Mechanism of local anesthetic action of crystalline tetrodotoxin and its derivatives

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The local anesthetic activity of tetrodotoxin and its derivatives was tested on the guinea-pig's skin, on the desheathed crayfish abdominal nerve fiber preparation and on the cornea of rabbits and guinea-pigs. The crayfish nerve fibers were far more sensitive to the anesthetic action of tetrodotoxin than the other preparations. In the crayfish, 3 × 10 −8 μM tetrodotoxin produced conduction block of the nerve in 15 min. This is the smallest active concentration of the toxin which has been found so far as we know. In experiments on conduction block in the same preparation, tetrodotoxin in alkaline solution was more effective in the sheathed preparation, and in neutral solution was more effective in the desheathed preparation. It is suggested that the cationic form, due to the guanidyl group, is the active form of tetrodotoxin and that tetrodotoxin penetrates nervous tissues more rapidly in its uncharged than in its charged form. When a tetrodotoxin solution was heated at alkaline pH, its activity decreased remarkably, but the same treatment at acidic pH caused no fall in activity. The activity was not influenced by the presence of glucose, polysaccharides, taurine, or serum albumin in solution. All the tetrodotoxin derivatives examined had local anesthetic action, but their activities were lower than that of tetrodotoxin. Among the derivatives, desoxytetrodotoxin had high activity, and tetrodonic acid low activity. With the exception of diacetylanhydrotetrodotoxin and tetrodonic acid, the derivatives were more active than the reference drugs procaine and dibucaine. Their degree of activity was parallelled by their toxicity. The mechanism of binding of tetrodotoxin to the nerve receptor is discussed in the light of a theoretical electron analysis.