Mechanisms of General Anesthetics

By Sherin Kuriakose

What is Anesthesia?

The discovery of general anesthetics in 1846 has advanced the work of physicians and surgeons in medical science and clinical care, and has also eased the trauma that surgery can cause for patients. In the past, surgery without anesthesia was the only option, and only the simplest and quickest of operations could be tolerated such as amputations, bladder stones and cranial trephinations.  General anesthesia works to cause analgesia (pain relief), amnesia (memory loss), hypnosis, and immobility making surgery less of a threat.  There is no single anatomic pathway that anesthesia acts on. In fact composed of several components that target different sites in the central nervous system. It can also be separated into the two categories, which differ in the administration of the anesthetic: volatile, or vaporous, anesthesia and intravenous anesthesia. Volatile anesthetics cause immobility through target sites in the spinal cord, which include the glycine receptors, gamma-aminobutyric acid (GABA)(A) receptors, glutamate receptors, and TREK-1 potassium channels [1]. Glycine, is a neuronal nicotinic highly involved in memory much like GABAA

The Mechanism Behind General Anesthetics

Each receptor has its own function and location though it may communicate and effect many other receptors and systems.  Volatile anesthetics alter the functions of the “superfamily” of ligand-gated fast ion channels and the glutamate family of receptors.   This family of ligand gated ion channel receptors is diverse in their methods of regulating synaptic transmission.  Of many, the three focused on in studies are the GABA receptors in the central nervous system, which theory suggests are the main targets for general anesthetics, glycine, the major inhibitor receptor in the spinal cord, and the glutamate receptors, which are the major excitatory receptors in the brain depressed by vapor anesthetics [2,3].

General anesthetics work at the molecular level by interfering with the work of neurons.  Normally, neurons are triggered by chemical signals and molecules, which either depolarize the neuron for an excitatory response or hyperpolarize the membrane for an inhibitory effect.  General anesthetics either enhance the signals that inhibit responses or block the signals that cause excitatory responses.  No current anesthetic works solely on one ion channel but several at a time.  The GABA receptor is the most abundant fast inhibitory neurotransmitter receptor in the central nervous system and work to influence synaptic transmission and integration.  Anesthetics enhance the opening of channels causing a hyperpolarization of the membrane and therefore inhibit the neurotransmitter GABA from being released. Though there is no direct evidence for this claim, it is theorized that because GABA receptors are key functions of memory, consciousness and awareness, the inhibiting anesthesia molecules causes hypnosis, spinal relaxation and amnesia [4].  Glycine, the inhibitor receptor in the spinal cord, is neuronal nicotinic which is also highly influenced by volatile anesthetics and effects memory much like the GABA receptors [3].

Testing Spinal Cord Responses to Anesthetics

Previously the cerebrum was thought to mediate anesthetics but recent studies such as those conducted by professor of anesthesiology and neurological surgery at Stony Brook School of Medicine, Dr. Ira Rampil, M.S.E.E, M.D., suggest that spinal sites, not the cerebrum, mediate immobility caused by anesthetics. The spinal cord is a crucial site wherein anesthetics suppress movement in response to harmful stimuli including, surgical incisions [5].

This theory was tested noninvasively by F-wave analysis in which the right tibial nerve is stimulated with a cathodal needle electrode in the back of the knee pit. F-wave analysis is the process of stimulating a nerve and recording the action potentials of the muscles in the limbs or spine supplied by the nerve to evaluate the conduction between the two. The M-waves observed in the data represent muscle depolarization and the F-waves represent recurrent motor activity.  To measure the F-wave amplitude, the F/M ratio is taken [6].  In the experiment conducted, with each increasing dose of anesthetic tested, the F/M ratio reduced the minimum alveolar concentration, or MAC, required for a patient to respond to a stimulus [6,7].

All the anesthetics tested by F-wave analysis had shown that volatile anesthetics hyperpolarize spinal cord motor neurons. This supports the hypothesis that spinal cord sites mediate surgical immobility by anesthetics. There is currently not enough information to specifically state where the anesthetics that cause depression of excitability work in pre or postsynaptic mechanisms [3,6].

Volatile Anesthetics that Cause Surgical Amnesia

Recently a series of general anesthetics were tested and found to cause amnesia, which is inhibition of learning, but without immobility or loss of consciousness.  This is a point of interest in future research since usually, the results of anesthetics are amnesia coupled with immobility and loss of consciousness.  Since there is no evidence showing where these anesthetics are targeting, it is possible that the failure to learn is the result of some other reason and may interfere with the process of making associations between conditioned and unconditioned stimuli.  A study was conducted with rats to test the hypothesis that these non-immobilizers do not interfere with auditory perception but with the lateral neural processing involved in making associations.  The results showed that the non-immobilizers did not affect the rats’ auditory perception but did interfere with learning. Dr. Rampil is currently testing the mechanisms by which volatile anesthetics cause surgical amnesia [8].

There is still much more to discover about the mechanisms of general anesthetics but previous have classified the effects of anesthetics as well as shown the GABA receptor to be the most targeted by anesthetics.  In addition, current research, such as the one being done by Dr. Rampil, is studying the specific mechanisms of general anesthetics.


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