Comfortably numb: anesthetics are slowly giving up the secrets of how they work

Science News, July 3, 2004 by John Travis

Take a stroll through the Boston Public Garden, the nation's oldest botanical garden, and you'll find an array of plaques, monuments, and memorials honoring famous people of history. Not far from a statue of George Washington on horseback, there's a tall monument that honors not a person, but a chemical. This tribute to ether is probably the world's only monument to a drug. A statue representing the Good Samaritan tops the structure, which displays the inscription, "There shall be no more pain."

Erected in the 19th century, the tribute commemorates ether's first use as a surgical general anesthetic, which took place in 1846 at the Massachusetts General Hospital in Boston. Today, it's hard to imagine what surgery was like before this discovery and the subsequent development of inhaled and injected chemicals that are even more effective in rendering people unconscious and insensitive to pain.

General anesthesia has a "magical quality to it; says anesthesiologist James Sonner of the University of California, San Francisco. "It was and still is amazing that you can ... make an organism comatose, unresponsive enough to perform surgery, and reverse the whole thing."

Almost as remarkable, scientists until recently had little solid evidence of how these drugs perform their magic. "Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience," Sonner says.

Anesthesia research "has been for a long time a science of untestable hypotheses," notes Neil L. Harrison of Cornell University.

However, last year, a European research group put a leading theory to the test. The team reported using genetically engineered mice to confirm a proposed mechanism for two anesthetics that are delivered by injection. That research strategy is now being brought to bear on the more complex and contentious issue of how inhaled anesthetics work. Many investigators expect this effort to succeed, although they say that it could take 5 to 10 years

"Most of the injectable anesthetics appear to act on a single molecular target," says Sonner. "It looks like inhaled anesthetics act on multiple molecular targets. That makes it a more difficult problem to pick apart."

BEYOND THE ETHER Combining amnesia, sedation, immobility, and insensitivity to pain, general anesthesia is an unnatural state: a physician-induced "central nervous system dysfunction," in the words of Roderic Eckenhoff of the University of Pennsylvania in Philadelphia.

Many millions of people in the United States undergo general anesthesia annually. Seeking quicker-acting agents with fewer side effects, modern anesthetists have moved beyond ether. Among the inhaled anesthetics, ether derivatives halothane, isoflurane, and enflurane are the most common, but nitrous oxide (laughing gas), cyelopropane, and xenon, which aren't related to ether, also work. Two of the most commonly injected anesthetics are propofol and etomidate.

One of the central questions of anesthesia research has been whether all these drugs work in the same manner. Until the last few decades, investigators generally held that, despite chemical differences, the drugs share a mechanism of action.

One long-standing theory was based on the simple observation that the more soluble an anesthetic is in olive oil, the more effective it is. Drawing upon that oddity, scientists since the early 1900s argued that anesthetics suppress brain function by dissolving into and altering the structure of lipid-based membranes of nerve cells. This, in turn, would change the function of ion channels, the pores that govern the electrical activity of the cells.

In the 1970s, the lipid theory faced its first serious challenge. Researchers including Nicholas P. Franks and William R. Lieb of Imperial College in London argued that anesthetics act as traditional drugs do. That is, they bind to specific protein targets on nerve cells and activate the molecules or disrupt their function.

These scientists' initial suspicion centered on neurotransmitter receptors, the cell-surface proteins that respond to the chemical signals that nerve cells secrete. The receptors for brain chemicals such as glutamate, glycine, and gamma-amino butyric acid (GABA) drew particular attention because they control the flow of ions into nerve cells.

Glutamate is the primary excitatory signal used by these cells, whereas glycine and GABA typically shut down nerve cell activity. Therefore, anesthetics might work by blocking glutamate receptors or by activating GABA or glycine receptors. Research in the 1980s produced growing evidence that various anesthetic agents, particularly the injected ones, bind to such receptors. In tests on cells grown in the laboratory, scientists even pinpointed specific regions of the receptors where the anesthetics seemed to act.

But showing that a drug affects a protein in a laboratory dish is a far cry from proving that the drug uses that protein to produce anesthesia in a person. So, researchers turned to genetically engineered mice to address whether glutamate, glycine, or GABA receptors are the targets of anesthetics. The initial forays into this area relied on knockout mice, animals in which scientists have mutated a single gene to prevent the production of its protein.