Pathway may provide target for treating chronic pain

October 17, 1999

St. Louis, Oct. 18, 1999 -- Researchers have found that cells in the spinal cord can transmit sensations of pain through a network of cellular receptors not previously associated with pain. This network may be responsible for transmitting chronic pain, and blocking its activity may provide a new strategy for pain management.

Scientists from Washington University School of Medicine in St. Louis and Howard Hughes Medical Institute investigators at Massachusetts General Hospital and Harvard Medical School reported this finding in the November issue of Nature Neuroscience. They say serotonin--a neurotransmitter in the central nervous system (CNS)--and a cell-surface receptor called AMPA can activate silent synapses in the CNS. These synapses--junctions between nerve cells--then transmit pain signals even when no painful stimulus is present.

"Most pain medications target signals carried through a different system of receptors, so they have little or no effect on chronic pain signals transmitted at AMPA receptor sites," said Min Zhuo, Ph.D., the study's principal investigator and an assistant professor of anesthesiology and neurobiology at Washington University School of Medicine in St. Louis.

When we encounter a painful event, receptors on the skin, muscle or internal organs trigger an electrical impulse that travels along a nerve fiber to the dorsal horn of the spinal cord. That fiber connects with a nerve cell that passes the pain signal up the spinal cord to the brain. Because the signals cross junctions--synapses--on their way to the brain, they can be modified en route. For example, opioid drugs prevent signals from crossing synapses, preventing patients from feeling pain.

Silent synapses provide a second network of junctions that normally are not used, but through which pain signals can travel to the brain. Their existence was suggested more than 20 years ago but, until last year, technical limitations prevented detailed studies of how and why they become active.

In Nature last year, Zhuo and colleague Ping Li, M.D., a research associate in anesthesiology, reported that they could identify silent synapses by monitoring electrical responses of individual neurons. After these synapses were awakened, they remained active and able to relay painful sensory information to the brain even after the painful stimulus was gone.

In those experiments, the researchers showed that the silent synapses could be activated both by strong pain signals and by messages from a brain region called the rostroventral medulla (RVM), which sends chemical signals to the dorsal horn of the spinal cord. But little was known about what happens inside a nerve cell when a silent synapse is activated.

In the current study, Zhuo and colleagues found that activation of silent synapses involves an interaction between AMPA receptors and a protein called glutamate receptor interacting protein (GRIP).

"One hypothesis is that GRIP binds to the cell at an AMPA receptor site inside of the cell," Zhuo said. "Then, under certain conditions, the receptor moves itself to the synaptic part of the neuron. That movement activates the formerly silent synapse."

Receptors at synapses receive messages from other neurons. AMPA receptors are sensitive to a brain chemical called glutamate.

"AMPA receptors are highly dynamic," said co-investigator Morgan Sheng, M.D., Ph.D., associate professor of neurobiology at Massachusetts General Hospital and Harvard Medical School and assistant investigator with the Howard Hughes Medical Institute. "They can be recruited to and removed from the synapse. It's actually a marvelously simple way to regulate synaptic strength. You silence a synapse by taking away receptors and strengthen it by adding more receptors."

Zhuo compares the process to an overnight courier service. Each evening, many packages come in. But the next morning, those packages go back out, allowing the office to maintain a balance between arriving and departing packages. Too many arrivals or too few departures leads to a buildup of packages at the office and also can harm businesses that don't receive them on time.

The balance between adding and subtracting AMPA receptors appears to play a role in chronic pain. Zhuo believes most people don?t suffer from chronic pain because silent synapses remain silent under normal conditions. The GRIP protein recruits AMPA receptors and activates silent synapses only when the chemical messenger serotonin is released by nerve fibers descending from the brain.

In these experiments, Zhuo, Sheng and colleagues manufactured a protein fragment, called a peptide, to compete with GRIP at AMPA receptors in neurons. When that synthetic peptide bound to the receptors, the latter were unable to move to the synaptic site, and the silent synapse remained silent. The cells maintained their normal conversations with other neurons, however.

"That means it may be possible to prevent or reverse the activation of silent synapses without affecting other communications between neurons as a strategy for treating chronic pain," Zhuo said.

Treatment methods might include blocking serotonin on the outside of the cell or using peptides to inhibit the interaction between GRIP and AMPA inside the cell. Another strategy could involve a substance called protein kinase C (PKC). Like serotonin, large quantities of PKC can activate silent synapses. In these experiments, Zhuo and colleagues have shown that PKC activates silent synapses via the AMPA receptor, providing two potential targets for therapy.

"I think this study really supports the idea that pain can be caused by pathways that normally are not painful," Zhuo said. "The more of those targets we can identify, the greater the odds we can find medicines to help patients who are not helped by traditional drugs," Zhuo said.
This research was supported by grants from the National Institutes of Health.

For more information, refer to Li, Ping et. al., "AMPA receptor-PDZ interactions mediate synaptic facilitation in mammalian spinal cord," Nature Neuroscience 2(11), 972-977, Nov. 1999.

Washington University School of Medicine

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