Summary: Researchers report that the brain can suppress the sensation of chronic pain when mice are hungry.
Source: University of Pennsylvania
Pain serves an important protective role. It prevents us from repeating actions that cause immediate harm, such as keeping our hand on a hot surface. But prolonged pain—like inflammatory pain that follows injury—can be debilitating, interfere with daily activities, and reduce survival chances in natural environments by causing lethargy and impaired foraging.
Neuroscientists at the University of Pennsylvania report that the brain can prioritize hunger over chronic pain, allowing an animal to seek food even while injured. Their experiments identified a very small population—on the order of 300 neurons—that suppresses inflammatory pain during hunger without disabling responses to acute, potentially life-saving pain. These neurons and their signaling pathways may become targets for new therapies to treat persistent pain.
“Neuroscience often studies one behavior at a time,” says J. Nicholas Betley, assistant professor of biology in Penn’s School of Arts and Sciences. “My lab studies hunger, and we can identify neurons that drive hunger and manipulate them. But animals in the wild don’t experience a single, isolated drive. We wanted to understand how the brain balances competing needs and chooses an optimal behavior.”
Coauthor Alhadeff adds, “We did not expect hunger to so strongly change pain perception, but the behavioral results were clear. For a hungry animal, overcoming the discomfort of an injury to find food can be essential for survival.”
The full study is published in the journal Cell. Betley and Alhadeff collaborated with Zhenwei Su, Elen Hernandez, Michelle L. Klima, and Sophie Z. Phillips of Penn Arts and Sciences; Ruby A. Holland and Bart C. De Jonghe of Penn’s School of Nursing; and Caiying Guo and Adam W. Hantman of the Howard Hughes Medical Institute.
Betley’s lab investigates how hunger reshapes perception. To explore how hunger interacts with pain, the team studied mice that had been food-deprived for 24 hours and measured their reactions to acute nociceptive stimuli and to sustained inflammatory pain, a form of pain associated with sensitized neural circuits.
The researchers observed that hungry mice continued to react normally to acute pain signals (e.g., immediate withdrawal from a painful stimulus) but showed a reduced behavioral and affective response to inflammatory pain compared with well-fed mice. In many behavioral tests, the hungry mice acted similarly to animals treated with an anti-inflammatory analgesic: they did not display the avoidance or negative affect that typically follows inflammatory pain.
For example, in a conditioned-place-avoidance test, hungry mice did not avoid a chamber associated with inflammatory pain, while sated mice did avoid it—indicating that hunger selectively diminished the aversive, lasting aspects of inflammatory pain rather than eliminating the ability to sense acute harm.
To locate the neural circuitry responsible, the team activated agouti-related protein (AgRP) neurons, a well-known hunger-sensitive population. Activation of AgRP neurons recapitulated the hunger effect: inflammatory pain behaviors were suppressed while acute nociceptive responses remained intact.
Seeking greater specificity, the investigators examined projection-defined subpopulations of AgRP neurons. Stimulating individual AgRP subgroups revealed that a projection of only a few hundred AgRP neurons targeting the parabrachial nucleus (PBN) in the hindbrain was sufficient to suppress inflammatory pain. “It was striking,” Alhadeff says. “Acute pain responses were preserved, but inflammatory pain was markedly reduced.”
“The remarkable part is that from a brain of billions of cells, a specific behavior is regulated by roughly 300 neurons,” Betley notes.
Further experiments identified the neurotransmitter responsible for the selective suppression: neuropeptide Y (NPY). NPY signaling in the PBN mediated the anti-nociceptive effect associated with hunger. Pharmacologically blocking NPY receptors in the PBN reversed the suppression and restored inflammatory pain behaviors, demonstrating the pathway’s causal role.
The authors emphasize the potential clinical relevance: if similar circuits exist in humans, selectively targeting NPY signaling in the PBN or the AgRP→PBN pathway might relieve chronic inflammatory pain without eliminating acute pain perception—a desirable goal that could reduce reliance on broad-acting opioids.
“We do not want to eliminate pain altogether—pain is adaptive and protective,” Alhadeff says. “But being able to target inflammatory or persistent pain specifically could improve recovery and quality of life.”
Looking ahead, the team plans to map the neural circuits that govern inflammatory pain more precisely and to identify additional targets that could suppress chronic pain selectively. They will also continue exploring how the brain integrates and prioritizes competing survival drives—such as hunger, thirst, and pain—so that behavior best serves an animal’s immediate needs.
“We’ve opened a new way of thinking about behavioral prioritization,” Betley says. “Rather than routing all information to higher cognitive centers, the brain appears to use hierarchical competition among drives that can resolve conflicts before a sensation like pain reaches conscious perception.”
Funding: This study was supported by Penn’s School of Arts and Sciences, the American Heart Association, the Whitehall Foundation, and the National Institutes of Health (grants DG33400158, DK114104, DK731436, DK112561, and DK112812).
Source: Katherine Unger Baillie, University of Pennsylvania
Publisher: Organized by NeuroscienceNews.com
Image source: NeuroscienceNews.com (public domain)
Original research: Open access research published in Cell (doi: 10.1016/j.cell.2018.02.057).
University of Pennsylvania. “Being Hungry Turns Off Perception of Chronic Pain.” NeuroscienceNews, 22 March 2018. Retrieved March 22, 2018.
Abstract
A Neural Circuit for the Suppression of Pain by a Competing Need State
Highlights
• Hunger reduces inflammatory pain without affecting acute pain responses
• Hunger-sensitive AgRP neurons projecting to the parabrachial nucleus (PBN) suppress inflammatory pain
• Neuropeptide Y (NPY) signaling in the PBN mediates hunger-driven attenuation of inflammatory pain
Summary
Hunger and pain represent competing survival signals that the brain must resolve. This study shows that hunger diminishes behavioral and affective responses to inflammatory pain while leaving acute nociceptive reactions intact. The effect is mediated centrally: activity in AgRP-expressing, hunger-sensitive neurons abolishes inflammatory pain responses. Projection-specific analysis revealed convergence on the hindbrain parabrachial nucleus (PBN); activation of AgRP→PBN neurons blocked inflammatory pain as effectively as hunger or analgesic drugs. The anti-nociceptive effect relies on NPY signaling in the PBN. These findings identify a neural circuit that mediates competing survival needs and highlight NPY Y1 receptor signaling in the PBN as a candidate target for selective suppression of inflammatory pain.