Morphine dependency blocked by single genetic change

Jan 28, 2008

Morphine’s serious side effect as a pain killer – its potential to create dependency – has been almost completely eliminated in research with mice by genetically modifying a single trait on the surface of neurons. The study scientists think a drug can be developed to similarly block dependency.

The research was published online January 17 by “Current Biology” and appears in the journal’s January 23 print edition. The scientists were led by Jennifer Whistler, PhD, an investigator in the UCSF-affiliated Ernest Gallo Clinic and Research Center, and associate professor of neurology at UCSF.

Millions of people in the U.S. are given the opiate drug morphine for extreme pain caused by cancer, surgery, nerve damage and other conditions. It remains the pain killer of choice for many types of short-term pain, such as surgery, according to Whistler, but it is less useful for the treatment of chronic pain because its effectiveness decreases with continued use in a process called tolerance. As a consequence, an increasingly larger dose is required to treat the pain, thereby increasing the chance of addiction.

The body’s natural pain killers, such as endorphins, ease pain by first binding to receptors on the surface of neurons. The receptors cycle on and off “like a light switch,” Whistler says, regulating the intake of endorphin. This crucial control is absent when the neurons encounter morphine. The researchers’ strategy in their study was to try to trick neurons into responding to morphine in the more regulated way.

Strong evidence suggests that the natural on-off cycling occurs because the endorphin receptor withdraws from the cell surface, toward the cell’s interior, Whistler says. The migration from the cell surface is called endocytosis.

When the neuron receptors encounter morphine the light switch is broken, and the nervous system responds by becoming more tolerant of the drug, making the recipient more dependent on the drug.

To demonstrate their hunch that morphine’s unwanted effects were caused by the failure of its receptor to withdraw from the cell surface, the researchers genetically engineered mice with a single difference from normal mice: Receptors that encounter morphine in these mice can undergo endocytosis, as they normally do in the presence of endorphins. The researchers showed that with this single change, morphine remained an excellent pain killer without inducing tolerance and dependence.

“As more pain medications are being removed from the market, new strategies to overcome chronic pain become crucial,” Whistler says. “If new opiate drugs can be developed with morphine’s pain killing properties but also with the ability to promote endocytosis, they could be less likely to cause the serious side effects of tolerance and dependence.”

The research is the first direct demonstration that this single cellular change can block the body’s tendency to become tolerant of the drug, she points out.

Several strategies are now being tested to counter morphine addiction, Whistler says. These include development of morphine derivatives such as oxycontin, that are delivered in a time released manner or only once they have been processed in the digestive system. Other approaches seek to develop morphine derivatives that target only certain opioid receptors but not others.

“The most promising aspect of these other approaches is that they have the potential to prevent or delay dependence and addiction to morphine, but few of them address the development of tolerance,” Whistler said.

Source: University of California - San Francisco

Explore further: Secret of tetanus toxicity offers new way to treat motor neuron disease

add to favorites email to friend print save as pdf

Related Stories

Can stress management help save honeybees?

29 minutes ago

Honeybee populations are clearly under stress—from the parasitic Varroa mite, insecticides, and a host of other factors—but it's been difficult to pinpoint any one of them as the root cause of devast ...

Time in space exposes materials to the test of time

43 minutes ago

Much like that pickup truck rusting in your backyard thanks to time, rain and the elements, extended stays in the brutal environment of space can take its toll on spacecraft, satellites and space stations. ...

Italian natural history museums on the verge of collapse?

47 minutes ago

Are Italian natural history museums (NHMs) on the verge of collapse? A new analysis published in the open access journal ZooKeys points out that these institutions are facing a critical situation due to pro ...

Avoiding ecosystem collapse

48 minutes ago

From coral reefs to prairie grasslands, some of the world's most iconic habitats are susceptible to sudden collapse due to seemingly minor events. A classic example: the decimation of kelp forests when a ...

US northeast braces for flooding after record snow

18 hours ago

Weather forecasters and emergency officials warned Sunday that melting snow would lead to heavy flooding in parts of the US northeast, with hundreds of thousands of people told to brace for fast-rising waters.

Recommended for you

Stroke damage mechanism identified

17 hours ago

Researchers have discovered a mechanism linked to the brain damage often suffered by stroke victims—and are now searching for drugs to block it.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.