Compound may improve morphine's effectiveness

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Compound may improve morphine's effectiveness

By Merritt McKinney

NEW YORK, Jan 25 (Reuters Health) - One of the problems with morphine is

that patients taking the drug for chronic or severe pain usually develop

a tolerance to its effects, requiring doctors to up the dose--and the

risk of addiction--to keep pain under control. Now California

researchers have found a potential way to prevent morphine tolerance--at

least in rats.

Rats given a small dose of a compound called DAMGO along with morphine

did not develop tolerance to the pain-killing drug, Dr. L.

Whistler of the University of California, San Francisco, and colleagues

report in the January 25th issue of the journal Cell.

DAMGO, the compound that keeps morphine from losing its effect on rats,

is not suitable for humans, but there are several drugs that might have

the same effect in people, Whistler told Reuters Health in an interview.

To find a way to keep morphine's effects from diminishing, Whistler and

her colleagues had to reconsider the conventional thinking about a

cellular process called endocytosis.

Morphine works by binding to a receptor on nerve cells. Once it attaches

to the receptor, morphine sends out pain-relieving signals.

In the absence of morphine, the body has natural pain-killing molecules

that latch onto these receptors, Whistler explained. After these natural

painkillers bind to the receptors, the receptors are deactivated and are

moved into the cell in a process called endocytosis. Once in the cell,

the receptors are reactivated and returned to the cell surface, and the

cycle begins again, she said.

By reducing the number of receptors that are available to bind with

morphine, endocytosis has been thought to promote tolerance, Whistler

said. This idea makes a lot of sense, but " it doesn't fit with the

available data, " she said.

The California researcher compared the cycle to a set of flashing

lights. When a natural painkiller attaches to a receptor, a light

flashes, but then it turns off as the receptor is taken into the cell

during endocytosis. Once the receptor has been returned to the cell

surface and it binds with another pain-killing molecule, the light

flashes again, and the cycle continues.

Instead of reducing the number of receptors available for binding with

morphine, endocytosis, by recycling the receptors, actually helps

maintain an adequate supply of receptors on the surface of a cell,

according to Whistler.

But when morphine binds to a receptor, endocytosis does not take place,

so the receptor remains on the cell surface, Whistler explained. Rather

than turning on and off, " the light is on all the time. "

Instead of providing continuous pain relief, having the morphine light

on all the time actually makes cells resistant to the drug's effect,

according to Whistler.

" The cells put on dark glasses, " she said.

But Whistler and her colleagues found that rats given DAMGO along with

morphine do not develop tolerance. What happens, she said, is that

endocytosis starts when DAMGO binds to a receptor, causing the receptor

to move into the cell.

DAMGO does not go alone, however. It drags the morphine-bound receptors

along with it, Whistler said. All of the receptors are reactivated and

returned to the surface of the cell, where they are available once again

to link up with morphine.

The " lights " on the morphine receptors are not on all the time, the

cells do not need to put on " dark glasses " so they stay responsive to

morphine, Whistler said.

DAMGO will not work in people, since it is not able to cross from the

blood into the brain, Whistler said. However, she said that there are

several opiate drugs that might work in people. These drugs can have

serious side effects, but these could probably be avoided, Whistler

noted, since only a very small dose would be sufficient to jumpstart the

endocytosis process in patients taking morphine.

Besides preventing patients from developing a tolerance to morphine,

Whistler said that encouraging endocytosis may prevent or reduce

withdrawal once people stop taking the drug. She and her colleagues plan

to test this approach in their next set of animal experiments.

SOURCE: Cell 2002;108:271-282.