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Duke Researchers Test New Pain Targets

June 1, 2016
Researcher could lead to the development of new agents, including 16-8, that blocks TRPV4 and TRPA1—promising targets for the treatment of pain, itch, and inflammation.

A potential new class of drugs that simultaneously block pain and itch have been discovered by a team of researchers at Duke University in Durham, North Carolina.

Although only it is preliminary stages, the research could lead to the development of a new agent to treat conditions including skin irritation and itching, headaches, temporomadibular disorders, and visceral pain.

“We are very pleased with what is a first chapter in a highly promising story,” said Wolfgang Liedtke, MD, PhD, a professor of neurology, anesthesiology, and neurobiology at Duke University School of Medicine. “We hope to be able to develop these compounds for clinical use in humans or animals.”
Wolfgang Liedtke, MD, PhD, is a Duke professor of neurology and anesthesiology, and an associate professor of neurobiology and a member of the Duke Institute for Brain Sciences. Photo courtesy of Duke University.
In the new study, the researchers initially aimed to develop more effective blockers of transient receptor potential vanilloid 4 (TRPV4), a molecule their previous research had shown transmits skin irritation elicited by sunburn, and painful sensations coming from the head and face.1 Dr. Liedtke and his Duke collaborator Farshid Guilak used a prototype TRPV4 blocker in a 2009 study and then set out to develop more potent versions.2

Compared to the prototype, one of the new candidate drugs, called “16-8,” worked 10 times more effectively in cells with active TRPV4 that are key for the development of osteoarthritis, noted a press release from Duke University.  It also worked well in another cell type involved in nerve cell injury, stroke, and epilepsy.

When assessing the specificity of 16-8, the scientists were surprised to discovered that it also blocked transient receptor potential cation channel, subfamily A, member 1 (TRPA1), which is a promising target in pain and itch research.

“As a physician, I soon realized the enormous potential that these compounds might have, given how beneficial dual-target molecules can be in clinical medicine,” Dr. Liedtke said.

Both TRPV4 and TRPA1 are members of the family of TRP ion channels, which function in sensory nerve cells to directly sense painful stimuli. Other research groups are now targeting these channels in clinical trials for pain relief.

In this study, the drug 16-8 effectively managed pain in animal models, including pancreatitis in mice. Pancreatitis is extremely painful and difficult to treat, and new cases are on the rise globally, said study co-author Rodger Liddle, MD, of the Duke University School of Medicine and a member of the Duke Institute for Brain Sciences.

Dr. Liedtke sees potential for the 16-8 drug to treat osteoarthritis and other types of joint pain as well as head, face and jaw pain. In general, it might also treat visceral pain and neuropathies.

According to Duke, the researchers preclinical work will focus on "understanding the compound’s potential use in these conditions as well as learning more about how it works."

The study was supported by the National Institutes of Health (DE018549, AR48182, AR48182-S1, AR48852, AG15768, AR50245, AG46927, DK064213, DK091946, DK098796, F33DE024668, K12DE022793, K12CA100639, the U.S. Department of Defense (W81XWH-13-1-0299), the U.S. Department of Veterans Affairs, the National Science Foundation (1445792), the Arthritis Foundation, and the Harrington Discovery Institute Scholar-Innovator Award. Duke’s Office of Licensing and Ventures is pursuing patent applications on this work.

Last updated on: June 1, 2016
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