An investigational non-opioid drug that targets receptors on immune cells may be an effective way to treat chronic pain, a study with mice shows.
Faced with the epidemic of opioid addiction, researchers looking for other strategies to treat pain have largely focused on nerve cells that transmit signals to the spinal cord and brain.
The new research, which appears in the Journal of Neuroscience, shows that a non-opioid, investigational drug called EMA401 has promise as a treatment for lingering nerve pain following shingles infection.
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While trying to understand how the drug helped control pain, the researchers were surprised to find that it doesn’t hit nerve cells; rather, it targets a receptor on immune cells.
“We are in dire need of good pain-killing drugs, particularly non-opioid drugs,” says principal investigator D.P. Mohapatra, associate professor in anesthesiology at Washington University School of Medicine in St. Louis.
“Generally, scientists have the understanding that targets for treating pain must be within the nervous system. It turns out that the target here is not on nerve cells, but on immune cells called macrophages.”
The investigational drug inhibits the angiotensin II type 2 receptor that is targeted by medications that lower blood pressure. Angiotensin is a hormone that causes blood vessels to constrict, increasing blood pressure.
This drug was thought to work by interacting with the type 2 receptor on nerve cells—the same cells that carry pain signals. But when Mohapatra and colleagues at the Washington University Pain Center looked more closely, they found that theory was wrong.
“When we took nerve cells from mice, put them in a culture dish, and added the angiotensin hormone, nothing happened,” says co-investigator Andrew Shepherd, an instructor in anesthesiology. “There was no angiotensin type 2 receptor on sensory neurons, so pain signals couldn’t be transmitted.”
But in other experiments in which they injected the angiotensin hormone into mice, the animals indicated they felt pain and withdrew their paws when touched.
“We found that the receptor the drug affected wasn’t on the nerve cells; it was on macrophages, the immune cells,” Shepherd says. “When we added macrophages to the dish alongside the nerve cells, the angiotensin could ‘talk’ to the macrophages, and then the macrophages ‘talked’ to the nerve cells, which then transmitted pain signals.”
When researchers reduced the number of macrophages in mice, the animals didn’t appear to feel pain in response to an angiotensin injection. But as the macrophages repopulated over the course of a few days, the response returned.
To support these observations in mice and the culture dish, the researchers also found increased numbers of macrophages alongside degenerating nerve fibers in skin biopsies taken from the legs of patients who have diabetic neuropathy.
Increasing the number of potential targets for painkillers and including targets such as receptors on immune cells may make it possible to develop more effective drugs with fewer side effects, Mohapatra says.
“The beauty of this drug is that, unlike an opioid, it doesn’t cross the blood-brain barrier, so right away you eliminate a number of potentially harmful side effects, including addiction and the potential for abuse,” he says. “And by widening the scope of potential targets to macrophages, it may be possible to develop more effective therapies for chronic, neuropathic pain.”
The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of of Neurological Disorders and Stroke, the National Heart, Lung and Blood Institute, and the National Cancer Institute of the National Institutes of Health supported the work. Additional funding came from the Washington University Pain Center, the Danish Diabetes Academy (supported by the Novo Nordisk Foundation, and from the University of Texas STARs (Science and Technology Acquisition and Retention) program.