The Thermodynamics of General Anesthesia
Reversible unconsciousness induced by chemical agents defines general anesthesia. While the significant effects of anesthetics have been widely explored (analgesia, amnesia, immobility), the mechanisms underlying the anesthetic effect are not yet known. Many theories describe what makes the body particularly sensitive to general anesthetics. Von Bibra and Harless made the first proposition for a nonspecific mechanism of general anesthetic action in 1847. They proposed that anesthetic agents reacted by dissolving in the fatty fraction of brain cells and removing fatty constituents from them, thus changing the activity of brain cells and inducing anesthesia. Later, Meyer and Overton proposed that the lipid solubility-anesthetic potency correlation where the action of general anesthetics is proportional to their coefficient in lipid membranes [1-3].
Other proposals relate anesthetic agents to specific proteins of the cellular membrane of neurons. The membrane protein hypothesis of general anesthetic action observation was remarkably important because it demonstrated that proteins could be inactivated by clinical doses of anesthetic in the total absence of lipids. General anesthetics may also interact with transmitter-gated ion channels. In this theory, the ligand (neurotransmitter)-gated ion channels contain an anion conducting channel whose function is altered by allosteric effects of a number of compounds. A ligand-gated membrane ion channels example is the gamma-aminobutyric acid (GABAa) 5-HT3 acetylcholine glutamate glycine (GABAa) receptors. GABAa receptors are the major inhibitory neurotransmitter receptors, and they account for 30% of all inhibitory synapses. The GA agents can also inhibit channel functions of excitatory receptors or potentiate functions of inhibitory receptors. One example of membrane protein interactions is the key-lock mechanism hypothesis that proposes that general anesthetic binds to its target ion channel and changing its structure dramatically from open to closed conformation or vice versa [3].
The study of tandem two-pore potassium channels (K2Ps) has also given some insights into general anesthetic mechanisms. It is known that some general anesthetics promote the opening of some of these channels, enhancing potassium currents and producing a reduction in neuronal excitability that contributes to the transition to unconsciousness. These transmitters promote K2P channel closure and thus an increase in neuronal excitability [4]. The two-pore domain k+ ion channels found pre and post-synaptically throughout the nervous system are voltage-independent, and they can be hyperpolarized by some anesthetic agents, especially the volatile halogenated hydrocarbons [5].
Although the Meyer-Overton rule is considered now an outdated model, the correlation with potency can be improved. The modern version of the lipid hypothesis states that redistribution of lateral membrane pressures produces the anesthetic effect after solubilization. Recently in an article published by Biophysical Society, T. Heimburg and A. Jackson propose a thermodynamic extension of the Meyer-Overton rule based on free energy changes in the system and that incorporates the effects of melting point depression [1]. Other research from the Biophysical Journal utilizes molecular dynamics (MD) simulations for a membrane with anesthetics (xenon) by changing the lateral pressure within the membrane to elucidate the mechanism of pressure reversal of general anesthesia. Since the effect of general anesthetic can be controllable by the ambient pressure, the properties of the lipid bilayer at high pressure are returned to that without xenon molecules at 0.1 MPa. Furthermore, it is shown that xenon molecules are distributed in the middle of the membrane at high pressures by the pushing effect, and the diffusivity of a xenon molecule is suppressed. These results suggest that the pressure reversal originates from a jamming of xenon molecules in the lipid bilayer [6].
[1] Heimburg, T., & Jackson, A. D. (2007). The Thermodynamics of General Anesthesia. Biophysical Journal, 92(9), 3159–3165. https://doi.org/10.1529/biophysj.106.099754
[2] Núñez, G., & Urzúa, J. (1998). Mechanism of action of general anesthetics. Effect on ion channel proteins or on membrane phospholipids? Revista Medica de Chile, 126(8), 993–1000. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9830753
[3] Cross, M. E., & Plunkett, E. V. E. (2014). Physics, Pharmacology and Physiology for Anaesthetists. https://doi.org/10.1017/cbo9781107326200
[4] Li, Y., Xu, J., Xu, Y., Zhao, X.-Y., Liu, Y., Wang, J., … Zhang, Z. (2018). Regulatory Effect of General Anesthetics on Activity of Potassium Channels. Neuroscience Bulletin, 34(5), 887–900. https://doi.org/10.1007/s12264-018-0239-1
[5] Steinberg, E. A., Wafford, K. A., Brickley, S. G., Franks, N. P., & Wisden, W. (2014). The role of K2P channels in anaesthesia and sleep. Pflügers Archiv – European Journal of Physiology, 467(5), 907–916. https://doi.org/10.1007/s00424-014-1654-4
[6] Yamamoto, E., Akimoto, T., Hirano, Y., Yasuoka, K., & Yasui, M. (2012). A Possible Mechanism on Pressure Reversal of General Anesthesia in Membrane. Biophysical Journal, 102(3), 85a. https://doi.org/10.1016/j.bpj.2011.11.487