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Targeting immune cells could relieve chronic pain

Study finds macrophages talk to sensory nerves to elicit chronic pain caused by nerve damage

by Cici Zhang
July 16, 2018


A graphic shows how macrophages communicate to sensory nerves to elicit pain.
Credit: J. Neurosci.
When AT2R receptors on skin macrophages (left) become active, the cells release reactive oxygen species (red circles) that then activate TRPA1 ion channels in nearby sensory nerve cells (right). This excites the nerves, which then pass along pain signals to the brain.

When looking for new ways to treat chronic pain, researchers and doctors want to find drugs that have fewer side effects than opioids do. In particular, they’re searching for agents with less addiction potential. Novartis is currently testing a compound called EMA401 in Phase II clinical trials for two different conditions. This molecule has the potential to ease pain with a lower risk of side effects because it acts outside of the brain, where pathways associated with addiction and other side effects exist.

A team led by Durga P. Mohapatra of Washington University School of Medicine in St. Louis now reports that the conventional thinking about how this molecule works may be wrong. Instead of acting on nerve cells as previously thought, the pathway the molecule targets may produce pain indirectly through a type of immune cell called macrophages (J. Neurosci. 2018, DOI: 10.1523/jneurosci.3542-17.2018).

The chemical structures of EMA200 and EMA401 are shown here.

The study provides surprising insights into how this pain pathway works, says Clifford Woolf, a neurobiologist at Harvard Medical School. Common nonsteroidal anti-inflammatory drugs like aspirin act on macrophages to reduce pain, Woolf adds, so the findings reinforce the idea that macrophage-neuronal crosstalk is a useful target for developing nonopioid painkillers.

Researchers previously thought that EMA401 inhibited a receptor called angiotensin II type 2 receptor (AT2R) on sensory nerve cells. But they didn’t understand how the molecule that turns on the receptor, a hormone called angiotensin II that helps control blood pressure, was involved in pain signaling.

Mohapatra’s team decided to look at angiotensin signaling in immune cells because these cells are involved in pain caused by injury, inflammation, and nerve damage. When an injury occurs, macrophages rush to the site, clear cell debris, and engulf pathogens. During chronic pain caused by damage to nerve fibers, or neuropathy, they do something similar.

In the current study, the researchers found that after angiotensin II activates the AT2R receptors on skin macrophages in mice, the immune cells release reactive oxygen species (ROS). The ROS then infiltrate nearby sensory nerve cells and activate a pain-inducing ion channel called TRPA1 by oxidizing cysteine residues in the protein. The oxidized cysteines change the conformation of the ion channels, opening them and allowing positive ions such as sodium and calcium to rush into the nerve cells. This influx of ions triggers the nerve cells to fire, transmitting pain signals to the brain.

When the team blocked these AT2R receptors in mouse cells using an inhibitor related to EMA401, called EMA200, they shut down this signaling pathway. Mice given EMA200 showed a reduced sensitivity to pain in lab experiments.

In cell culture studies, Mohapatra and his coworkers found the same angiotensin II signaling pathway existed between human macrophages and nerve cells. They also observed increased numbers of macrophages alongside damaged nerve fibers in skin biopsy samples taken from patients with diabetic neuropathy, as well as those with chemotherapy-induced peripheral neuropathy.

As a next step, the team plans to investigate whether AT2R inhibitors work in animal models of these disease-related neuropathies, Mohapatra says. He thinks further study of this pathway could yield new therapies for chronic pain with fewer side effects.



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