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Summary: Chronic pain affects nearly 50 million Americans; However, new research reveals that the brain may have an internal switch that can slow it down. The scientists identified a group of neurons in the brainstem that regulate long-term pain by integrating signals related to hunger, fear and thirst.
When survival needs take priority, these neurons buffer pain through neuropeptide Y signaling, suggesting a built-in “override” system. The discovery opens new possibilities for brain-based pain treatments that could be addressed through drugs or behavioral interventions.
Key facts:
Pain override circuit: Y1 receptor neurons in the brain stem reduce chronic pain when hunger or fear takes priority. Neuropeptide Y Function: Acts as a messenger to silence pain signals during competing survival needs. Therapeutic potential: Could inspire biomarkers and treatments targeting brain circuits rather than local lesions.
Original research: University of Pennsylvania
Acute or short-term pain, despite its bad reputation, usually saves life. It acts as a temporary negative sensory experience that helps us avoid danger.
Touch a hot stove, stub your toe, or hit your head on a low branch and the nervous system will emit an “Ouch!” In time, the pain fades, the wound heals, but the lesson remains.
Chronic pain is different; The alarm continues to sound long after the fire has been extinguished, and then the pain itself becomes the problem. Nearly 50 million people in the United States live with chronic pain, an invisible and often untreatable condition that can persist for decades.
“It’s not just an injury that won’t heal,” says University of Pennsylvania neuroscientist J. Nicholas Betley, “it’s a brain input that has become sensitized and overactive, and determining how silencing that input could lead to better treatments.”
Now, research led by Betley and collaborators at the University of Pittsburgh and the Scripps Research Institute has identified a key to regulating long-term pain states: a group of cells called neurons that express the Y1 receptor (Y1R) in the lateral parabrachial nucleus of the brainstem (lPBN).
These neurons are activated during states of long-lasting pain, but they also integrate information about hunger, fear, and thirst, allowing pain signals to be modulated by other brain circuits that signal more urgent needs.
Their findings, published in Nature, suggest that there is hope because “there are circuits in the brain that can reduce the activity of neurons that transmit the pain signal.”
Tracking pain in the brain
As part of a collaboration with the Taylor lab at Pitt, researchers used calcium imaging to observe neurons firing in real time in preclinical models of acute and chronic pain. They found that Y1R neurons not only activated briefly in response to acute pain, but also continued to function steadily during long-lasting pain, a state neuroscientists call “tonic activity.”
Betley compares this to an engine left to idle, where the pain signals continued to rumble and tick even when the external pain signals had faded. This persistent activity may encode the state of lasting pain that people feel long after an accident or surgery.
The impetus to look deeper into these neurons came from a simple observation Betley and his team made shortly after joining Penn in 2015: hunger could dampen long-term pain responses.
“From my own experience, I felt that when you are very hungry you will do almost anything to get food,” he says. “When it came to chronic, persistent pain, starvation seemed to be more powerful than Advil in reducing pain.”
The current work began when Nitsan Goldstein, who at the time was a graduate student in Betley’s lab, discovered that other urgent survival needs, such as thirst and fear, can also reduce long-lasting pain.
That finding supported by behavioral models developed in collaboration with the Kennedy Laboratory at Scripps suggests that filtering sensory information in the parabrachial nucleus can block long-lasting pain when other, more acute needs exist.
“That told us that 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 change,” Goldstein says.
A key part of that change 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 a built-in override switch,” explains Goldstein. “If you’re starving or facing a predator, you can’t afford to be overwhelmed by persistent pain. Neurons activated by these other threats release NPY, and NPY silences the pain signal so other survival needs take priority.”
A scattered signal
The researchers also characterized the molecular and anatomical identity of Y1R neurons in the lPBN. They found that Y1R neurons did not form two ordered anatomical or molecular populations. Instead, these neurons were dispersed in many other cell types.
