Non-opioid Pain Reliever Targets Immune Cells

A non-opioid, investigational drug called EMA401 doesn’t hit nerve cells; rather, it targets a receptor on immune cells, researchers have found.

Faced with the epidemic of opioid addiction, scientists have been charged with finding other strategies to treat pain. Their efforts largely have focused on nerve cells that transmit pain signals to the spinal cord and brain.

But the results from this new research, led by scientists at Washington University School of Medicine in St. Louis, show that targeting receptors on immune cells may be more effective, particularly for chronic pain.

“We are in dire need of good pain-killing drugs, particularly non-opioid drugs. 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,”

said principal investigator D.P. Mohapatra, PhD, an associate professor in anesthesiology.

AT2R Blocker

The investigational drug EMA401 inhibits the angiotensin II type 2 receptor (AT2R) that is targeted by medications that lower blood pressure. Angiotensin is a hormone that causes blood vessels to constrict, increasing blood pressure.

EMA401 has shown promise as a treatment for lingering nerve pain following shingles infection. It 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 his 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. There was no angiotensin type 2 receptor on sensory neurons, so pain signals couldn’t be transmitted,”

said co-investigator Andrew Shepherd, PhD, an instructor in anesthesiology. 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. 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,”

Shepherd said.

Fewer Side Effects

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, Mohapatra said.

“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. And by widening the scope of potential targets to macrophages, it may be possible to develop more effective therapies for chronic, neuropathic pain,”

he said.

Angiotensin II is a peptide hormone that increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction).

In addition, angiotensin II acts at the Na+/H+ exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H+ excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH, which is why ACE inhibitors are major anti-hypertensive drugs.

Andrew J. Shepherd, Bryan A. Copits, Aaron D. Mickle, Páll Karlsson, Suraj Kadunganattil, Simon Haroutounian, Satya M. Tadinada, Annette D. de Kloet, Manouela V. Valtcheva, Lisa A. McIlvried, Tayler D. Sheahan, Sanjay Jain, Pradipta R. Ray, Yuriy M. Usachev, Gregory Dussor, Eric G. Krause, Theodore J. Price, Robert W. Gereau, Durga P. Mohapatra
Angiotensin II triggers peripheral macrophage-to-sensory neuron redox crosstalk to elicit pain
Journal of Neuroscience 5 July 2018, 3542-17; DOI: 10.1523/JNEUROSCI.3542-17.2018

Image: In skin biopsies from the legs of healthy people (left) there are abundant sensory nerve fibers (green) but few macrophages (red). Meanwhile, in biopsies from patients with pain due to diabetic neuropathy (right), macrophages (red) surround degenerating nerve fibers (green). Credit: Mohopatra lab