For centuries, doctors have tried to find effective ways to treat chronic pain, a devastating neurological disorder that affects almost 90 million Americans. A new study shows that two proteins in the brain trigger the neuronal changes that amplify and sustain this type of pain. The finding may lead to new ways of treating chronic pain.
"This is the first [chronic pain] study to show clear molecular targets in the brain," says Min Zhuo, Ph.D., of Washington University in St. Louis, Missouri, senior author of the report. "Drugs that inhibit these two proteins may help to reduce chronic pain." The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the November 14, 2002, issue of Neuron. 1
Unlike the short-term, acute pain that people feel when they stub a toe or burn themselves, chronic pain is a disorder of the nervous system that persists for months or years and cannot be fully relieved by standard pain medications. It often includes burning, shooting, or shocking sensations. Chronic pain also may cause a problem called allodynia, in which people experience pain from stimuli that are not normally painful, such as a light touch or a breeze, or pain in places other than the area that is stimulated. There are many different kinds of chronic pain, including central pain, chronic regional pain syndrome (also called reflex sympathetic dystrophy), and peripheral neuropathy.
Most studies of chronic pain have focused on signals in the spinal cord and in the peripheral nerves, which carry pain messages from the limbs and other parts of the body to the spinal cord. However, recent studies have suggested that the brain not only receives pain signals from the spinal cord but also undergoes changes in neuronal connections that may permanently strengthen its reactions to those signals. Researchers believe these changes are key to the development of chronic pain.
In the new study, Dr. Zhuo and his team tested pain-related behavior in normal (control) mice and in mice missing the gene for two proteins called adenylyl cyclase 1 and 8 (AC1 and AC8). These two enzymes are found primarily in a part of the forebrain called the anterior cingulate cortex (ACC). Previous studies have shown that this region is important for feeling pain.
The two groups of mice reacted the same way to stimuli that cause acute pain. However, in tests of chronic pain, the mice without AC1 and AC8 had much smaller reactions than the control mice, suggesting that they did not feel as much pain. When the researchers gave these mice a substance that increases the amount of a chemical called cyclic AMP, which triggers changes in neuronal connections, they began to react to painful stimuli like the normal mice did. This showed that disabling the two genes blocked chronic pain by preventing pain-related changes in neuronal connections, rather than by permanently altering the brain during development.
The neuronal changes that underlie chronic pain are similar in many ways to those that occur when long-term memories are stored. Studies have found that animals with memory genes missing or "knocked out" often have reduced pain sensitivity, and that increasing the amount of cyclic AMP - which is crucial for long-term memory - increases animals' chronic pain sensitivity. Nature often uses proteins and systems in more than one way, Dr. Zhuo says. This is efficient from a biological standpoint, but it makes it difficult to design drugs without unwanted side effects.
"Hopefully, we can find a magic protein that is only involved in pain - not memory or other functions," Dr. Zhuo says. However, researchers have so far been unsuccessful at identifying pain drugs without potentially serious side effects, he adds.
Previous studies have shown that mice without AC1 and AC8 have impairments of several kinds of memory, including contextual memory (learning to avoid a specific situation when it is paired with an unpleasant stimulus). However, the mice can perform other kinds of memory tasks without difficulty, and the two proteins do not affect existing memories, Dr. Zhuo says. The potential memory impairment from drugs or gene therapy to inhibit these proteins may be acceptable to patients who otherwise have to live with intense pain, he suggests.
While the researchers do not know of any existing drugs that can inhibit AC1 and AC8, it might be possible to identify or design drugs for this purpose, Dr. Zhuo says. "Our study makes a good argument for drug companies to look at these proteins," he adds. He and his colleagues are now planning experiments to study the proteins and mechanisms that are triggered by AC1 and AC8. Those studies may lead to other potential targets for therapy.
The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.
1 Wei F, Chang-Shen Q, Kim SJ, Muglia L, Maas JW Jr., Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, Zhuo M. "Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenyl cyclases." Neuron, November 14, 2002, Vol. 36, pp. 713-726.
-by Natalie Frazin
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