No quick fix

时间:2019-03-07 13:11:00166网络整理admin

By Nell Boyce DRUGS such as morphine are known to make nerve cells cultured in the lab “eat” their receptors. But the idea that this is what increases our bodies’ tolerance to these drugs has now received a blow from the observation that the body’s own painkillers remove even more receptors. Cells chronically exposed to addictive drugs have fewer opiate receptors on their surfaces—at least as judged by the number of radioactively tagged opiates that bind to them. Scientists assumed that drug tolerance develops as a result of these disappearing receptors, reasoning that addicts would have to take higher doses to get the same effect. But when Mark von Zastrow of the University of California in San Francisco and Chris Evans of the University of California in Los Angeles developed a method of tagging the receptors instead of the opiates they immediately made an intriguing observation. Cells would quickly absorb or “internalise” their receptors when exposed to any opiate, but the number of receptors taken into the cell differed depending on whether the substance was one of the body’s own opiates or a drug such as morphine. Surprisingly, the cells internalised fewer receptors when exposed to morphine than when they were exposed to the body’s own painkillers, which are seen as less addictive than drugs. Since natural opiates activate receptors more potently than morphine, von Zastrow and his colleagues decided to see if this explained the difference. They compared the amount of activation and receptor internalisation for morphine, methadone and DAMGO, a chemical similar to the body’s own painkillers. Each drug had a different ratio of receptor activation to internalisation, showing that the two events are not directly linked. Both DAMGO and morphine showed relatively high activation, but morphine caused much less internalisation ( Neuron, vol 23, p 737). The researchers argue that removing receptors from the cell surface may actually protect against the development of tolerance in the short term, because less addictive drugs such as DAMGO and methadone caused higher levels of receptor removal. They speculate that tolerance may develop when drugs don’t make cells “eat” their receptors, because this would leave them vulnerable to prolonged, abnormal stimulation that could lead to pathological changes. Natural opiates and addictive drugs working on the same receptor may make the cell do different things, and von Zastrow believes this may lie at the heart of addiction. “Even though we think of receptors as being on/off switches, there may be different kinds of being on,” says von Zastrow. “To me that is a very inviting and exciting idea.” “It is an unusual finding,” says Jean Bidlack at the University of Rochester in New York, who studies opiate receptors and tolerance. She says that when von Zastrow presented his results at a recent narcotics research meeting, it was viewed as a major advance in understanding opiates. “It’s very good work,