SUMMARY

We remain uncertain about the site of anesthetic action at the macroscopic, microscopic, and molecular levels ( Table 4-3 ). We do know that inhaled anesthetics disrupt neuronal transmission in many areas of the CNS. They

TABLE 4-3 -- Possible sites of anesthetic action

Anatomic Level	Site of Action	Comments
Macroscopic	Central nervous system (CNS)
	Brain vs. spinal cord	Anesthetics disrupt transmission throughout the CNS; decerebration does not alter the minimum alveolar concentration (MAC).
Microscopic	Axons vs. synapses	Higher concentrations of inhaled anesthetic are typically required to disrupt axonal than synaptic transmission.
	Excitatory vs. inhibitory synapses	Anesthetics may block excitatory and enhance inhibitory transmission.
Molecular	Presynaptic vs. postsynaptic membrane	Anesthetics may alter release of presynaptic neurotransmitter (perhaps through changes in intracellular Ca2+ ) and modify flow of ions through postsynaptic channels.
		Meyer-Overton rule implies a hydrophobic site of molecular membrane action. Critical volume hypothesis purports anesthetic action through membrane expansion.
		Possible importance of membrane-aqueous interface.
	Lipid vs. protein	Lipid fluidization theories cannot account for the production of the anesthetic state. Evidence is accumulating for direct binding of anesthetics to excitable membrane proteins.

may enhance or depress excitatory or inhibitory transmission through axons or synaptic regions. Presynaptic and postsynaptic effects have been found. Regardless of the macroscopic site of action, the ultimate action of inhaled agents is on neuronal membranes. Although a direct neuronal plasma membrane interaction seems likely, the possibility remains that inhaled anesthetics act indirectly by production of a second messenger. The correlation between lipid solubility and anesthetic potency suggests that anesthetics have a hydrophobic or amphipathic site of action. The discovery of nonimmobilizers, lipid-soluble compounds that do not alter the MAC, implies the site of action is different for different anesthetic end points. Anesthetics bind to and perturb membrane lipids and proteins, but it is uncertain which of these components is most important and how such perturbations may lead to the anesthetic state. Future advances in anesthetic mechanisms will go hand in hand with the development of molecular biology techniques used to clone and characterize excitable membrane channels and biophysical and biochemical advances used to study neuronal interactions. The development of animal models with sustained alterations in anesthetic potency will allow testing of the hypotheses that specific molecular changes in selected regions of the CNS are important in the production of anesthesia.