Molecular mechanisms of nerve block by local anesthetics.
Local anesthetics block nerve conduction by preventing the increase in membrane permeability to sodium ions that normally leads to a nerve impulse. Among anesthetics containing tertiary amine groups, the cationic, protonated form appears to be more active than the neutral form. However, the neutral forms, as well as uncharged molecules like benzocaine and the aliphatic alcohols, also depress sodium permeability. Studies of single myelinated nerves and squid axons show no direct interaction between calcium ions and local anesthetics, thus disproving theories based on competition between these two agents. Likewise, hypotheses attributing local anesthesia to changes in electrical potentials at the membrane-water interface are disproven by the demonstrated potencies of electrically uncharged anesthetics. Hypotheses that propose that local anesthetics act by expanding the nerve membrane and causing a change in protein conformation that blocks sodium permeability are vague in conception and difficult to test experimentally. Evidence from voltage-clamp studies of single nerve fibers indicates that anesthetic molecules interact with the sodium channels directly, from the inner side of the nerve membrane. Anesthetics bind within sodium channels which have opened during membrane depolarization, preventing the normal sodium ion flux. Anesthetic molecules can dissociate from open channels, but not from channels that remain closed when the nerve is kept at rest. The "gating" properties that regulate the opening and closing of sodium channels are reversibly modified during anesthesia. Specifically, the inactivation function responds more slowly and requires more negative membrane potential changes to reach the same values as in unanesthetized nerves. A second, slow inactivation is observed following external application of tertiary amine anesthetics. The selective binding of anesthetics to open sodium channels provides a simple explanation for Wedenski inhibition, in which the block increases with the frequency of nerve impulses. When impulses occur at higher frequencies more sodium channels are open over a period of time comparable to the time necessary for the anesthetic binding reaction, thus more channels are blocked. In addition the changes of the inactivation function result in a longer refractory period and, thus, a decrease of impulse height at higher frequencies. Charged anesthetic molecules may bind in the pore of the sodium channel. Their binding can be modulated by the electrical field in the membrane. The channel has a higher affinity for larger anesthetic molecules, but this may result from their greater hydrophobicity as well as from their size. The binding site favors molecules that contain more polar linkages between the amine group and the aromatic residue. Binding of amine anesthetics is weakly stereospecific and, surprisingly, shows no absolute requirement for the terminal alkyl ammonium moiety present in most local anesthetics...
Molecular mechanisms of nerve block by local anesthetics. Local anesthetics block nerve conduction by preventing the increase in membrane permeability to sodium ions that normally leads to a nerve impulse. Among anesthetics containing tertiary amine groups, the cationic, protonated form appears to be more active than the neutral form. However, the neutral forms, as well as uncharged molecules like benzocaine and the aliphatic alcohols, also depress sodium permeability. Studies of single myelinated nerves and squid axons show no direct interaction between calcium ions and local anesthetics, thus disproving theories based on competition between these two agents. Likewise, hypotheses attributing local anesthesia to changes in electrical potentials at the membrane-water interface are disproven by the demonstrated potencies of electrically uncharged anesthetics. Hypotheses that propose that local anesthetics act by expanding the nerve membrane and causing a change in protein conformation that blocks sodium permeability are vague in conception and difficult to test experimentally. Evidence from voltage-clamp studies of single nerve fibers indicates that anesthetic molecules interact with the sodium channels directly, from the inner side of the nerve membrane. Anesthetics bind within sodium channels which have opened during membrane depolarization, preventing the normal sodium ion flux. Anesthetic molecules can dissociate from open channels, but not from channels that remain closed when the nerve is kept at rest. The "gating" properties that regulate the opening and closing of sodium channels are reversibly modified during anesthesia. Specifically, the inactivation function responds more slowly and requires more negative membrane potential changes to reach the same values as in unanesthetized nerves. A second, slow inactivation is observed following external application of tertiary amine anesthetics. The selective binding of anesthetics to open sodium channels provides a simple explanation for Wedenski inhibition, in which the block increases with the frequency of nerve impulses. When impulses occur at higher frequencies more sodium channels are open over a period of time comparable to the time necessary for the anesthetic binding reaction, thus more channels are blocked. In addition the changes of the inactivation function result in a longer refractory period and, thus, a decrease of impulse height at higher frequencies. Charged anesthetic molecules may bind in the pore of the sodium channel. Their binding can be modulated by the electrical field in the membrane. The channel has a higher affinity for larger anesthetic molecules, but this may result from their greater hydrophobicity as well as from their size. The binding site favors molecules that contain more polar linkages between the amine group and the aromatic residue. Binding of amine anesthetics is weakly stereospecific and, surprisingly, shows no absolute requirement for the terminal alkyl ammonium moiety present in most local anesthetics...