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Explaining General Anesthesia

Studies of fireflies and fish suggest how these drugs really work
aging



J. W. Stewart
ether op
Source: HARVARD UNIVERSITY

ETHER IN OPERATION. On October 16, 1846, 27-year-old William Thomas Green Morton gave the first public display of ether use as John Collins Warren operated on the neck of Edward Gilbert Abbott, age 20. Warren exclaimed to the surgery's audience, "Gentlemen, this is no humbug."
For many people, the knife isn't the scary part of surgery. It's the "going under" that gets them. To be sure, general anesthesia renders patients pain-free, but it also leaves them unconscious, immobile and unable to remember what has happened. It powerfully affects the brain and other organs--and perhaps most frightening, no one really knows how it works at the cellular level.

Scientists do, however, have some ideas. And at the annual meeting of the American Society of Anesthesiologists last week, one group led by Issaku Ueda described laboratory experiments with fireflies and goldfish that support one leading theory about general anesthesia's molecular actions. And if this explanation holds true, it could lead to anesthetics with fewer side effects and better drugs for bringing patients back up out of anesthesia-induced sleep.

Ueda and his colleagues at the University of Utah-Salt Lake City performed a series of experiments building on the observation--first made in 1942--that an increase in hydrostatic pressure can reverse anesthesia's effects. In particular, they set out to test the implication that under anesthesia, individual protein molecules in the brain somehow become larger than normal and that shrinking them rouses a person awake again.

chart
Source: after UEDA et al.

MYRISTIC MAGIC. Goldfish in tanks with myristic acid (colored dots) consistently recovered more quickly from the effects of the anesthetic halothane at different concentrations--presumably because the acid shrank protein molecules in the brain.

To do so, the group initially examined luciferase--the same chemical that makes fireflies light up. Using calorimetry and spectroscopy, they calculated how the luciferase enzyme responded physically to anesthetics and found that it was extraordinarily sensitive. The anesthetics relaxed the molecules, making them expand in size. In contrast, myristic acid--a fatty acid common in many foods--tightened them back up. "Without volume expansion," Ueda explained, "anesthesia does not ensue." Thus, they concluded that the increase in protein size was most likely responsible for anesthesia's powers.

More recently, they re-tested the opposite theory--that shrinking proteins reverses anesthesia--in living subjects. Instead of using hydrostatic pressure, though, Ueda and his co-workers exposed anesthetized goldfish to myristic acid. First they bubbled the anesthetic gas halothane into four jars of goldfish. One jar contained plain water; three others contained water and varying concentrations of the fatty acid. And after 30 minutes, they gauged how unconscious the goldfish were by stimulating them with a weak electrical current.

In the tank with the highest levels of myristic acid, more goldfish started swimming after the shock--suggesting that they were more recovered from the dose of halothane. And in other tanks, fewer and fewer fish responded as the concentrations of myristic acid decreased. This steady correlation seen across the four tanks only further confirms the idea that anesthesia works its magic by expanding protein volume in the brain.

The researchers plan to continue investigating myristic acid and possibly other similar substances in the lab. The ultimate goal is developing drugs to reverse general anesthesia quickly and safely--so that patients recovering from surgery do not have to simply wait for the residual grogginess to wear off. These medications could also help treat malignant hyperthermia, a rare but sometimes fatal reaction to anesthesia.

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