Pathway may provide target for treating chronic pain

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 m

Contact: Jim Dryden
Washington University School of Medicine

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