By Maryam Sarah Ahmed
In a public demonstration in 1846, surgeon John Collins Warren removed a tumour from the neck of a patient under ether anaesthesia. Although the use of general anaesthesia would be considered standard in such a procedure now, back then it was so monumental that the event was honoured by both a statue (the Ether Monument, which still stands in the Boston Public Garden) and an oil painting (The First Operation with Ether, one of the most famous paintings in medical history). It was after this demonstration that anaesthesia started to be used regularly in surgical procedures, making painless surgery a possibility.
Now, over 170 years later, general anaesthesia is routinely used during operations; patients undergo their surgery in a state of controlled unconsciousness. However despite the importance of this medical treatment, the exact mechanism by which it works has remained a mystery for a long time.
General anaesthesia is a medical treatment that causes a state of unconsciousness in a patient so that they won’t feel pain—or any other sensation—during surgery. Around the beginning of the 20th century, two researchers discovered that, for many general anaesthetics, the greater the solubility of the anaesthetic in olive oil (i.e. the greater its solubility in lipids), the greater its effectiveness. This was called the Meyer-Overton Correlation, named after the two researchers, and it led to many theories suggesting that anaesthesia works by targeting the lipid region of cell membranes.
Other theories suggested that anaesthesia directly targeted cell membrane proteins such as ion channels. One kind of anaesthetic, isoflurane, was shown to inhibit sodium ion channels, and thus inhibit nerve impulses, without disrupting the lipid bilayer — however, this was only at normal anaesthetic concentrations. At higher concentrations, isoflurane did affect the lipid region of the cell membrane. Other anaesthetics also targeted membrane proteins, but it was shown that they did affect the lipid bilayer as well, although minimally.
A 2020 study by researchers at the Scripps Research Institute has revealed that the answer may involve both lipids and proteins in the cell membrane. According to the study, clusters of ordered lipids within the membrane, called lipid rafts, become disordered when exposed to some anaesthetics. This causes the activation of a certain kind of membrane protein called TREK-1. TREK-1 is a potassium ion channel which, when activated, hyperpolarizes nerve cells to inhibit nerve impulses, resulting in the temporary unconsciousness brought about by general anaesthesia.
Although there is still much to be discovered about the mechanism of general anaesthesia, these findings are a significant step forward and will be helpful in studying not only anaesthetics, but also sleep and consciousness. With further research, hopefully the mystery of how general anaesthesia works will be entirely solved.
References
1. Chaturvedi, R., & Gogna, R. L. (2011, October). Ether day: an intriguing history. Medical Journal, Armed Forces India, 67(4), 306-308. doi:https://doi.org/10.1016/S0377-1237(11)60098-1
Cleveland Clinic. (2020, September 30). Anesthesia. Retrieved from https://my.clevelandclinic.org/health/treatments/15286-anesthesia
2. Desai, S. P., Desai, M. S., Maddi, R., & Battit, G. E. (2007, May). A Tale of Two Paintings: Depictions of the First Public Demonstration of Ether Anesthesia. Anesthesiology, 106, 1046–1050. doi:https://doi.org/10.1097/01.anes.0000265166.14383.0d
3. Herold, K. F., Sanford, R. L., Lee, W., Andersen, O. S., & Hemmings Jr, H. C. (2017, March). Clinical concentrations of chemically diverse general anesthetics minimally affect lipid bilayer properties. Proceedings of the National Academy of Sciences of the United States of America, 114(12), 3109-3114. doi:https://doi.org/10.1073/pnas.1611717114
4. La Jolla, C. A., & Jupiter, F. L. (2020, May 29). Solving the 175-year-old medical mystery of anesthesia’s effects. Retrieved from Scripps Research: https://www.scripps.edu/news-and-events/press-room/2020/20200529-hansen-lerner-anesthesia.html
5. Lugli, A. K., Yost, C. S., & Kindler, C. H. (2009, October). Anaesthetic mechanisms: update on the challenge of unravelling the mystery of anaesthesia. European Journal of Anaesthesiology, 26(10), 807-820. doi:https://doi.org/10.1097/EJA.0b013e32832d6b0f
6. Pavel, M. A., Peterson, E. N., Wang, H., Lerner, R. A., & Hansen, S. B. (2020, May). Studies on the mechanism of general anesthesia. Proceedings of the National Academy of Sciences of the United States of America, 117(24), 13757-13766. doi:https://doi.org/10.1073/pnas.2004259117
7. Robinson, D. H., & Toledo, A. H. (2012, June). Historical development of modern anesthesia. Journal of Investigative Surgery, 25(3), 141-149. doi:10.3109/08941939.2012.690328