Two more current theories help explain where and how local anesthetics work: the membrane expansion theory and the specific receptor theory. Of these two, the specific receptor theory is more widely accepted today.
Membrane Expansion Theory
The membrane expansion theory suggests that local anesthetic molecules penetrate and diffuse into the lipid regions of the nerve membrane, disrupting its structure. This disruption results in the expansion of certain critical areas of the membrane, which in turn affects the permeability of sodium ions, preventing nerve impulses from propagating. Local anesthetics that are highly lipid-soluble can easily enter the hydrophobic regions of the nerve membrane, causing the membrane to change shape, which results in a narrowing of sodium channels. This inhibits the flow of sodium ions into the neuron, effectively blocking the generation of an action potential and preventing the nerve from transmitting pain signals.
This theory also accounts for the effectiveness of anesthetics such as benzocaine, which does not exist in a charged form (and therefore cannot act via conventional mechanisms). Benzocaine's potency as a topical anesthetic is explained by its ability to dissolve into the lipid bilayer of the nerve membrane and disturb its structure, supporting the membrane expansion theory. However, while this theory explains certain aspects of local anesthetic activity, there is no direct evidence to suggest that nerve conduction is blocked entirely by membrane expansion alone.
Specific Receptor Theory
The specific receptor theory is currently the most widely accepted explanation for where and how local anesthetics work. This theory suggests that local anesthetics bind to specific receptors located within the sodium channels of nerve membranes. The action of these drugs is direct, as they physically block the sodium channels from within, thereby preventing the influx of sodium ions required for the initiation and propagation of nerve impulses. This theory emphasizes that the anesthetic does not simply alter the membrane’s overall properties but interacts with specific sites on the sodium channels.
Biochemical and electrophysiologic research has confirmed that there are specific binding sites for local anesthetics within sodium channels, located either on the external surface of the channel or the internal axoplasmic surface. Once the local anesthetic binds to these receptors, the permeability of the channel to sodium ions is reduced or completely blocked, halting the nerve’s ability to conduct signals. Without the influx of sodium, the nerve cell cannot generate the action potential needed to send pain signals to the brain, effectively inducing anesthesia.
