How does anesthesia work?
William J. Perkins, associate professor of anesthesiology at the Mayo Clinic College of Medicine in Rochester, Minn., offers this explanation:
ANESTHETICS WORK by blocking transmission of nerve signals to pain centers in the central nervous system. The exact mechanisms for general anesthetics are not completely understood.
In 1846 physician Oliver Wendell Holmes, Sr., coined the term “anaesthesia” for drug-induced inability to experience sensation (particularly pain) after the first publicized demonstration of inhaled ether rendered a patient unresponsive during a surgical procedure. Today two broad classes of such agents, called local and general, can induce anesthesia.
Targeted Pain Relief
Local anesthetics, such as novocaine, bind to and inhibit the function of the sodium channel in the nerve cell membrane. The channel allows passage of charged molecules called sodium ions from outside to inside the nerve cell, which is required for the propagation of nerve impulses that ultimately send messages about pain to the brain. Novocaine’s action obstructs the movement of nerve impulses from tissue innervated by, or containing, nerves at the site of a local-anesthetic injection but causes no changes in awareness and sense perception elsewhere in the body.
In contrast, general anesthetics provide overall insensibility to pain. The patient loses awareness, yet his vital physiological processes, such as breathing, continue to function. The most commonly used such agents are inhaled, and their chemical structure is related to ether. Globally speaking, they primarily act on areas of the central nervous system. Unlike local anesthetics, general anesthetics reduce nerve transmission at the synapses, the sites at which chemical messengers called neurotransmitters are released by neurons, causing the adjacent nerve cells to respond. General anesthetics interfere with the response of receptors and ion channels to neurotransmitters, thereby decreasing nerve cell activity and transmission.
Sites of Action
General anesthetics bind only very weakly to their sites of action and functionally interact with cellular proteins in a lipid environment (which is not water-soluble). Both factors make it difficult for scientists to determine their exact binding structure.
Because the general anesthetics bind only weakly, high concentrations, often more than 1,000 times greater than those for typical receptor- or protein-targeting drugs, are needed to achieve an anesthetic state. This fact results in anesthetic binding to, or interaction with, cell membranes and large numbers of proteins in a nonspecific manner. It also affects the function of many proteins in nerve cell membranes, making it challenging to ascertain which of them are the key mediators of anesthetic action. The second problem, that protein-signaling interaction is in a lipid environment, makes it harder to gain detailed structural information for membrane proteins than it is for water-soluble proteins. Such structural data are essential for understanding how anesthetics exert their effects on membrane proteins. These proteins do not easily crystallize, which is a requirement for the current molecular structure “gold standard,” x-ray crystallography.
Because of the lack of structural data, it remains unclear whether anesthetics exert their primary effects by direct interaction with these proteins or by indirect interaction with the lipids surrounding them. Despite such limitations, researchers are taking advantage of methods to better discern how anesthetics work at the molecular level.
Genetic tools, for example, enable investigators to alter specific functions of a protein and then determine whether this protein can be linked to sensitivity or resistance to anesthetic action in less complex organisms. Other approaches, including sophisticated structural modeling of anesthetic binding to protein targets, also show promise. The protein targets for different agents do not appear to be the same, so probably no single molecular mechanism of action exists for all anesthetics.
Thus, the simple answer to the question of how anesthesia works is that although we know a great deal about the physiological effects and macroscopic sites of action, we do not yet know the molecular mechanisms of action for general anesthetics. Many of the tools necessary to probe these mechanisms are now available, and in coming years we can look forward to new insights into how this great boon to humanity works at the molecular level.
Have a question? Send it to editors@sciammind.com
William J. Perkins, associate professor of anesthesiology at the Mayo Clinic College of Medicine in Rochester, Minn., offers this explanation:
ANESTHETICS WORK by blocking transmission of nerve signals to pain centers in the central nervous system. The exact mechanisms for general anesthetics are not completely understood.
In 1846 physician Oliver Wendell Holmes, Sr., coined the term “anaesthesia” for drug-induced inability to experience sensation (particularly pain) after the first publicized demonstration of inhaled ether rendered a patient unresponsive during a surgical procedure. Today two broad classes of such agents, called local and general, can induce anesthesia.
Targeted Pain Relief
Local anesthetics, such as novocaine, bind to and inhibit the function of the sodium channel in the nerve cell membrane. The channel allows passage of charged molecules called sodium ions from outside to inside the nerve cell, which is required for the propagation of nerve impulses that ultimately send messages about pain to the brain. Novocaine’s action obstructs the movement of nerve impulses from tissue innervated by, or containing, nerves at the site of a local-anesthetic injection but causes no changes in awareness and sense perception elsewhere in the body.
In contrast, general anesthetics provide overall insensibility to pain. The patient loses awareness, yet his vital physiological processes, such as breathing, continue to function. The most commonly used such agents are inhaled, and their chemical structure is related to ether. Globally speaking, they primarily act on areas of the central nervous system. Unlike local anesthetics, general anesthetics reduce nerve transmission at the synapses, the sites at which chemical messengers called neurotransmitters are released by neurons, causing the adjacent nerve cells to respond. General anesthetics interfere with the response of receptors and ion channels to neurotransmitters, thereby decreasing nerve cell activity and transmission.
Sites of Action
General anesthetics bind only very weakly to their sites of action and functionally interact with cellular proteins in a lipid environment (which is not water-soluble). Both factors make it difficult for scientists to determine their exact binding structure.
Because the general anesthetics bind only weakly, high concentrations, often more than 1,000 times greater than those for typical receptor- or protein-targeting drugs, are needed to achieve an anesthetic state. This fact results in anesthetic binding to, or interaction with, cell membranes and large numbers of proteins in a nonspecific manner. It also affects the function of many proteins in nerve cell membranes, making it challenging to ascertain which of them are the key mediators of anesthetic action. The second problem, that protein-signaling interaction is in a lipid environment, makes it harder to gain detailed structural information for membrane proteins than it is for water-soluble proteins. Such structural data are essential for understanding how anesthetics exert their effects on membrane proteins. These proteins do not easily crystallize, which is a requirement for the current molecular structure “gold standard,” x-ray crystallography.
Because of the lack of structural data, it remains unclear whether anesthetics exert their primary effects by direct interaction with these proteins or by indirect interaction with the lipids surrounding them. Despite such limitations, researchers are taking advantage of methods to better discern how anesthetics work at the molecular level.
Genetic tools, for example, enable investigators to alter specific functions of a protein and then determine whether this protein can be linked to sensitivity or resistance to anesthetic action in less complex organisms. Other approaches, including sophisticated structural modeling of anesthetic binding to protein targets, also show promise. The protein targets for different agents do not appear to be the same, so probably no single molecular mechanism of action exists for all anesthetics.
Thus, the simple answer to the question of how anesthesia works is that although we know a great deal about the physiological effects and macroscopic sites of action, we do not yet know the molecular mechanisms of action for general anesthetics. Many of the tools necessary to probe these mechanisms are now available, and in coming years we can look forward to new insights into how this great boon to humanity works at the molecular level.
Have a question? Send it to editors@sciammind.com
