Sci. Aging Knowl. Environ., 13 April 2005
Inflaming Chronic Pain
Immune cells might trigger mysterious untreatable pain
Certain molecules help immune cells recognize bacteria and viruses. But prodding one of these so-called receptors might help trigger a form of pain, neuropathy, that even powerful drugs can't quell, according to new research. The work shows that obliterating a Toll-like receptor in a type of immune cell that lurks in the nervous system alleviates the rodent version of this condition. The results might help researchers illuminate the pathway that torments many patients and tease out immune cells' role in pain.
For patients with neuropathic pain, even the pressure of clothes on the skin can be excruciating (see "Gain on Pain"). This sometimes-crippling pain can result from surgery or diseases such as diabetes, and it becomes more prevalent with age (see "The Burden of Pain on the Shoulders of Aging"). Morphine often doesn't relieve patients' suffering, and researchers don't know why the nerves become hypersensitive. Recent work implicates immune cells. For instance, prodding these cells in the spine causes release of inflammatory compounds and increases nerve sensitivity. Microglia, defensive cells in the nerves, carry a molecule in their cell membrane called the Toll-like receptor 4 (TLR4) that detects invading microbes. Last year, neuroscientist Joyce DeLeo of Dartmouth Medical School in Lebanon, New Hampshire, and colleagues showed that nerve injuries roused the cells and spurred then to deploy more TLR4. The researchers wanted to find out whether stimulating TLR4 unleashes neuropathic pain.
They simulated the condition in mice by cutting one of the spinal nerves that services the hind legs. The procedure makes the animals hypersensitive. The researchers operated on normal rodents and on genetically altered animals that either lacked the TLR4 gene or carried a defective version of it. They then gauged the rodents' responses to gentle pressure on the foot and having their tail dipped in hot water. Compared to genetically normal mice with snipped nerves, the engineered animals pulled away more slowly when their feet were prodded and took longer to jerk their tails out of hot water. Altered animals carried less messenger RNA for two molecules that mark active microglia and for three inflammation-promoting proteins. The findings suggest that removing TLR4 defuses the hypersensitivity that usually follows nerve injury. The team performed a similar procedure on nonengineered rats. They cut the same nerve and injected into the spine snippets of DNA that trim TLR4 production. Rats that received the blocker pulled away slowly from light pressure. Together, the results indicate that microglia in the nerves fire up neuropathic pain when something jolts TLR4 molecules on their surface, says DeLeo. So far, researchers haven't identified what TLR4 responds to in this situation, she adds.
"This is a big step forward," says neuroscientist Michael Salter of the Hospital for Sick Children in Toronto, Canada. The paper provides "the best evidence for a specific molecule between nerve injury and microglia activation," he says. Researchers should now fill in the circuit by determining what prods TLR4 and how activating microglia leads to overzealous nerves, he says. That work might someday help researchers learn to muffle TLR4 and silence neuropathic pain.
April 13, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150