WASHINGTON -- Three opioid receptors have been cloned inthe past year, researchers said at a press conference here atthe annual meeting of the Society for Neuroscience onWednesday. This research, it is hoped, could lead to new,superior treatments for drug addiction.
Already, "our technology transfer office at Indiana Universityhas been contacted by many ... small biotechnology companies,"said Lei Yu of the Department of Medical and MolecularGenetics at Indiana University School of Medicine, who clonedthe mu receptor.
But the medical potential of these clonings extends beyondprospective treatments for drug addiction. Opioid receptors areinvolved in alcoholism, pain, certain reproductive systemdisorders, irritable bowel syndrome, endocrine disorders andeven modulation of the immune system. This line of researchmay be important for hepatitis B and C, lupus, rheumatoidarthritis and possibly even AIDS, said Mary Jeanne Kreek, headof the laboratory of biology of addictive diseases at RockefellerUniversity.
Previously, scientists had largely been unable to separate thepain-killing, euphoric and addiction-causing effects of opioids.Now, thanks to genetic techniques, the molecular details areemerging. The big payoff would be opiates that are clinicallyeffective and non-addictive.
Can this be done by designing drugs that bind selectively toone of the three receptors? Or will it be necessary to stimulatedifferent receptors at once, like different chords on a musicalinstrument?
Early studies are providing clues to drug design. The moreaddictive medically valuable opioids, such as morphine,methadone and fentanyl, bind selectively to the mu receptor,according to Yu and Terry Reisine of the Department ofPharmacology at the University of Pennsylvania.
Nonetheless, withdrawal reactions occur in cells containing anyof the three types of receptors, as Yu has shown for mureceptors. He inserted them into Chinese hamster ovary cells,laboratory cell lines that normally lack the receptors. When headded morphine there was reduced response of second-messenger compounds inside the cell. But when he withdrewthe drug after hours of chronic exposure, second-messengercompounds over-responded.
This overshooting occurs in heroin addicts when the drug istaken away, but not in patients receiving a steady dose of amedical opioid, said Kreek. This finding, which has importantimplications for patients, can now be explained through morecell modeling, she said.
Stimulating different parts of receptors may provide importantinsights for drug design, said Reisine. Working with kappareceptors, researchers discovered different binding sites foractivators and blockers. This was the first evidence thatactivating and blocking sites can be separated, he said.(Unfortunately, currently available kappa activators are oflimited use because they induce psychosis, said Reisine.)
Kreek's research has shed light on cocaine addiction, which haslong been associated with depletion of dopamine. She foundthat following binges, mu and kappa receptors bind morestrongly than normal in those parts of the brain wheredopaminergic fibers have terminals and where cocaine affectslevels of dopamine. Increased levels of dinorphin are evident,as well, and this endorphin may serve as a feedback controllerof dopamine release, said Kreek.
Site-directed mutagenesis and chimera work "will allow us tolook at how and where the ligands are binding veryspecifically," she added.
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.