Treatment Targets Pain in Rats

A sensory neuron. Isabella Gavazzi, Wellcome Images

Researchers have developed a combination treatment using two drugs that selectively blocks pain in rats without impairing movement or other sensations such as touch. The technique may lead to new pain treatments for people.

Most pain relievers used for surgical procedures, including lidocaine — the most commonly used local anesthetic — block activity in all types of neurons (nerve cells). This can cause numbness, paralysis and other nervous system problems. Researchers at Massachusetts General Hospital and Harvard Medical School set out to develop a more targeted pain treatment. Their work was funded by NIH's National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Dental and Craniofacial Research (NIDCR) and National Institute of General Medical Sciences (NIGMS).

The new approach, reported in the October 4, 2007, issue of Nature, uses a combination of capsaicin — the substance that makes chili peppers hot — and a drug called QX-314. QX-314 is a lidocaine derivative that, unlike lidocaine, cannot pass through cell membranes by itself to block electrical activity in nerve cells.

That's where capsaicin comes in. It opens a type of ion channel called TRPV1 that is found only in the cell membranes of pain-sensing neurons. Ion channels such as TRPV1 are essentially pores in the cell membrane that control the flow of electrically charged ions into and out of cells. When these channels are opened by capsaicin, QX-314 can pass through.

The researchers tested the drug combination on neurons in the laboratory. They found that the drugs blocked pain-sensing neurons without affecting other nerve cells. They then injected the drugs into the paws of rats and found that the treated animals could tolerate much more heat than usual. The drug combination took half an hour to fully block pain, but the pain relief lasted for several hours.

The researchers also injected the two drugs near the sciatic nerve that runs down the hind leg. The rats showed no signs of pain, and 5 of the 6 animals continued to move and behave normally. These results show that the combination blocks the activity of pain-sensing nerve cells without impairing signals from other cells.

"I'm not aware of any other strategy that uses a channel within cells to deliver a drug to a select set of cells," said Dr. Clifford J. Woolf, one of the researchers.

This strategy builds on research dating back to the 1970's, largely supported by NIH, into electrical signaling in the nervous system. Dr. Bruce Bean, another researcher on the project, said, "This project is a nice illustration of how research trying to understand very basic biological principles can have practical applications."

This type of treatment strategy has potential to improve pain treatment during childbirth, dental procedures and surgery, the researchers say. It may also prove effective for treating chronic pain that's resistant to standard medical treatments. The investigators are now looking for ways to improve the treatment further. Eventually, they hope to be able to develop pills that could stop pain signals without requiring injections.