Medical science is full of fascinating facts, though few are more mind-boggling than this: no one knows how anesthetics cause people to lose consciousness. Yet after 175 years of sparing people from the horrors of surgery without really understanding how, researchers may have finally discovered the mechanism by which their knock-out drugs lull patients into oblivion.
General anesthesia was first used in Massachusetts General Hospital in 1848 when a tumor patient was put to sleep after inhaling ether, and has gone on to become a game-changer in surgical science. At the turn of the 20th century, it was discovered that the potency of various anesthetics was linked to their solubility in lipids, leading to the theory that they probably interact with lipids on the membranes of brain cells in some unknown way.
More than a century of stagnation followed as our understanding of these compounds failed to advance, yet a new study in the Proceedings of the National Academy of Science seems to have finally cracked the mystery.
Researchers first bathed cells in chloroform, and observed as neatly packed lipid clusters called GM1 suddenly expanded and became disordered. Located on the cell membrane, these GM1 clusters spilled their contents, releasing an enzyme called phospholipase D2 (PLD2).
After tagging PLD2 with a fluorescent marker, the researchers were able to track its movement towards another type of lipid cluster called PIP2, which contains gateways known as TREK1 potassium ion channels that regulate the passage of potassium through the membrane, thereby altering signaling within the cell.
The activation of TREK1 is known to cause neurons to shut down, resulting in a loss of consciousness, so the researchers conclude that inhaled anesthetics like chloroform, isoflurane, and diethyl ether must activate these channels via PLD2.
To test their conclusion, the team genetically modified fruit flies to lack PLD2, and found that this made them far less susceptible to the effects of numerous anesthetics. Interestingly, though, massive doses of these compounds did knock the flies out, indicating that PLD2 may not be the only factor at play.
"All flies eventually lost consciousness, suggesting PLD helps set a threshold, but is not the only pathway controlling anesthetic sensitivity," explain the study authors.
Regardless, this finding represents a major step towards solving what study author Richard Lerner calls “the granddaddy of medical mysteries,” and could give you something to ponder the next time you’re staring up from the operating table, counting down from 10 and waiting for the soothing embrace of unconsciousness.
