Pain may be unpleasant, but in most cases it plays a vital, even lifesaving, role. Short bursts 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 instantly delivers an "Ow!" that prompts you to pull back before more damage occurs. The pain fades, the body heals, and you remember what not to do next time.
Betley, along with collaborators from the University of Pittsburgh and Scripps Research Institute, has discovered an important piece of the chronic pain puzzle. Their research points to a specific group 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 they also process signals related to hunger, fear, and thirst. This suggests that the brain can adjust pain responses when other, more urgent needs demand attention.
The findings, published in Nature, indicate 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 signal of pain."
Tracking pain in the brain
Working with the Taylor lab at the University of Pittsburgh, Betley's team used calcium imaging to visualize neuron activity in real time in animal models of both short-term and long-term pain. They observed that Y1R neurons did not simply react to quick bursts of pain; instead, they kept firing steadily during prolonged pain, a phenomenon known as "tonic activity."
Betley compares this to an engine left running even after you've parked the car. The pain signals continue to hum in the background even when physical recovery seems complete. This ongoing neural activity may explain why some people continue to feel pain long after an injury or surgery.
The research originated from an unexpected observation Betley made after joining Penn in 2015: hunger seemed to lessen chronic pain.
"From my own experience, I felt that when you're really hungry you'll do almost anything to get food," he says. "When it came to chronic, lingering pain, hunger seemed to be more powerful than Advil at reducing pain."
That insight inspired further investigation. Former graduate student Nitsan Goldstein found that other critical survival states—such as thirst and fear—can also suppress long-term pain. In collaboration with the Kennedy lab at Scripps, the team showed that the brain's parabrachial nucleus can filter sensory input to quiet pain when immediate survival takes priority.
"That told us the brain must have a built-in way of prioritizing urgent survival needs over pain, and we wanted to find the neurons responsible for that switch," says Goldstein.
A key part of that switch is neuropeptide Y (NPY), a signaling molecule that helps the brain juggle competing needs. When hunger or fear takes priority, NPY acts on Y1 receptors in the parabrachial nucleus to dampen ongoing pain signals.
"It's like the brain has this built-in override switch," Goldstein explains. "If you're starving or facing a predator, you can't afford to be overwhelmed by lingering pain. Neurons activated by these other threats release NPY, and NPY quiets the pain signal so that other survival needs take precedence."
A scattered signal
The researchers also characterized the molecular and anatomical identity of the Y1R neurons in the lPBN. They found that Y1Rneurons didn't form two tidy anatomical or molecular populations. Instead, these neurons were scattered across many other cell types.
"It's like looking at cars in a parking lot," Betley says. "We expected all the Y1R neurons to be a cluster of yellow cars parked together, but here the Y1R neurons are like yellow paint distributed across red cars, blue cars, and green cars. We don't know exactly why, but we think this mosaic distribution may allow the brain to dampen different kinds of painful inputs across multiple circuits."
Explorations of pain treatment
What excites Betley with this discovery is the further exploration of its potential 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 is no clear 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 injury, but in the brain circuit itself. If we can target these neurons, that opens up a whole new path for treatment."
This research also suggests that behavioral interventions such as exercise, meditation, and cognitive behavioral therapy may influence how these brain circuits fire, just as hunger and fear did in the lab.
"We've shown that this circuit is flexible, it can be dialed up or down," he says. "So, the future isn't just about designing a pill. It's also about asking how behavior, training, and lifestyle can change the way these neurons encode pain."
J Nicholas Betley is an associate professor in the Department of Biology at the University of Pennsylvania's School of Arts & Sciences.
Nitsan Goldstein was a graduate student in the Betley Lab at Penn Arts & Sciences during this study. He is currently a postdoctoral researcher at the Massachusetts Institute of Technology.
Other authors include Michelle Awh, Lavinia Boccia, Jamie R. E. Carty, Ella Cho, Morgan Kindel, Kayla A. Kruger, Emily Lo, Erin L. Marble, Nicholas K. Smith, Rachael E. Villari, and Albert T. M. Yeung of Penn Arts & Sciences; Niklas Blank and Christoph A. Thaiss of Penn's Perelman School of Medicine; Melissa J. Chee and Yasmina Dumiaty of Carleton University; Rajesh Khanna of University of Florida College of Medicine,; Ann Kennedy and Amadeus Maes of Scripps Research Institute; and Heather N. Allen, Tyler S. Nelson and Bradley K. Taylor of the University of Pittsburg.
This research was supported by the Klingenstein Foundation, the University of Pennsylvania School of Arts and Sciences, the National Institutes of Health (grants F31DK131870, 1P01DK119130, 1R01DK133399, 1R01DK124801, 1R01NS134976, F32NS128392, K00NS124190, F32DK135401, T32DK731442, R61NS126026, R01NS120663, R01NS134976-02, R00MH117264, 1DP1DK140021-01), the National Science Foundation Graduate Research Fellowship Program, the Blavatnik Family Foundation Fellowship, the American Neuromuscular Foundation Development Grant, the American Heart Association (25POST1362884), the Swiss National Science Foundation (206668), the Canadian Institutes of Health Research Project Grant (PJT-175156), the Simons Foundation, a McKnight Foundation Scholar Award, and a Pew Biomedical Scholar Award.
