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INTRODUCTION SECTION (NO HEADING)

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[ BEGIN INTRODUCTION ]

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Membrane-mediated [[ anesthesia ]] or anaesthesia (UK) is a mechanism of action that involves an [[ anesthetic agent ]] exerting its [ pharmaceutical ] effects [ primarily ] through [ interaction with ] the [[ lipid bilayer membrane ]].

The relationship between volatile (inhalable) general anaesthetics and the cellular lipid membrane has been well established since around 1900, based on the Meyer-Overton Correlation.[1][2][3][4] Since 1900 there have been extensive research efforts to characterize these membrane-mediated effects of anesthesia, leading to many theories but few answers. During the 1980s the focus of anesthetic research shifted from membrane lipids to membrane proteins,[5][6][7] where it currently remains.[8][9][10][11] Accordingly, the specific membrane-mediated anesthetic effects remain mostly undiscovered.[9][12][13][14]

[ Recent research has demonstrated promising ] mechanisms of [[ membrane-mediated ]] anesthetic action for both [[ general ]] and [[ local ]] anesthetics. [ These studies suggest that ] the anesthetic [[ binding site ]] [ in the membrane ] is within ordered lipids. [ This ] [[ binding ]] disrupts the function of the ordered lipid[s, forming lipid rafts that dislodge a membrane-bound phospholipase involved in a metabolic pathway that actives anesthetic sensitive potassium channels.[[ [15][16] ]] Other recent studies show similar lipid-raft-specific anesthetic effects on sodium channels.[17]

See Theories of general anaesthetic action for a broader discussion of purely theoretical mechanisms.

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The Meyer-Overton Correlation for Anesthetics

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At the turn of the twentieth century, one of the most important anesthetic-based theories began to take shape. At the time, the research of both German pharmacologist Hans Horst Meyer (1899)[1] and British-Swedish physiologist Charles Ernest Overton (1901)[2] reached the same conclusion about general anesthetics and lipids:

[[[ BEGIN EMPHASIS ]]]

There is a direct correlation between anesthetic agents and lipid solubility. The more lipophillic (soluble) the anesthetic agent is, the more potent (efficacious) the anesthetic agent is.[3][8][18]

[[[ END EMPHASIS ]]]

This principle became known as the Meyer-Overton Correlation. It originally compared the anesthetic partition coefficient in olive oil (X-axis) to the effective dose that induced anesthesia in 50% (i.e., EC50) of the tadpole research subjects (Y-axis).[1][2][3][4] Modern renditions of the Meyer-Overton plot usually compare olive oil partition coefficent of the Inhalational or Intravenous drug (X-axis) to the minimum alveolar concentration (MAC) or the effective dose 50 (i.e., ED50) of the anesthetic agent (Y-axis).[citation needed]

Despite more than 175 years of anesthetic use and research, the exact connection between phospholipids, the bilayer membrane, and general anesthetic agents remains mostly unknown.[4][10][9] Accordingly, the means of membrane-mediated anesthesia remain mostly theoretical.[12][19]Cite error: A <ref> tag is missing the closing </ref> (see the help page).

The Lateral Pressure Profile theory suggests that anesthetic agents partition into the lipid bilayer, increasing the horizontal (lateral) pressure on proteins imbedded in the membrane. The added pressure causes a conformational change in protein structure, forcing the neuronal channel into an open or closed state (e.g., hyperpolarization) that generates the Inhibitory state of general anesthesia in the central nervous system (CNS).[20][21][citation needed]

This is the first hypothesis to explain the correlations of anesthetic potency with lipid bilayer structural characteristics, describing both mechanistic and thermodynamic rationale for the effects of general anesthesia.[citation needed]

General anesthetics

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[[ [15] ]] [[ [14] ]] [[ [22] ]] [[ [23] ]]

PLD2

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[[ [24] ]] [[ [23] ]]

TREK-1

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[[ [25] ]] [[ [15] ]]

GABAAR

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[[ [26] ]]

Endocytosis

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[[ [27] ]]

Local anesthetics

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[[ [16] ]] [[ [27] ]]

History

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More than 100 years ago, a unifying theory of anesthesia was proposed based on the oil partition coefficient. [ insert Meyer-Overton history ] In the 70s this concept was extended to the disruption of lipid partitioning.[[ [28] ]] Partitioning itself is an integral part of forming the ordered domains in the membrane,[[ [citation needed] ]] and the proposed mechanism is very close to the current thinking, but the partitioning itself is not the target of the anesthetics.[[ [citation needed] ]] At clinical concentration, the anesthetics do not inhibit lipid partitioning.[[ [15] ]] Rather they inhibit the order within the partition and/or compete for the palmitate binding site.[[ [citation needed] ]] Nonetheless, several of the early conceptual ideas about how disruption of lipid partitioning could affect an ion channel have merit.[[ [citation needed] ]]

