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CHICAGO, July 7 (Xinhua) — A new research in mice led by researchers at Washington University School of Medicine in St. Louis shows that targeting receptors on immune cells may be more effective in relieving pain, particularly chronic pain.
When researchers at the university tried to find how a non-opioid, investigational drug called EMA401 helped control pain, they were surprised to find that the drug doesn’t hit nerve cells; rather, it targets a receptor on immune cells.
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.
The researchers first thought the drug works by interacting with the type 2 receptor on nerve cells that carry pain signals, but found it is wrong after experiments.
“When we took nerve cells from mice, put them in a culture dish and added the angiotensin hormone, nothing happened,” said 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 when the researcher 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 said. “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 the 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 to pain returned.
To support these observations in mice and the culture dish, the researchers also have 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 painkilling drugs with fewer side effects, said principal investigator D.P. Mohapatra, an associate professor in anesthesiology at the university.
“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,” Mohapatra said. “And by widening the scope of potential targets to macrophages, it may be possible to develop more effective therapies for chronic, neuropathic pain.”
The findings were published on July 2 in the Journal of Neuroscience.

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