Scientists have for the first time determined the three-dimensional atomic structure of a human opioid（阿片样物质） receptor, a molecule on the surface of brain cells that binds to opioids and is centrally involved in pleasure, pain, addiction, depression, psychosis, and related conditions. Dozens of legal and illegal drugs, from heroin to hospital anesthetics（麻醉药） , work by targeting these receptors. The detailed atomic structure information paves the way for the design of safer and more effective opioid drugs. "This finding is going to have a major impact on understanding the fundamental principles of opioid receptor recognition and evolution," said Raymond Stevens, PhD, a professor at The Scripps Research Institute. Stevens is the senior author of the new study, which appears online in the journal Nature on March 21, 2012.

 A Symphony of Activity

Opioid receptor subtypes in the human brain work together in a symphony of activity that is still not fully understood. The "mu" opioid receptors mediate feelings of pleasure and pain-relief; they are the prime targets of the body's own endorphin neurotransmitters as well as heroin, morphine（吗啡） , and most other opioid drugs. By contrast, "kappa" opioid receptors are bound by neurotransmitters known as dynorphins, and when activated can depress mood and produce dissociative, psychedelic（迷幻剂） experiences. The plant Salvia divinorum, which was originally cultivated by Mesoamerican societies for religious ceremonies and is now used widely as a recreational drug, has an active ingredient, Salvinorin A, that binds selectively and with high affinity to kappa opioid receptors.

"We don't know why kappa receptors evolved, but we know that they have been around for a long time in evolutionary terms; even frogs have them," said Bryan Roth, a professor of pharmacology and an opioid receptor expert at the University of North Carolina, whose group teamed with the Stevens lab for the new study.

If their psychedelic and mood-darkening effects could be avoided somehow, kappa opioid receptor activators, or "agonists," could be very useful medically. In animal studies, they act as mild and non-addicting pain-relievers, weaken the addictive effects of other drugs, and reduce irritable bowel signs. "Antagonist" compounds that block kappa opioid receptor activity also show promise as treatments for depression, anxiety, and other psychiatric conditions. Even the psychedelic effects associated with kappa receptor activation could be useful in providing insights into perception and consciousness. "This is a receptor that is important for how we see reality," said Roth.