J. Nicholas Betley has led collaborative research seeking the neural basis of long-term sustained pain and finds that a critical hub in the brainstem holds a mechanism for stopping pain signals from reaching the rest of the brain. Their findings could help clinicians better understand chronic pain and lead to new, more efficacious treatments.
4 min. read
Key Takeaways
Nearly 50 million people in the U.S. live with chronic pain, an invisible and often stubborn condition that can last for decades.
Now, collaborative research led by neuroscientist J. Nicholas Betley finds that a critical hub in the brainstem, has a built-in “off switch” to stop persistent pain signals from reaching the rest of the brain.
Their findings could help clinicians better understand chronic pain. “If we can measure and eventually target these neurons, that opens up a whole new path for treatment,” says Betley.
Collaborative research on the neural basis of chronic pain led by neuroscientist J. Nicholas Betley finds that a critical hub in the brainstem, has a built-in “off switch” to stop persistent pain signals from reaching the rest of the brain. Their findings could help clinicians better understand chronic pain. (Pictured) Flurorescence imaging reveals hunger neurons in the arcuate nucleus of the hypothalamus labeled in maroon with nuclei shown in blue.
(Image: J. Nicholas Betley)
Acute or short-lived pain, despite its bad reputation, is usually a lifesaver. It acts as a transient negative sensory experience that helps us avoid danger. Touch a hot stove, stub a toe, or bonk your head on a low branch, and the nervous system cues up an “Ow!” Over time, the sting fades, the wound heals, but the lesson sticks.
Chronic pain is different; the alarm keeps blaring long after the fire is out, 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 linger for decades. “It’s not just an injury that won’t heal,” says neuroscientist at the University of PennsylvaniaJ. Nicholas Betley, “it’s a brain input that’s become sensitized and hyperactive, and determining how to quiet that input could lead to better treatments.”
Now, research led by Betley and collaborators at the University of Pittsburgh and Scripps Research Institute has identified a key to regulating long-term pain states: a group of cells called Y1 receptor (Y1R)-expressing neurons in the brainstem’s lateral parabrachial nucleus (lPBN). These neurons are activated during enduring pain states, but they also integrate information about hunger, fear and thirst, allowing for pain signals to be modulated by other brain circuits signaling 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 signal of pain.”
Tracking pain in the brain
As part of a collaboration with the Taylor lab at Pitt, the researchers used calcium imaging to watch neurons fire in real time in preclinical models of acute and chronic pain. They found that Y1R neurons didn’t just flare briefly in response to acute pain—they also kept firing steadily during enduring pain, a state neuroscientists call “tonic activity.”
Betley likens this to an engine left idling, where signals of pain continued to rumble and tick even when outward signs of pain had faded. This persistent activity may encode the lasting pain state people feel long after an accident or surgery.
The drive to look deeper into these neurons grew out of a simple observation Betley and his team made shortly after he joined Penn in 2015—hunger could dampen long-term pain responses.
Fluorescent imaging of NPY+ neurons (green) throughout the brain are shown in addition to neurons in magenta that send projections to the PBN.
(Image: J. Nicholas Betley)
“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.”
The current work started when Nitsan Goldstein, who was a graduate student in Betley’s lab at the time, found that other urgent survival needs such as thirst and fear can also reduce enduring pain. That finding supported behavioral models developed in collaboration with the Kennedy lab at Scripps, suggest filtering of sensory input at the parabrachial nucleus can block out long-lasting pain when other more acute needs exist.
“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. She 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.
Penn engineers and collaborators have developed a transparent, micro-engineered device that houses a living, vascularized model of human lung cancer—a “tumor on a chip”—and show that the diabetes drug vildagliptin helps more CAR T cells break through the tumor’s defenses and attack it effectively.
Tumor-on-a-chip offers insight into cancer-fighting cells in immunotherapy
Penn engineers and collaborators have built a living tumor on a chip to expose how cancers block immune attacks, and how one existing drug could make immunotherapy like CAR T more effective against solid tumors.
Professor of city and regional planning Erick Guerra recently published a book exploring the economic and societal impacts of American highways. He explains some of the pitfalls associated with an ever-expansive highway system, arguing that spending more on highways might not be the solution to the country’s transportation issues.
Penn urban planner Erick Guerra’s new book, “Overbuilt,” argues that additional spending on building more highways might not be the solution to the country’s transportation issues. In a Q&A, Guerra shares his insights.
Xin Sun prepares samples collected from the Eastern Tropical North Pacific aboard a research vessel. By adding stable isotope tracers to these vials, Sun and her team can track how different microbial groups convert nitrogen compounds into nitrous oxide, revealing how subtle shifts in oxygen and organic matter change the ocean’s chemistry.
Can tiny ocean organisms offer the key to better climate modeling?
In the shadowy layers of the Pacific, microbes decide how much nitrous oxide—a potent greenhouse gas—rises skyward. New research from Penn’s Xin Sun offers an improved understanding of microbial ecology and geochemistry—key to forecasting global emissions in response to natural and man-made climate change.
Two X-ray plates from Arthur Goodspeed, believed to have created the world’s first X-ray image, were donated by his family to Penn’s University Archives.
