Engineered mice point to new target for pain relief

December 23, 1999

DURHAM, N.C.--Duke University Medical Center scientists have discovered a biological mechanism in mice that prolongs morphine's painkilling effects. Their findings could lead to the development of new drugs that make morphine last longer and relieve pain at lower doses.

The researchers report in the Dec. 24 Science that morphine prevents pain longer and more completely when administered to mice engineered to lack a protein switch called "beta-arrestin 2." Beta-arrestin normally comes into play after morphine is administered by blocking the chemical signal that morphine sends to the brain to suppress pain sensation. Thus, when the researchers genetically altered mice to lack beta-arrestin, morphine remained effective for longer periods in those mice, and lower morphine doses were required to achieve pain relief in these mice.

The findings come from the laboratories of Dr. Robert Lefkowitz and Marc Caron, both Howard Hughes Medical Institute investigators at Duke Medical Center.

At the heart of the study is a metabolic process known as "desensitization," in which an initially receptive cell develops a reduced response to a chemical stimulus. For example, desensitization occurs when a person who has entered a coffee shop quickly becomes accustomed to the aroma and no longer notices it. The stimulus hasn't disappeared, but the olfactory sensory cells that first responded to the smells ignore the stimulus after a time.

Beta-arrestin is part of the cell's machinery that produces desensitization to morphine after the morphine molecule initially binds to a receptor on the surface of nerve cells. Receptors are proteins that relay chemical signals from outside the cell to the cell's machinery to cause a cellular response.

"When the morphine receptor is activated by binding morphine, it transmits a message that initially suppresses pain perception," explained Laura Bohn, a postdoctoral fellow in Caron's laboratory who performed the experiments with the mice. "It also triggers beta-arrestin to turn off the receptor so it isn't constantly being activated. Without beta-arrestin, morphine's action is enhanced and lasts longer."

The scientists discovered that when morphine was given to mice that had the gene for beta-arrestin knocked out, the mice were resistant to a standard, mildly uncomfortable exposure to a warmed surface almost three times longer than were normal mice.

Because beta-arrestin is important for turning off the response to a variety of signals that a cell receives, the researchers were not surprised that the mice would show a change in their response to morphine. They were surprised, however, to discover the extent of the role that beta-arrestin plays to cause morphine's effects to subside.

"We were amazed that beta-arrestin was, in fact, very important in determining how quickly the analgesic properties of morphine wear off," recalled Caron.

If the findings in mice apply to humans, new drugs might be developed to block the action of beta-arrestin, said Caron. Such drugs might be used in combination with lower doses of morphine to extend the amount of pain relief it can provide and reduce the side effects, he said.

Morphine is currently the "gold standard" of analgesic drugs and is used to treat moderate to severe pain following surgery and chronic pain experienced, for example, by cancer patients. However, morphine sometimes produces nausea, and may suppress breathing if given in too great a dose. Also, chronic administration of morphine produces tolerance, such that patients need greater and greater doses to achieve pain relief.

The scientists also emphasized the possibility that blocking beta-arrestin might not only enhance morphine's action, but may also prevent the process of tolerance and even addiction.

"We don't yet know how tolerance and physical dependence will relate to desensitization," said Lefkowitz. "But there is a chance that maybe the beta-arrestin-deficient mice won't become tolerant or physically dependent. That's why it's exciting to think about the potential uses of these mice."

Other contributors to the study include Raul Gainetdinov, a research assistant professor of cell biology in Caron's laboratory; Karsten Peppel, a research assistant professor of medicine at Duke; and Fang-Tsyr Lin, a postdoctoral fellow in Lefkowitz's laboratory who created the mutant mice by genetic engineering.
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Duke University Medical Center

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