References

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  1. ^ a b c Meyer, Hans (1899-03-01). "Zur Theorie der Alkoholnarkose". Archiv für experimentelle Pathologie und Pharmakologie (in German). 42 (2): 109–118. doi:10.1007/BF01834479. ISSN 1432-1912.
  2. ^ a b c Overton, Charles Ernest (1901). Studien über die Narkose: zugleich ein Beitrag zur allgemeinen Pharmakologie (in German). G. Fischer.
  3. ^ a b c Missner, Andreas; Pohl, Peter (2009-07-13). "110 Years of the Meyer–Overton Rule: Predicting Membrane Permeability of Gases and Other Small Compounds". ChemPhysChem. 10 (9–10): 1405–1414. doi:10.1002/cphc.200900270. ISSN 1439-4235. PMC 3045804. PMID 19514034.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ a b c Lynch, Carl III (2008-09). "Meyer and Overton Revisited". Anesthesia & Analgesia. 107 (3): 864. doi:10.1213/ane.0b013e3181706c7e. ISSN 0003-2999. {{cite journal}}: Check date values in: |date= (help)
  5. ^ Bean, B P; Shrager, P; Goldstein, D A (1981-03-01). "Modification of sodium and potassium channel gating kinetics by ether and halothane". Journal of General Physiology. 77 (3): 233–253. doi:10.1085/jgp.77.3.233. ISSN 0022-1295. PMC 2215432. PMID 6265590.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ Franks, N. P.; Lieb, W. R. (1984-08). "Do general anaesthetics act by competitive binding to specific receptors?". Nature. 310 (5978): 599–601. doi:10.1038/310599a0. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Bovill, J. G. (2000-08). "Mechanisms of anaesthesia: time to say farewell to the Meyer-Overton rule". Current Opinion in Anaesthesiology. 13 (4): 433–436. doi:10.1097/00001503-200008000-00006. ISSN 0952-7907. PMID 17016337. {{cite journal}}: Check date values in: |date= (help)
  8. ^ a b Clayton, Thomas; Ode, Kenichi (2023-04). "Mechanisms of action of general anaesthetic drugs". Anaesthesia & Intensive Care Medicine. 24 (4): 235–237. doi:10.1016/j.mpaic.2022.12.031. ISSN 1472-0299. {{cite journal}}: Check date values in: |date= (help)
  9. ^ a b c Reigada, Ramon (2013-01-02). "Atomistic Study of Lipid Membranes Containing Chloroform: Looking for a Lipid-Mediated Mechanism of Anesthesia". PLOS ONE. 8 (1): e52631. doi:10.1371/journal.pone.0052631. ISSN 1932-6203. PMC 3534722. PMID 23300982.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  10. ^ a b Hao, Xuechao; Ou, Mengchan; Zhang, Donghang; Zhao, Wenling; Yang, Yaoxin; Liu, Jin; Yang, Hui; Zhu, Tao; Li, Yu; Zhou, Cheng. "The Effects of General Anesthetics on Synaptic Transmission". Current Neuropharmacology. 18 (10): 936–965. doi:10.2174/1570159X18666200227125854. PMC 7709148. PMID 32106800.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ Franks, Nicholas P. (2006-01). "Molecular targets underlying general anaesthesia". British Journal of Pharmacology. 147 Suppl 1 (Suppl 1): S72–81. doi:10.1038/sj.bjp.0706441. ISSN 0007-1188. PMC 1760740. PMID 16402123. {{cite journal}}: Check date values in: |date= (help)
  12. ^ a b Antkowiak, Bernd (2001-05-01). "How do general anaesthetics work?". Naturwissenschaften. 88 (5): 201–213. doi:10.1007/s001140100230. ISSN 1432-1904.
  13. ^ Ramírez, Carlos (2022-03-07). "Lipids, Chloroform, and Their Intertwined Histories". Substantia. 6 (1): 133–143. doi:10.36253/Substantia-1498. ISSN 2532-3997.
  14. ^ a b Sezgin, Erdinc; Levental, Ilya; Mayor, Satyajit; Eggeling, Christian (2017-06). "The mystery of membrane organization: composition, regulation and roles of lipid rafts". Nature Reviews Molecular Cell Biology. 18 (6): 361–374. doi:10.1038/nrm.2017.16. ISSN 1471-0080. PMC 5500228. PMID 28356571. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  15. ^ a b c d Pavel, Mahmud Arif; Petersen, E. Nicholas; Wang, Hao; Lerner, Richard A.; Hansen, Scott B. (2020-06-16). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences. 117 (24): 13757–13766. doi:10.1073/pnas.2004259117. ISSN 0027-8424.
