Molecular Switch: Protein may influence chronic-pain disorder

A cell-surface protein found in the nervous system plays a central role in a chronic-pain condition known as neuropathy, a new study in rodents suggests.

In a normal reaction to injury or disease, pain signals activate immune cells in the central nervous system. These cells signal other cells and proteins, triggering inflammation and other healing processes.

Typically, this pain-inducing signaling subsides once healing is well under way. But in neuropathic pain the signaling persists. In this way, the nervous system generates its own pain.

Neuropathic pain can afflict people with diabetes, herpes, AIDS, amputated limbs, and other conditions. Its precise mechanism in the nervous system remains poorly understood and long-lasting treatments can have side effects.

To address those issues, Joyce A. DeLeo of Dartmouth Medical School in Lebanon, N.H., and her colleagues conducted a series of experiments on mice and rats to clarify the role in neuropathic pain of a cell-surface protein dubbed TLR4, short for toll-like receptor 4. TLR4 is displayed prominently by microglia, the primary immune cells residing in the central nervous system.

The scientists induced a form of neuropathic pain in the rodents by severing a nerve near the spinal cord, an injury that throws the animals’ nervous systems into disorder and causes the same kind of hypersensitivity to temperature and touch experienced by people with neuropathy.

DeLeo and her colleagues first compared groups of mice—some normal and some genetically engineered to lack TLR4 or to make a defective version of it. During the 2 weeks after a nerve was severed, mice lacking a functional TLR4 showed fewer signs of neuropathic-type pain than did normal mice when the animals were lightly poked on a paw or had their tails exposed to hot water.

The scientists next tested rats that had received a similar nerve cut to induce neuropathic-type pain. Normal rats reacted visibly to the contact and heat tests, whereas rats given a drug to block the action of TLR4 showed much less hypersensitivity, the scientists report in an upcoming Proceedings of the National Academy of Sciences.

Spinal-fluid samples showed that rodents with functional TLR4 produced more inflammatory proteins in their central nervous systems than did rodents lacking working TLR4. That suggests that the microglial cells that display TLR4 signal the body to turn on inflammation and are involved in hypersensitivity to pain, DeLeo and her colleagues report.

The data are the first to demonstrate that TLR4 plays “a key role” in pain hypersensitivity, the researchers conclude. However, even in the mice lacking TLR4, hypersensitivity wasn’t completely wiped out, suggesting that other factors play a part in neuropathic pain.

“I think our understanding of the basic mechanisms of pain is still primitive,” says Michael J. Iadarola of the National Institute of Dental and Craniofacial Research in Bethesda, Md. However, this and other recent work are revealing “the intersection between inflammation and pain,” he says.

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