Naloxone and “Receptorology”

The power of the opiates revealed

The breakthrough that laid the groundwork for the first truly scientific understanding of addictive drugs took place in 1972, when researchers discovered the existence of specific receptor sites in the brain for the opium molecule.

At roughly the same time, emergency room doctors were baffled to discover that timely injections of a drug called naloxone completely reversed the effects of heroin intoxication. Minutes after an injection of naloxone, heroin addicts were awake, fully recovered, and instantly into the rigors of heroin withdrawal. Naloxone, and a similar drug called naltrexone, rescued O.D. victims from respiratory failure. Like a magic bullet, naloxone--trade name Narcan-- blocked the effects of heroin.

At Johns Hopkins University School of Medicine in Baltimore, Dr. Solomon Snyder and a young doctoral candidate named Candace Pert devised a method for testing this theory. By making molecules of naloxone radioactive, and following the course of the molecules with the aid of a radiation counter, Snyder and Pert were able to show that naloxone attached itself very specifically to certain neurons in certain parts of the brain. If naloxone molecules were capable of locking into specific sites, then presumably these were the same sites in the brain where the opiates did their work.

The sites in question were mean for naturally occurring painkillers called endorphins. The only reason opium worked so dramatically to relieve pain was because a part of the opium molecule was similar in shape to the naturally occurring endorphins. Heroin “fooled” the receptors designed for the shape of an endorphin molecule. Not only that, but heroin and the other opiates stimulated these receptors just as effectively as the natural endorphins did.

The stunning power of the opiates had been revealed as an architectural quirk of nature.

Naloxone was a heroin antagonist—it blocked the effect of the drug at specific sites on nerve cells in the brain. (If the drug fits the receptor and elicits a response, it is called an agonist. If it simply blocks the receptor site without stimulating a response, it is an antagonist.)

The naloxone molecule also bore an uncanny resemblance to the shape of natural endorphin molecules, and when doctors gave an O.D. victim a shot of naloxone, the naloxone molecules knocked the opium molecules right off their receptors. Then they bound themselves to the endorphin sites even more tightly than the heroin molecules did. Naloxone was capable of snapping onto the receptor sites without triggering the release of endorphin.

The brain scans developed for studying this chemical activity were produced by introducing radioactive atoms into naloxone. Wherever naloxone stuck to a receptor site in the brain of a rat, the “hot” connection lit up on special film. These maps of receptor geography in the brain led Dr. Pert and her colleagues to christen the new science “receptorology.” Likening these snapshots to “tiny sparkling grains in a sea of colorfully stained brain tissue,” Pert was helping to invent a new field of study.

“Receptorology” came to be known as neuroscience, or neuropharmacology, and operated under a deceptively simple premise: If it is a drug, and if it has an effect on the brain, then it must have a brain receptor site to which it binds. Find its site of action, and you find out what it is, what it does, and where it does it.