A shot at pain prevention: nerve-healing protein relieves rats' misery.

A chemical that spurs growth of nerve cells during fetal development may provide a new way to treat severe chronic pain that results from nerve damage, according to a study of rodents.

"Is this a promising candidate for a drug? The answer is, absolutely yes," says Frank Porreca of the University of Arizona Health Sciences Center in Tucson. "It works in multiple models of neuropathic pain."

Neuropathic pain was recognized during the Civil War. From that conflict, physicians for the first time encountered large numbers of patients with bullet wounds that elicited intense, ongoing pain despite seemingly minor tissue damage. The 19th-century neurologist S. Weir Mitchell documented many cases in which pain persisted for years and where even a slight breeze could trigger a severe burning sensation on a patient's skin.

Physicians now know that neuropathic pain derives from nerve damage that never heals properly. The nerves, injured by trauma, diabetes, stroke, or one of many other insults, send pain signals to the brain. The signals may be constant or may occur whenever surrounding tissue is perturbed.

"These neuropathic pains are often very extreme, they're often very long-lasting, and they're often refractory to conventional analgesics, including opiates," such as morphine, says Stephen McMahon of King's College London.

Newer drugs, such as the antiseizure agent gabapentin, sometimes provide modest pain relief but only by dulling the entire nervous system, essentially sedating the patient.

In the past few years, researchers have investigated another treatment strategy: fixing the injured nerves rather than stifling the pain signals. In 2000, McMahon and his colleagues reported promising results after giving rodents a protein called glial-derived neurotrophic factor (GDNF). It and similar chemicals support the growth of the developing nervous system and promote the survival of damaged nerve cells in adult animals. "The [chemicals] are kind of a chicken soup that keeps neurons happy," says McMahon.

In an upcoming Nature Medicine, Porreca and his coauthors report that artemin, a relative of GDNF, also shows promise for treating neuropathic pain. They tested the protein on rats with spinal-nerve damage that makes the animals hypersensitive to touch and heat. In this model of neuropathic pain, periodic injections of artemin largely reversed the animals' hypersensitivity, the researchers found. The protein has also shown similar promise against other forms of neuropathic pain, Porreca says.

The changes in nerve cell shape and biochemistry that underlie neuropathic pain unfold in well-understood ways. "One of [artemin's] characteristics is to reverse a lot of the changes that occur in the nervous system," Porreca says.

Artemin interacts with cell-surface proteins that are found only on sensory nerves, so it may have fewer side effects than do conventional pain medications or even GDNF, Porreca suggests. For the recent experiments, he worked with Biogen, a biotech firm in Cambridge, Mass., which controls the patent rights to artemin and is considering whether to continue developing it into a drug. Most drug companies shy away from protein-based drugs because they have to be injected, McMahon notes. So far, he adds, investigators have had little luck finding smaller molecular mimics of GDNF and artemin that could be taken as oral drugs.

QUOTE

"Is this a promising candidate for a drug? The answer is, absolutely yes."

FRANK PORRECA

University of Arizona Health Sciences Center