A small group of nerve cells deep in the brain may control how strongly the body experiences pain. Under normal conditions, this system can suppress pain signals traveling through the spinal cord. After a nerve injury, however, the same brain circuits may become overactive and help sustain chronic neuropathic pain.
Researchers at Washington University School of Medicine in St. Louis have identified a mechanism that may explain how this change occurs—and how it might be reversed. In experiments with mice, the researchers found that receptors on cells in the brain’s major alertness and stress center act as biological brakes on pain. These receptors were previously recognized for their role in stress regulation, but the new findings suggest they can also quiet pain-producing circuits and reduce chronic neuropathic pain caused by nerve damage.
The study, published August 17 in Current Biology, identifies the locus coeruleus as a potential target for future chronic pain treatments designed to work more precisely in the brain.
“Millions of adults live with chronic neuropathic pain caused by nerve injury,” said Jordan McCall, Ph.D., associate professor in the Center for Clinical Pharmacology in the Department of Anesthesiology at Washington University School of Medicine and senior author of the study. “Pain is difficult to treat, and traditional opioid drugs bind to receptors throughout the body and brain, often leading to side effects, tolerance and addiction. Understanding how local receptors in the locus coeruleus act as gatekeepers could lead to more targeted and effective pain treatments with fewer risks.”
How nerve damage causes chronic pain
Neuropathic pain develops when damaged nerve fibers repeatedly send abnormal signals to the brain. These faulty messages can produce shooting, stinging, burning or heightened sensitivity to touch and heat. Diabetes, viral infections and compressed nerves are among the conditions that can cause neuropathic pain.
To better understand how this process might be stopped, McCall’s team—including co-lead authors Chaochen Kuo, Ph.D., a postdoctoral fellow, and Makenzie R. Norris, Ph.D., a former graduate student—focused on the locus coeruleus, a brain region known to help regulate pain and stress responses.
For the first time, researchers showed that nerve damage can transform the locus coeruleus into an active pain generator. When the team temporarily silenced cells in this region in mice with neuropathic pain, the animals became less sensitive to touch and heat than untreated mice with nerve injury.
Mu-opioid receptors act as biological brakes
The researchers next examined opioid-responsive receptors on cells in the locus coeruleus, focusing specifically on mu-opioid receptors.
Mu-opioid receptors are found throughout the brain and spinal cord. When naturally produced opioids—or synthetic opioids such as morphine and fentanyl—bind to these receptors, pain signaling through the nervous system is reduced. Because the locus coeruleus contains many mu-opioid receptors, the researchers investigated whether these receptors play a central role in controlling pain in this brain region.
The team removed mu-opioid receptors from locus coeruleus brain cells in mice with neuropathic pain. Without the receptors, the animals became even more sensitive to touch and heat than mice that retained mu-opioid receptors in those cells.
When the researchers restored the receptors to the same neurons, the heightened sensitivity was reversed, effectively reducing the animals’ increased pain response.
More precise treatments for chronic neuropathic pain
The findings suggest that chronic nerve pain may disrupt the ability of mu-opioid receptors to suppress activity in locus coeruleus cells, sometimes called “blue spot” neurons because of the region’s name.
Researchers are now exploring ways to change activity in the locus coeruleus without affecting opioid receptors in other parts of the nervous system. Their goal is to develop treatments that selectively activate mu-opioid receptors in this brain region. Such therapies could reduce chronic neuropathic pain while limiting the risks associated with opioids that act broadly throughout the brain and body.
Kuo CC, Norris MR, Dunn SS, Becker LJ, Kim JR, Vazquez CR, Borges G, Tan LV, O’Brien JT, Parker KE, McCall JG. Mu opioid receptors gate the locus coeruleus pain generator. August 17, 2026. Current Biology.
This study was funded by the National Institutes of Health through grants R01NS117899, R01NS135401, F31NS124301 and F31DA065440; the National Science Foundation through grant DGE-2139839; the McDonnell Center for Systems Neuroscience; the Collaborative Support Initiative Award for Translational Anesthesiology Research (COSTAR) from the Department of Anesthesiology at Washington University School of Medicine; the Rita Allen Foundation; and the Open Philanthropy Project. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Source: www.sciencedaily.com