Danger Zone: How the Nervous System Encodes Pain, Hunger and Other Threats

Nerve cells in a brain region called the PBN help animals prioritize threats and behave appropriately. Image credit: wetzkaz/123RF Stock Photo.

Survival is of utmost concern to every animal, and it takes work. Animals—including humans—are under constant threat from starvation, thirst, extreme temperatures and life-threatening injury and illness. But when multiple threats compete for attention, animals must prioritize the most urgent among them and adjust behaviors suitably.

Two recent studies tackle what happens in the nervous system, at a cellular level, in the face of pain, hunger and other survival threats, with each identifying a role for nerve cell activity in the parabrachial nucleus (PBN). This is a key structure in the hindbrain (one of the three main regions of the brain) where sensory information coming into the nervous system is integrated with information from higher brain centers to assess threats and prioritize behaviors.

The first study, from Nicholas Betley and colleagues at the University of Pennsylvania, identifies a specific group of nerve cells that signal to the PBN to dampen ongoing inflammatory—but not acute (immediate)—pain during extreme hunger. The study was published March 22 in the journal Cell.

The second study, from Richard Palmiter and colleagues at the University of Washington, identifies a group of nerve cells in the PBN that serve as a detector of multiple threats, including pain and itch. The study appeared March 29 in the journal Nature.

Together, the studies open a window into how the brain ranks the threats faced by animals and how they respond to them.

Pain or hunger: which threat wins?
Betley’s group has been studying nerve cells that control feeding behavior for years. But they wanted to study how hunger interacted with other stressors.

“We wanted to see what other behaviors are changed with hunger, with either negative or positive consequences,” Betley said. “We reasoned that individuals must prioritize the most acute threat to survival and behave accordingly,” he said, so they paired two competing threats: pain and extreme hunger.

To begin, mice were deprived of food for 24 hours—roughly the equivalent of a person going five to six days without food. “That’s massive hunger,” Betley said.

The researchers then injected formalin into the paws of the animals. Formalin is a chemical that causes acute inflammatory pain as well as longer-lasting inflammatory pain, each of which elicits specific behaviors in the animals, such as licking of the paw.

After receiving the injection, the hungry mice displayed less paw licking in the 15 to 45 minutes following injection, compared to fed mice. But, behaviors immediately after injection were similar in both groups of mice: the hungry animals responded to a painful poke or a hot plate just as fed mice did.

Together, the results showed that hunger somehow decreased persistent inflammatory pain, but not acute pain.

The researchers were surprised that hunger blunted long-term but not acute pain, but Betley said “it made a lot of sense.” This is because acute pain poses a high-priority threat, but an animal with persistent pain must forage and eat to avoid starvation.

How did hunger ease pain?
To explain their findings, the researchers looked to the hypothalamus. This is a region of the brain that receives input from the body and brain to direct behaviors that keep organisms in balance—a state referred to as “homeostasis.”

Previous studies had identified a group of nerve cells in the hypothalamus that contain a protein called AgRP. These cells are critical regulators of eating behaviors. Betley and colleagues thought the AgRP cells might explain how hunger reduced pain.

So the group turned to technology called optogenetics, which uses light to activate or quiet nerve cells. Using optogenetics in awake mice, the researchers found that activating the AgRP nerve cells in fed animals that had received formalin mimicked the effect of extreme hunger—that is, it reduced long-term but not acute pain.

Betley and colleagues had previously mapped out areas of the brain to which the AgRP nerve cells send their axons (an axon is the long threadlike part of a nerve cell that conducts electrical impulses towards other nerve cells). They discovered that each AgRP nerve cell sent its axon to only one other brain region. And so they wanted to figure out which of those regions was responsible for the pain-relieving effect of hunger.

When they used light to activate individual subsets of the AgRP nerve cells, they found that only those that sent their axons to the PBN could relieve pain in the mice.

“When we saw that just the subset projecting to the PBN regulated pain—that was exciting because it showed that the convergence of inflammatory pain and hunger is occurring at the PBN,” Betley said.

In another experiment, the researchers identified the specific neurotransmitter (a natural chemical released by nerve cells) used by the AgRP nerve cells to communicate to those in the PBN, called neuropeptide Y. That insight might allow researchers to one day directly manipulate nerve cells in the PBN to dampen pain independent of hunger.

Detecting real—and possible—danger
In the second study, Palmiter and colleagues also looked at nerve cells in the PBN that control eating. The specific cells they studied contain a protein called CGRP, and become activated when an animal becomes full, providing the signal to stop eating.

The researchers found, though, that other threats also activated these same nerve cells. When they manipulated the nerve cells so they emitted a fluorescent signal when they became activated, they saw that these cells responded to acute pain, itch, visceral pain (which comes from internal organs), and even just to a potential threat, such as a novel food.

It appears, then, that the CGRP nerve cells in the PBN act as a general danger sensor without revealing the nature of the threat, which Palmiter likened to a home alarm.

“The alarm goes off while you’re away, and you don’t know if it’s a broken window, an intruder, or a fire—you just know that something bad has happened.”

And this means that even just the possibility of a threat, like something new to eat, can activate the CGRP nerve cells.

“Even a palatable novel food—something that ultimately might become your favorite food—is scary at first,” Palmiter said. “Novelty sends a warning: taste it gingerly, don’t poison yourself.”

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.