The mode of action of local anesthetics on nerve axons: A diffusion-reaction process

The mode of action of tertiary-amine local anesthetics on nerve axon activity was investigated. The axons were those from lobster (Homerus americanus) and squid (Loligo paelii). Anesthetics used were benzocaine, procaine, lidocaine, tetracaine and permanently-charged quaternary amine local anesthetic QX-314. The action potential and its time derivative were measured by the standard electrophysiological method, and a degree of anesthesia was determined as a reduction of the time derivative of the action potential to a certain degree. Using the model we developed for diffusion of local anesthetics into the axon and binding of the local anesthetics to the membrane receptor site, the permeability of uncharged form of local anesthetics and the binding constants of both positive charged and neutral forms were obtained. For squid axon at pH_o, the permeability of the neutral form of procaine was 11 × 10−4 cm/sec and the binding constants of the positively charged and neutral forms of procaine were 293 M−1 and 166 M−1, respectively. For tetracaine, the respective values were 1.8 × 10−4 cm/sec, 3800 M−1 and 994 M−1. Comparable values were obtained for the case of lobster. The permanently charged local anesthetic, QX314, did not affect the axon activity extracellularly and supposedly did not permeate across the membrane. From these experimental results, the mode of action of local anesthetics is proposed as follows: when a tertiary amine local anesthetic is applied extracellularly, only the neutral form penetrates through the axon membrane and both positive charged and neutral forms act intracellularly. Therefore, the mode of action depends upon the pH values of intracellular and extracellular compartments, pK_a of anesthetics, and the binding affinities of local anesthetics to the action sites of ionic channels. It was found that the charged form blocks up to 30 to 60 times more ion channels than the neutral form, although the neutral form also plays a definite role in contributing to the overall action but in a minor degree. The proposed mode of action has its originality in analyzing quantitatively the dual modes (both charged and neutral forms) of action of tertiary-amine anesthetics on nerve axon excitability.