Washington, DC - In a study that could lead to new treatments for chronic pain, scientists have relieved pain in rats by dispatching molecular "smart bombs" to selectively destroy certain nerve cells in the spinal cord. Because this approach targets just those nerve cells, or neurons, that send pain messages to the brain, it shouldn't cause the side effects of drugs such as morphine or the complications of surgery. The study appears in the 19 November issue of Science.
Thus far, the scientists' method kills the pain-signaling neurons, so its uses may be limited to stopping the extreme pain of terminally ill patients. However, designing a less drastic variation that would temporarily silence the neurons should now be "a very do-able thing," according to Patrick Mantyh, of the University of Minnesota and the Veterans Affairs Medical Center in Minneapolis, who led the research team.
The team of scientists also includes Michael L. Nichols, Brian J. Allen, Scott D. Rogers, Joseph R. Ghilardi, Prisca Honore, Nancy M. Luger, and Matthew P. Finke, from the University of Minnesota and the Veterans Affairs Medical Center in Minneapolis; Jun Li and Donald A. Simone, from the University of Minnesota, in Minneapolis; and Douglas A. Lappi, from Advanced Targeting Systems, in San Diego.
Chronic pain is an extremely common affliction that occurs in a variety of forms, from the specific pain of a migraine headache to the mysterious all-over body pain of fibromyalgia. In all of its incarnations, chronic pain seems to be the result of faulty signaling by a small group of neurons in the spinal cord. These signals can either make patients hypersensitive to stimuli that are minimally painful (such as a pinprick), or they can cause patients to feel pain in response to stimuli that are not painful at all (a warm shower, for example).
The group of neurons responsible for these inappropriate responses transmit electrical signals to each other with the help of a chemical messenger called "substance P." These neurons, which collectively make up less than five percent of all the neurons in the spinal cord, wear a receptor protein on their surface that serves as the docking point for a substance P molecule as it jumps from one neuron to the other. Once substance P binds with the receptor, the neuron then envelops both molecules into its interior.
Mantyh and his colleagues targeted these particular neurons using a Trojan horse-type strategy. They linked together molecules of a potent neurotoxin with molecules of substance P, and injected the hybrid pairs into the spinal cords of rats. When the substance P bound with the receptor on certain neurons, the cells brought about their own destruction by ushering these molecules and their neurotoxin companions inside.
A short while later, the rats became far less sensitive to stimuli that caused two key types of pain: inflammatory pain due to an injury and "neuropathic" pain caused when the neural signaling process itself goes awry-with no tissue damage required.
The rats' loss of sensitivity appeared to be permanent. In contrast, earlier efforts to treat chronic pain by surgically severing part of the spinal cord only provided temporary relief. In these cases, the pain probably returned because the surgeons cut through hundreds of other neurons in addition to those that expressed the substance P receptor. The damage to these additional neurons could have induced the brain to experience pain even without a real stimulus.
"That's the beautiful thing about this technique," said Mantyh. "We can pick out the neurons expressing substance P receptors and leave the other neurons intact."
Another important advantage of the scientists' approach is that it doesn't interfere with the mechanism by which morphine works. Physicians who wanted to administer this type of treatment to their patients should therefore find it reassuring that they could still use morphine as a standby.
Mantyh and his colleagues believe that it should also be possible to attach other molecules to substance P that would quiet--but not kill--the neurons after sneaking inside. One possible candidate might be a molecule known to temporarily shut down the neurons' powerhouses, the mitochondria.
The team's findings also provide researchers the opportunity to investigate what causes chronic pain to begin with. Scientists can now compare normal neurons expressing substance P receptors with those that are sending inappropriate pain signals. They can search, for example, for genes that are "turned on" in the misfiring neurons. It may then be possible someday to use gene therapy to correct the problem.
For the moment, Mantyh and his colleagues are planning a toxicology study to learn whether the neurotoxin they used in the rats would be safe to use the same way in terminally ill humans who are desperate for pain relief.
ORDER ARTICLE #24: "Transmission of Chronic Nociception by Spinal Neurons Expressing the Substance P Receptor," by M. L. Nichols, B. J. Allen, S. D. Rogers, J. R. Ghilardi, P. Honore, N. M. Luger, M. P. Finke, J. Li, D. A Simone, and P. W. Mantyh, at U of Minnesota, in Minneapolis, MN; M. L. Nichols, B. J. Allen, S. D. Rogers, J. R. Ghilardi, P. Honore, N. M. Luger, M. P. Finke, and P. W. Mantyh are also at Veterans Affairs Medical Center, in Minneapolis, MN; D. A. Lappi, at Advanced Targeting Systems, in San Diego, CA.
CONTACT: Patrick W. Mantyh at 612-626-0180 (phone), 612-626-2565 (fax), or manty001@maroon.tc.umn.edu (email).
For copies of this article please email scipak@aaas.org or call 202-326-6440.
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