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Scientists uncover brain circuit that overrides chronic pain

October 11, 2025
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Researchers at the University of Pennsylvania have identified a group of brainstem neurons that can suppress chronic pain signals when survival needs like hunger or fear arise. These Y1 receptor neurons in the lateral parabrachial nucleus act as a neural switchboard, prioritizing urgent biological demands over persistent discomfort. The discovery, published in Nature, offers potential new avenues for pain treatments.

Chronic pain affects about 50 million people in the United States, persisting long after injuries heal as a sensitized brain input. J. Nicholas Betley, a neuroscientist at the University of Pennsylvania, explains: "It's not just an injury that won't heal... it's a brain input that's become sensitized and hyperactive, and determining how to quiet that input could lead to better treatments."

Betley's team, collaborating with researchers from the University of Pittsburgh and Scripps Research Institute, focused on Y1 receptor (Y1R)-expressing neurons in the lateral parabrachial nucleus (lPBN). Using calcium imaging in animal models, they observed these neurons exhibit steady "tonic activity" during prolonged pain, unlike brief responses to acute pain.

The research stemmed from a 2015 observation that hunger reduces chronic pain. Betley noted: "From my own experience, I felt that when you're really hungry you'll do almost anything to get food... hunger seemed to be more powerful than Advil at reducing pain." Former graduate student Nitsan Goldstein extended this, finding thirst and fear also suppress pain. They identified neuropeptide Y (NPY) as key: when survival threats activate, NPY binds to Y1 receptors, dampening pain signals.

Goldstein described it as: "It's like the brain has this built-in override switch... Neurons activated by these other threats release NPY, and NPY quiets the pain signal so that other survival needs take precedence."

The Y1R neurons are scattered across various cell types in the lPBN, potentially allowing broad control over pain inputs. This mosaic distribution, Betley likened to "yellow paint distributed across red cars, blue cars, and green cars."

The findings suggest targeting these neurons could serve as a biomarker for chronic pain, shifting focus from injury sites to brain circuits. Betley added: "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."

Behavioral interventions like exercise and meditation might also modulate this flexible circuit, beyond pharmaceutical approaches. The study appears in Nature (2025; DOI: 10.1038/s41586-025-09602-x).

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