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University of Minnesota
July 27, 2010
New Regents Professor Horace Loh has made major contributions to understanding the mechanisms of pain relief and drug addiction.
Photo by Patrick O'Leary
Horace Loh's studies of opiate addiction and pain relief earn him a Regents Professorship
By Deane Morrison
A friendly man with a wide smile, Horace Loh is exactly the kind of person you would want to see win a big award.
As a major contributor to the understanding of how opiate drugs such as morphine work on the molecular level, Loh, a professor of pharmacology, has awards to burn.
Now, his work has earned him the title of Regents Professor, the University of Minnesota's highest faculty rank. And he is out to turn his research findings into better treatments for both opiate addiction and pain.
Anatomy of addiction
Loh's research group was the first to study the neurochemical mechanism of opiate addiction. It rests on the presence of structures called opiate receptors, which sit on the outer surfaces of nerve cells and respond to molecules of morphine or other opiate drugs as a lock responds to a key. As they interact, the drug changes the receptor's shape. This "activates" the receptor, setting off biochemical changes in the cell.
Figures 1 and 2 show how morphine works in the human brain.
Fig. 1: Nerve 1 "talks" to nerve 2 by releasing a chemical called GABA. GABA activates a receptor on nerve 2 (the thick blue bracket); this causes nerve 2 to release less dopamine, a chemical that causes a person to feel good.
Fig. 2: Morphine activates an opiate receptor on nerve 1. The effect is to shut off GABA release. Now, nerve 2 is free to release more dopamine, allowing the person to feel better.
But the discovery of receptors for morphine in the human brain raised a big question: Since morphine was unknown to humans for most of our evolutionary history, why would we be wired to respond to it? The answer came with the discovery by others that our brains make pleasure-causing morphine-like substances called endorphins, which Loh calls "the brain's own morphine."
It was Loh and his colleagues who found the most potent endorphin—beta-endorphin—and that it was not only 200 times as potent as morphine, but addictive as well. And no wonder.
"The opiate receptor [for endorphins] also is involved in other functions, such as sexual behavior and food intake," explains Loh.
'A better morphine'
Loh's driving passion is to understand how morphine produces addiction in order to find a chemical treatment for addiction and to design a painkiller without the side effect of addiction—in other words, a "better morphine."
With longtime colleague Ping-Yee Law, he has developed a gene therapy that works in animal models as a nonaddictive treatment for pain. Their approach is to modify the opiate receptor rather than modifying the morphine molecule, which is the traditional approach.
How it works: The researchers injected rat spinal cords with a gene for a mutated form of opiate receptor. Then they injected a chemical similar to morphine that activates the mutated receptor but not the normal one. The result: By activating the mutated receptor, they killed pain but produced no addiction.
Loh and Law are now searching for a small molecule that can cause the normal receptor to behave like a mutated one. This would bypass the need for gene therapy and allow doctors to treat pain with chemicals similar to morphine, without fear of causing addiction.
"That is the Holy Grail of our research," Loh says.
Published in 2010