View large image 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 Pennsylvania J. 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.
View large image 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)
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