A research team at Duke University has discovered a potential new class of small-molecule drugs that simultaneously block two sought-after targets in the treatment of pain. Their proof-of-concept experiments, published in Scientific Reports, could lead to the development of a new drug to treat conditions such as skin irritation and itching, headaches, jaw pain, and abdominal pain stemming from the pancreas and colon.
More than 100 million people live with chronic pain in the United States, according to a report from the Institute of Medicine, and new pain medications are badly needed.
“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 the Duke University School of Medicine. “We hope to be able to develop these compounds for clinical use in humans or animals.”
In the new study, the researchers initially aimed to develop more-effective blockers of TRPV4, a molecule that transmits skin irritation elicited by sunburn as well as painful sensations coming from the head and face. Liedtke and his Duke collaborator, Dr. Farshid Guilak, used a prototype TRPV4 blocker in a 2009 study and then set out to develop more-potent versions.
Compared with the prototype, one of the new candidate drugs, called 16-8, worked 10 times more effectively in cells with active TRPV4, which are key for the development of osteoarthritis. 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 discovered that it also blocked TRPA1, which is a promising target in pain and itch research. Both TRPV4 and TRPA1 are members of the family of TRP ion channels, which function in sensory nerve cells to directly sense painful stimuli.
In the new study, 16-8 also reduced pain in living animals, including abdominal aches in mice with pancreas inflammation. Pancreatitis is extremely painful and difficult to treat, and new cases are on the rise globally, according to co-author Rodger Liddle, MD.
Liedtke sees the potential for 16-8 to treat osteoarthritis and other types of joint pain as well as head, face, and jaw pain. The compound might also treat aches radiating from internal organs or resulting from nerve cell injury.
The researchers’ preclinical work will focus on understanding the use of 16-8 in these conditions as well as on learning more about how the compound works. They also hope to explore topical applications to mucous membranes, which are present throughout the body and skin.