Different behaviors are often studied in isolation, leaving a lot of unanswered questions about how the brain processes needs and prioritizes behaviors to ensure survival. Now, researchers have shown that pain and hunger interact in complex ways in mice: extreme hunger suppresses less-urgent inflammatory pain, so that the mice are willing to go find food, but leaves them able to feel and react to more life-and-death kinds of pain. The study, published March 22 in Cell, pinpoints a highly specific neural circuit -- made up of just 300 neurons -- that responds to hunger to create this analgesic effect.

"Neuroscience researchers, my lab included, have been really good at picking one behavior and one set of neurons to study. But behaviors don't occur in isolation, and for quite a while, I've been interested in how the brain processes multiple needs to lead to adaptive behavior," says J. Nicholas Betley, a neurobiologist at the University of Pennsylvania. He and first author Amber Alhadeff, a postdoctoral research fellow in the Betley Lab, suspected that hunger would change the way that animals reacted to the world, but the specificity with which hunger suppressed inflammatory pain took them by surprise.

Inflammatory pain is the duller, longer-lasting pain associated with swelling and the immune response that we -- and other animals -- experience a little while after an injury. It's different from acute pain, which results from the activation of pain-sensing neurons during an immediate threat, like when you put your hand on the stove or cut yourself with a knife.

The researchers found that mice that hadn't eaten in 24 hours still avoided and reacted to sources of acute pain. But when the hungry mice experienced inflammation in their paw, they licked their injured paw less often and for a shorter period of time than mice that weren't hungry. Their behavior was similar to that of mice that had been given an anti-inflammatory painkiller.

"We think this mechanism exists to enable an injured animal to find food. If an animal is in pain, it is lethargic and sits in its nest instead of going out to seek food," says Alhadeff. "So this mechanism inhibits the long-term and potentially maladaptive kinds of pain. But it leaves intact the ability to respond adaptively to imminent threats so that animals don't put themselves in danger." The researchers also found that acute pain could suppress hunger, suggesting a hierarchy of needs that prioritize the behavior that's most important to keeping the animal alive.

And it's not just a matter of being distracted by a more urgent need. "We're dealing with a pretty extreme form of hunger in this study, but I think what's really powerful about the mechanism we uncovered is that hunger itself isn't actually necessary for the suppression of pain," says Alhadeff. The researchers located the neural circuit responsible for this pain suppression by looking at neurons known to be active during hunger. Optogenetically activating one such group, known as AgRP neurons, was enough to stop pain-related paw-licking behavior. When they targeted a more specific subset of AgRP neurons -- those projecting to the parabrachial nucleus, a brain region that processes diverse signals from the periphery -- they saw even more dramatic pain suppression. "The suppression of pain was so striking that we thought the formalin had gone bad," says Betley. The analgesic effect, he says, is comparable to that of opiates like morphine. And activity in this subpopulation of AgRP neurons does not induce hunger, suggesting a true suppression of pain rather than simply a distraction from it.

The researchers point out that applying these findings to humans isn't straightforward. "I think that there's a lot of complexity, and hunger may not be the only circuit in the human brain that has the ability to suppress these longer-term properties of pain," Betley says. But longer-term inflammatory pain is often the kind of pain that needs to be managed clinically, and the circuit and molecular mechanisms discovered in this study do offer targets for developing new treatments.

For now, though, the researchers hope to continue mapping out the circuits involved in the interactions between pain and hunger -- and between other behaviors. "That's the ultimate goal, to create this network of different survival behaviors and how the circuits interact," says Betley. "And that gets us closer to understanding how the circuits in the brain work to enable behavior."

This work was supported by the University of Pennsylvania School of Arts and Sciences, the Whitehall Foundation, and the NIH.