“It’s like looking at cars in a parking lot,” says Betley. “We expected all Y1R neurons to be a group of yellow cars parked together, but here the Y1R neurons are like yellow paint spread 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 buffer different types of painful inputs through multiple circuits.”
Pain treatment explorations.
What excites Betley about this discovery is the further exploration of its potential to “use Y1 neuronal activity as a biomarker for chronic pain, something drug developers and clinicians have lacked for a long time,” he says.
“Right now, patients may go to an orthopedist or a neurologist and there is no clear injury. But they still feel pain,” he says.
“What we are showing is that the problem may not be in the nerves at the site of the injury, but in the brain circuitry itself. If we can target these neurons, it opens up a completely new avenue for treatment.”
This research also suggests that behavioral interventions such as exercise, meditation, and cognitive behavioral therapy can influence how these brain circuits are activated, just as hunger and fear did in the lab.
“We have shown that this circuit is flexible, it can be adjusted up or down,” he says. “So the future is not 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, College of Arts and Sciences, University of Pennsylvania.
Nitsan Goldstein was a graduate student at Penn Arts & Sciences’ Betley Lab during this study. He is currently a postdoctoral researcher at the Massachusetts Institute of Technology.
Other authors include Michelle Awh, Lavinia Boccia, Jamie RE Carty, Ella Cho, Morgan Kindel, Kayla A. Kruger, Emily Lo, Erin L. Marble, Nicholas K. Smith, Rachael E. Villari, and Albert TM 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 the University of Florida College of Medicine; Ann Kennedy and Amadeus Maes of the Scripps Research Institute; and Heather N. Allen, Tyler S. Nelson, and Bradley K. Taylor of the University of Pittsburgh.
Funding: This research was supported by the Klingenstein Foundation, the College of Arts and Sciences of the University of Pennsylvania, the National Institutes of Health (grants F31DK131870, 1P01DK119130, 1R01DK133399, 1R01DK124801, 1R01NS134976, F32NS128392, K00NS124190, F32DK135401, T32DK731442, R61NS126026, R01NS120663, R01NS134976-02, R00MH117264, 1DP1DK140021-01), National Science Foundation Graduate Research Grant Program, fellowship of the Blavatnik Family Foundation, American Neuromuscular Foundation Development Grant, 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.
Key questions answered:
A: They found a set of brainstem neurons that can suppress pain long-term when other survival signals, such as hunger or fear, are active.
A: It is controlled by neuropeptide Y, which binds to Y1 receptors in the brain to silence pain signals, prioritizing urgent needs over persistent discomfort.
A: It shifts the focus from treating chronic pain at the sites of injury to understanding and paying attention to the brain circuits that support it.
About this research news in chronic pain and neurology
Author: Nathi Magubane
Source: University of Pennsylvania
Contact: Nathi Magubane – University of Pennsylvania
Image: Image is credited to Neuroscience News.
Original research: Open access.
“A Parabrachial Center for As-Needed Enduring Pain Control” by J. Nicholas Betley et al. Nature
Abstract
A parabrachial center for long-term pain control on an as-needed basis
Sustained long-term pain after an acute physical injury is a prominent feature of chronic pain conditions.
Populations of neurons that respond rapidly to noxious stimuli or tissue damage have been identified in the spinal cord and in various nuclei of the brain.
Understanding the core mechanisms that indicate continued and sustained pain, even after tissue healing, remains a challenge.
Here we use spatial transcriptomics, neuronal manipulations, activity recordings, and computational modeling to demonstrate that activity in a set of anatomically and molecularly diverse parabrachial neurons that express the neuropeptide Y (NPY) receptor Y1 (Y1R neurons) increases after injury and predicts functional coping behavior.
Hunger, thirst, or predator cues suppressed sustained pain, regardless of injury type, by inhibiting parabrachial Y1R neurons through NPY release. Taken together, our results demonstrate an endogenous analgesic center in parabrachial Y1R pain-responsive neurons.
