A combination of two drugs can selectively block pain-sensing neurons in rats without impairing movement or other sensations such as touch, according to a new study by National Institutes of Health (NIH)-supported investigators. The finding suggests an improved way to treat pain from childbirth and surgical procedures. It may also lead to new treatments to help the millions of Americans who suffer from chronic pain.
The study used a combination of capsaicin — the substance that makes chili peppers hot — and a drug called QX-314. This combination exploits a characteristic unique to pain-sensing neurons, also called nociceptors, in order to block their activity without impairing signals from other cells. In contrast, most pain relievers used for surgical procedures block activity in all types of neurons. This can cause numbness, paralysis and other nervous system disturbances.
"The Holy Grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, coordination, or other vital functions of the nervous system. This finding shows that a specific combination of two molecules can block only pain-related neurons. It holds the promise of major future breakthroughs for the millions of persons who suffer with disabling pain," says Story C. Landis, Ph.D., director of the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH, which funds the investigators' research along with the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS). NINDS and NIDCR are co-chairs of the NIH Pain Consortium. The study appears in the October 4, 2007, issue of Nature.*
Lidocaine, the most commonly used local anesthetic, relieves pain by blocking electric currents in all nerve cells. Although it is a lidocaine derivative, QX-314 alone cannot get through cell membranes to block their electrical activity.
That's where capsaicin comes in. It opens large pores called TRPV1 channels — found only within the cell membrane of pain-sensing neurons. With these channels propped open by capsaicin, QX-314 can pass through and selectively block the cells’ activity.
The research team, led by Clifford J. Woolf, M.D., Ph.D., of Massachusetts General Hospital and Harvard Medical School and Bruce Bean, Ph.D., at Harvard Medical School, tested the combination of capsaicin and QX-314 in neurons isolated in Petri dishes and found that it 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. They also injected the two drugs near the sciatic nerve that runs down the hind leg. The treated rats did not show any signs of pain, and five of the six animals continued to move and behave normally. This showed that the drugs could block pain without impairing motor neurons that control movement.
The drug combination took half an hour to fully block pain in the rats. However, once it began, the pain relief lasted for several hours.
"Current nerve blocks cause paralysis and total numbness," Dr. Woolf says. "This new strategy could profoundly change pain treatment in the perioperative setting."
The treatment tested in this study is unique in that it uses a type of ion channel (TRPV1 channels) as an avenue to deliver medication. Ion channels are pores in the cell membrane that control the flow of electrically charged ions in and out of 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," Dr. Woolf says. The strategy builds on research done since the 1970's, largely supported by NIH, that shows how electrical signaling in the nervous system results from expression of dozens of different types of ion channels. Some of these ion channels are found only in specific types of neurons.
"This project is a nice illustration of how research trying to understand very basic biological principles can have practical applications," says Dr. Bean. This type of treatment has great potential to improve pain treatment during childbirth, dental procedures, and surgery, the researchers say. "Surgical pain is the obvious first application for this type of treatment," Dr. Woolf says. However, similar therapies might eventually be useful for treating chronic pain, he adds. Chronic pain continues for weeks, months, or even years and can cause severe problems, and is often resistant to standard medical treatments.
While the researchers focused on finding a treatment for pain, this strategy might also be useful for treating itch from eczema, poison ivy rashes, and other conditions, Dr. Woolf says. Like pain sensations, itch signals come from nociceptors. One problem with the combination treatment is that the capsaicin can cause unpleasant burning sensations until the QX-314 takes effect, Dr. Woolf says. Administering the QX-314 ten minutes before the capsaicin minimized this problem in rats. The investigators are now looking for ways to open the TRPV1 channels without the burning sensations, perhaps by finding an alternative to capsaicin. They also hope to find ways of prolonging the pain relief. Eventually, they might be able to develop pills that will stop pain signals without requiring injections, Dr. Woolf adds.
The NINDS is the nation's primary funder of research on the brain and nervous system. More information about pain and other neurological disorders can be found on the NINDS web site, http://www.ninds.nih.gov/. The NIDCR (http://www.nidcr.nih.gov/) is the nation’s leading funder of research on oral, dental, and craniofacial health. The NIGMS (http://www.nigms.nih.gov) supports basic biomedical research that is the foundation for advances in disease diagnosis, treatment, and prevention. The NINDS, NIDCR, and NIGMS are components of the National Institutes of Health (NIH). The NIH Pain Consortium, co-chaired by the NIDCR, the National Institute of Nursing Research, and the NINDS, strives to enhance pain research and promote collaboration among researchers across the many NIH Institutes and Centers that have programs and activities addressing pain.
The NIH - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
*Binshtok AM, Bean BP, Woolf CJ. "Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers." Nature, October 4, 2007, Vol. 449, No. 7162, pp. 607-610.
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