  16. ^ a b Pavel, Mahmud Arif; Chung, Hae-Won; Petersen, E. Nicholas; Hansen, Scott B. (2019-10). "Polymodal Mechanism for TWIK-Related K+ Channel Inhibition by Local Anesthetic". Anesthesia & Analgesia. 129 (4): 973. doi:10.1213/ANE.0000000000004216. ISSN 0003-2999. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Krogman, William L.; Woodard, Thomas; McKay, Robert S. F. (2024-07). "Anesthetic Mechanisms: Synergistic Interactions With Lipid Rafts and Voltage-Gated Sodium Channels". Anesthesia & Analgesia. 139 (1): 92. doi:10.1213/ANE.0000000000006738. ISSN 0003-2999. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Baskerville, Charles (1911-08-11). "The Chemistry of Anesthetics". Science. 34 (867): 161–176. doi:10.1126/science.34.867.161.
  19. ^ Brown, Emery N.; Pavone, Kara J.; Naranjo, Marusa (2018-11). "Multimodal General Anesthesia: Theory and Practice". Anesthesia & Analgesia. 127 (5): 1246. doi:10.1213/ANE.0000000000003668. ISSN 0003-2999. PMC 6203428. PMID 30252709. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  20. ^ Cite error: The named reference :7 was invoked but never defined (see the help page).
  21. ^ Cite error: The named reference :8 was invoked but never defined (see the help page).
  22. ^ Levental, Ilya; Lingwood, Daniel; Grzybek, Michal; Coskun, Ünal; Simons, Kai (2010-12-21). "Palmitoylation regulates raft affinity for the majority of integral raft proteins". Proceedings of the National Academy of Sciences. 107 (51): 22050–22054. doi:10.1073/pnas.1016184107. PMC 3009825. PMID 21131568.{{cite journal}}: CS1 maint: PMC format (link)
  23. ^ a b Petersen, E. Nicholas; Pavel, Mahmud Arif; Wang, Hao; Hansen, Scott B. (2020-01-01). "Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. Molecular biophysics of membranes and membrane proteins. 1862 (1): 183091. doi:10.1016/j.bbamem.2019.183091. ISSN 0005-2736. PMC 6907892. PMID 31672538.{{cite journal}}: CS1 maint: PMC format (link)
  24. ^ Petersen, E. Nicholas; Chung, Hae-Won; Nayebosadri, Arman; Hansen, Scott B. (2016-12-15). "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D". Nature Communications. 7 (1): 13873. doi:10.1038/ncomms13873. ISSN 2041-1723. PMC 5171650. PMID 27976674.{{cite journal}}: CS1 maint: PMC format (link)
  25. ^ Comoglio, Yannick; Levitz, Joshua; Kienzler, Michael A.; Lesage, Florian; Isacoff, Ehud Y.; Sandoz, Guillaume (2014-09-16). "Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid". Proceedings of the National Academy of Sciences. 111 (37): 13547–13552. doi:10.1073/pnas.1407160111. PMC 4169921. PMID 25197053.{{cite journal}}: CS1 maint: PMC format (link)
  26. ^ Yuan, Zixuan; Pavel, Mahmud Arif; Hansen, Scott B. (2024-04-29), GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons, doi:10.1101/2024.04.26.591395, PMC 11092523, PMID 38746110, retrieved 2024-11-28{{citation}}: CS1 maint: PMC format (link)
  27. ^ a b Yuan, Zixuan; Pavel, Mahmud Arif; Wang, Hao; Kwachukwu, Jerome C.; Mediouni, Sonia; Jablonski, Joseph Anthony; Nettles, Kendall W.; Reddy, Chakravarthy B.; Valente, Susana T.; Hansen, Scott B. (2022-09-14). "Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture". Communications Biology. 5 (1): 1–12. doi:10.1038/s42003-022-03841-8. ISSN 2399-3642. PMC 9472185. PMID 36104427.{{cite journal}}: CS1 maint: PMC format (link)
  28. ^ Trudell, James R. (1977-01-01). "A Unitary Theory of Anesthesia Based on Lateral Phase Separations in Nerve Membranes". Anesthesiology. 46 (1): 5–10. doi:10.1097/00000542-197701000-00003. ISSN 0003-3022. {{cite journal}}: no-break space character in |first= at position 6 (help)