Scientists have discovered a brain circuit that can stop chronic pain

Pain may be annoying, but in most cases it plays a vital, even life-saving, role. Brief bouts of pain act as warning signals that protect us from harm. When you touch a hot pan, stub your toe, or bump your head, your nervous system immediately emits an “ah!” Which prompts you to withdraw before more damage is done. The pain fades, the body recovers, and you remember what not to do next time.

But chronic pain is a completely different story. In this case, the warning signal does not stop even after the injury has healed. For about 50 million people in the United States, pain becomes a constant, invisible companion that can last for years or even decades. University of Pennsylvania neuroscientist J. Nicholas Beatley: “It’s not just an injury that doesn’t heal, it’s brain inputs that have become sensitive and overactive, and determining how to calm these inputs could lead to better treatments.”

With collaborators from the University of Pittsburgh and the Scripps Research Institute, Betley has discovered an important piece of the chronic pain puzzle. Their research points to a specific population of brainstem cells called Y1 receptor (Y1R)-expressing neurons, located in the lateral parabrachial nucleus (lPBN). These neurons are activated in persistent pain states, but also process signals related to hunger, fear, and thirst. This suggests that the brain can adjust pain responses when other, more pressing needs require attention.

Results published in natureShe suggests that relief may be possible because, as the researchers write, “there are circuits in the brain that can reduce the activity of neurons that transmit the pain signal.”

Tracking pain in the brain

Working with Taylor’s lab at the University of Pittsburgh, Petley’s team used calcium imaging to visualize real-time neuronal activity in animal models of short- and long-term pain. They observed that Y1R neurons did not simply react to rapid pain attacks; Instead, they continued to fire steadily during pain for a prolonged period, a phenomenon known as “tonic firing.”

Beatley compares this to an engine that stayed running even after the car was parked. Pain signals continue to appear in the background even when physical recovery appears complete. This persistent nerve activity may explain why some people continue to feel pain long after injury or surgery.

The research grew out of an unexpected observation Betley made after joining the University of Pennsylvania in 2015: Hunger appears to reduce chronic pain.

“From my own experience, I felt that when you are very hungry you will do almost anything to get food,” he says. “When it comes to chronic, persistent pain, Hunger appears to be more powerful than Advil at relieving pain.”

This vision inspired further investigation. Former graduate student Nitzan Goldstein has found that other critical survival states — such as thirst and fear — can also suppress long-term pain. In collaboration with the Kennedy Laboratory at Scripps, the team showed that the brain’s parabrachial nucleus can filter sensory input to dull pain when immediate survival is the priority.

“This told us that the brain must have a built-in way to prioritize immediate survival needs over pain, and we wanted to find the neurons responsible for this switch,” Goldstein says.

A key part of this switch is neuropeptide Y (NPY), a signaling molecule that helps the brain reconcile competing needs. When hunger or fear takes priority, NPY acts on Y1 receptors in the parabrachial nucleus to inhibit persistent pain signals.

“It’s as if the brain has a built-in override switch,” Goldstein explains. “If you’re starving or facing a predator, you can’t afford to feel constant pain. Neurons that are activated by these other threats release NPY, and NPY dampens the pain signal so that other survival needs take priority.”

Scattered signal

The researchers also determined the molecular and anatomical identity of Y1R neurons in the lPBN. They found that Y1R neurons do not form two ordered anatomical or molecular groups. Instead, these neurons were spread across many other cell types.

“It’s like looking at cars in a parking lot,” Beatley says. “We expected all the Y1R neurons to be a bunch of yellow cars parked together, but here the Y1R neurons are like yellow paint spread on red cars, blue cars, and green cars. We don’t know exactly. Why“But we think this mosaic distribution may allow the brain to suppress different types of painful input across multiple circuits.”

Explorations of pain treatment

What excites Betley about this discovery is further exploration of its ability to “use Y1 neural activity as a biomarker for chronic pain, something drug developers and clinicians have long lacked,” he says.

“Right now, patients may go to an orthopedist or a neurologist, and there’s no obvious injury. But they’re still in pain,” he says. “What we’re showing is that the problem may not be in the nerves at the site of the injury, but in the brain circuit itself. If we can target these neurons, it opens up a whole new avenue for treatment.”

This research also suggests that behavioral interventions such as exercise, meditation, and cognitive behavioral therapy may influence how these brain circuits are stimulated, just as hunger and fear did in the laboratory.

“We showed that this circuit is flexible and can be turned up or down,” he says. “So, the future is not like that only About pill design. “It’s also about asking how behavior, training and lifestyle can change the way these neurons encode pain.”

J. Nicholas Beatley is an associate professor in the Department of Biology in the College of Arts and Sciences at the University of Pennsylvania.

Nitzan Goldstein was a graduate student in the Betley Lab at the University of Pennsylvania for Arts and Sciences during this study. He is currently a postdoctoral researcher at MIT.

Other authors include Michelle Oh, Lavinia Puccia, Jamie R. Carty, Ella Chu, Morgan Kindle, and Kayla A. Krueger, Emily Lu, and Erin L. Marple, Nicholas K. Smith, Rachel E. Villari, and Albert T. M. Young of the University of Pennsylvania for the Arts and Sciences; Niklas Blank and Christoph A. Theis of the Perelman School of Medicine in Pennsylvania; Melissa J. Che and Yasmina Damietta from Carleton University; Rajesh Khanna of the University of Florida College of Medicine; Anne Kennedy and Amadeus Mays of the Scripps Research Institute; And Heather N. Allen, and Tyler S. Nelson, and Bradley K. Taylor from the University of Pittsburgh.

This research was supported by the Klingenstein Foundation, the College of Arts and Sciences at the University of Pennsylvania, and the National Institutes of Health (grants F31DK131870, 1P01DK119130, 1R01DK133399, 1R01DK124801, 1R01NS134976, F32NS128392, K00NS124190, National Science Foundation Graduate Research Fellowship Program, Blavatnik Family Foundation Fellowship, Foundation Development Grant American Neuromuscular, American Heart Association (25POST1362884), Swiss National Science Foundation (206668), Canadian Institutes of Health Research Project Grant (PJT-175156), Simons Foundation, McKnight Foundation Scholar Award, and Pew Biomedical Scholar Award.