 in concentrations which are insufficient for 

 complete anesthesia. 



The general fact that the anesthetic hinders 

 or prevents increase of permeability indicates 

 that the seat of its essential action is in the 

 plasma-membranes of the irritable tissue. 

 The characteristic permeability of the plasma- 

 membranes of cells to lipoid-soluble sub- 

 stances furnishes strong evidence that these 

 membranes consist largely of lipoid mater- 

 ial. The lipoid-solvents alter the membrane 

 by changing the state of its lipoid com- 

 ponents ; other substances may produce similar 

 effects by changing the state of the other col- 

 loids of the membrane. In general these ob- 



servations show that anesthesia is associated 

 with an increase in the resistance of the mem- 

 brane to the permeability-increasing action of 

 the stimulating agency. I infer, therefore, 

 that the essential condition of anesthetic action 

 is a modification of the physical properties of 

 the plasma membranes of the irritable ele- 

 ments, of such a kind that the membranes fail 

 to undergo, under the usual conditions of 

 stimulation, the increase of permeability es- 

 sential to this process. This modification may 

 be caused by lipoid-solvents, salts or other 

 substances; also by altering the electrical 

 polarization of the membrane by an external 

 electric current, as in anelectrotonus. Ap- 

 parently any condition that renders the mem- 

 brane incapable of rapid and reversible 

 changes of permeability renders the tissue re- 

 fractory to stimulation. On this view the 

 parallelism between the antistimulating and 

 anti-cytolytic actions becomes intelligible, 

 since increased permeability is the condition 

 of cytolysis as well as of stimulation. Sub- 

 stances or conditions that prevent the one ef- 

 fect will also prevent the other. 



These observations have a direct bearing on 

 the general theory of stimulation. They sup- 

 port the view that an essential feature of the 

 stimulation-process is a well-marked increase 

 in the permeability of the limiting membranes 

 of the irritable elements. It is obvious that 

 the problem of the nature of anesthetic action 

 involves the problem of the nature of the stim- 

 ulation-process, and study of the action of an- 

 esthetics thus forms one means of attacking 

 this wider problem. Any constant physical 

 modifications caused in the irritable elements 

 by the anesthetic, coincidently with the loss of 

 irritability, must furnish indications of the 

 nature of the processes concerned in the re- 

 sponse to stimulation. The above observations 

 thus agree with those of Nernst and his suc- 

 cessors, which localize the primary or critical 

 process in stimulation at the semi-permeable 

 membranes of the irritable elements. They 

 indicate further that in stimulation the per- 

 meability of these membranes is increased. 

 But changes of permeability must involve 



