EMERYVILLE, Calif., Jan. 24 (UPI) -- Researchers experimenting with rats say they can reduce the tolerance that normally develops to the powerful pain killer morphine by giving it along with a second drug -- which could have implications for pain management in humans.
Morphine is prescribed to treat pain that accompanies some cancers and neurological disorders. But tolerance to the drug almost always occurs and there is a limit to how much morphine a person can receive before it shuts down body functions, such as breathing. If the new research is validated, it may be possible to stop pain without increasing the dosage as much as currently is necessary.
Morphine works by attaching to a receptor on the surface of a cell, causing the receptor to send a signal into the cell that alleviates pain. Most receptors are taken into the cell, in a process called endocytosis, and recycled back up to the surface. But morphine tends to hold the receptor at the cell surface, resulting in a prolonged signal. As a result, the cell chemistry changes in response and a tolerance to the presence of the morphine results.
In humans, this results larger doses of morphine are needed to ease pain.
Much current thinking holds that the endocytosis process contributes to tolerance developing. The startling aspect of the new study is that it shows a little bit of endocytosis is a good thing as far as preventing tolerance from developing.
The researchers, lead by Jennifer Whistler, an assistant professor of neurology at the University of California-San Francisco's Ernest Gallo Clinic and Research Center in Emeryville, Calif., subjected rat tails to a few seconds of heat from a non-burning laser. Those rats that got the morphine plus another opiate called DAMGO did not develop the tolerance problem rats receiving only morphine did. DAMGO is closely related to an opiate-like substance that normally is present in humans.
The morphine-only rats felt no pain for four days, whereas the morphine-DAMGO rats did not experience pain for seven days, the duration of the experiment. Analysis of cells from the spinal cords of the rats showed the receptors had stayed on the surface with the morphine-only group, but had been taken into the cell and recycled in the morphine-DAMGO group.
Whistler hopes new drug combinations will be developed that can safely reduce the tolerance that develops in people with chronic pain. While acknowledging more work needs to be done, Whistler told United Press International, "We think we're going to alleviate withdrawal to morphine at the same time we alleviate the development of tolerance."
But as far as applicability to the treatment of addiction to another opioid, heroin, which is metabolized to morphine in the body, Whistler said, "I am very confident that we are going to be able to inhibit the development of dependence. I don't know how effective we're going to be at reversing dependence."
Some researchers see the results as a dramatic finding. David Self, an associate professor of psychiatry at University of Texas Southwestern Medical Center in Dallas who specializes in the neurobiology of addiction, told UPI, "Basically what she's saying is, `We've been looking at this all wrong.'"
Self said the quality of work looked excellent and added, "The punch line is that she's disproved the prevailing dogma and actually said that it's opposite of what we've been thinking for probably close to 25, 30 years."
Self said: "If you get a large amount of endocytosis, the cells are going to become tolerant to the opiate. But if you have a certain small degree of it, or you still preserve a certain amount of active effective opioid receptor ... at the (cell) membrane, you will prevent the biochemical tolerance while still preserving analgesia (pain relief).
"The magic bullet may lie in the combination of drugs which cause endocytosis with drugs which don't. And maybe part of the problem in the past is they'd never been studied in combination like that," he said.
One expert was a bit more cautions. Srinivasa Raja, a professor of anaesthesiology and critical care medicine at Johns Hopkins University School of Medicine in Baltimore, Md., where he is director of pain research, told UPI, "(The research) presents an interesting hypothesis that has potential clinical application with treatment of patients with longer term use of opioids for treatment pain.
"The conclusions would have to be taken with certain caveats. The studies were done in preparations where there is no ongoing pain," Raja said. "How ongoing pain affects the development tolerance to opioids needs to be examined further."
But John Williams, professor of neuroscience at the Vollum Institute at the Oregon Health Science University in Portland, told UPI: "I think it's a pretty amazing paper. It starts with real molecular tools and steps to neurons and then steps to animals." Williams said the techniques used were "outstanding."
Williams agreed with the central hypothesis. "A little bit of endocytosis kind of protects the receptor so that it can recycle back to the plasma membrane and then be functional," he said.
The study will spark interest and probably drive a lot more work, he said, but added much of the thinking about the mechanisms involved was entrenched and that experiments would probably be designed to show that other mechanisms may be operating to cause tolerance.
The study will appear in this week's issue of the journal Cell.
