University of Pennsylvania researchers have identified a group of just 300 neurons in the brain that act to prioritize hunger over long-term inflammatory pain, and could represent new targets for developing pain therapies.  The neurons, identified in mice, are activated when an animal is hungry, effectively dampening pain associated with chronic inflammation, so that the animal can answer to competing physiological cues to find or take in nourishment. What the neurons don’t do is diminish how the mice feel acute pain, which means that hungry animals can still respond to dangerous stimuli, such treading on something sharp.

“We didn’t set out having this expectation that hunger would influence pain sensation so significantly,” says Amber L. Alhadeff, Ph.D., at the University of Pennsylvania department of biology. “But when we saw these behaviors unfold before us, it made sense. If you’re an animal, it doesn’t matter if you have an injury, you need to be able to overcome that in order to find the nutrients that you need to survive.”

The researchers, led by J. Nicholas Betley, Ph.D., an assistant professor of biology in Penn’s School of Arts and Sciences, report their findings in Cell, in a paper entitled “A Neural Circuit for the Suppression of Pain by a Competing Need State.”

Pain is an adaptive mechanism that protects animals from dangerous stimuli. Acute pain is an important safety mechanism that makes us pull our hand away when touching something that is sharp, or too hot, for example. In contrast, chronic pain, such as inflammatory pain, can be “maladaptive,” the authors write. The two different types of pain are triggered by the activation of different neuronal circuits. “While acute pain is reflexive in that it is triggered by activation of primary sensory neurons (i.e., nociceptors) in the periphery, inflammatory pain is mediated at least in part by central mechanisms.”

However, as the authors point out, when physiological needs such as hunger increase, the body must overcome pain and respond to this competing survival signal. Dr. Betley’s lab studies hunger, and the neuronal activity that underpins the sensation. “…we can find neurons that make you hungry and manipulate those neurons and monitor their activity,” he states. “But in the real world, things aren’t that simple. You’re not in an isolated situation where you’re only hungry. This research was to try to understand how an animal integrates multiple needs to come to a behavioral conclusion that is optimal.”

Using the mouse as a model, the team first observed how animals that hadn’t eaten for 24 hours responded to either acute pain or longer-term inflammatory pain. They observed that hungry mice were far less responsive to inflammatory pain than the fed controls. In fact, the effects of hunger “almost completely abolished inflammatory pain responses, mimicking the effects of anti-inflammatory painkillers,” the authors state. “This profound suppression, even without the distractor of food, suggests an analgesic effect of hunger and provides a behavioral mechanism to facilitate food seeking following an injury.”

In contrast, withdrawing food for 24 hours had no effect on how the mice responded to stimuli that caused acute pain. This finding contrasts with previous studies suggesting that hunger can “modestly reduce” acute pain, the team notes. “Taken together, our observations demonstrate that hunger has the ability to selectively inhibit long-term pain responses while leaving intact the adaptive ability to respond to acutely painful stimuli.”

“It was really striking,” Dr. Alhadeff says. “We showed that acute response to pain was perfectly intact, but inflammatory pain was suppressed to a very significant extent.”

Neural circuits that are activated by hunger are well characterized, and to find out which circuits may be responsible for modifying the hunger-related response to inflammatory pain the authors looked to a group of nerve cells known as agouti-related protein (AgRP) neurons, which are known to be critical regulators of food intake. “AgRP neuron inhibition in hungry mice reduces food intake, while activation of AgRP neurons in sated mice robustly increases food intake,” the team explains.

Their studies in mice showed that stimulating the AgRP neurons was enough to reduce chronic pain, but not acute pain responses. Conversely, inhibiting AgRP neurons in food-deprived mice significantly reduced the usually protective effect of hunger on inflammatory pain. “…AgRP neuron activity during hunger is both necessary and sufficient to suppress inflammatory pain responses without affecting acute pain responses, recapitulating the behavioral interaction observed in hunger and identifying a neural mechanism for the suppression of inflammatory pain,” they write.

The next stage in the research was try and identify specific groups of AgRP neurons that might be responsible for the hunger-related analgesic effect, by systematically switching on specific AgRP neuron subpopulations. They found that stimulating a group of about 300 AgRP neurons that project into the parabrachial nucleus (PBN) region of the brain was enough to virtually eliminate inflammatory pain responses, without affecting acute pain responses. 

The researchers then found that the effects of AgRP stimulation were mediated by the neurotransmitter NPY, or neuropeptide Y. Studies showed that injections of NPY into the region of the PBN into which the AgRP neurons projected was enough to block inflammatory pain responses, without affecting acute pain responses or food intake. Conversely, when NPY receptors in the PBN region of food-deprived mice were blocked, the analgesic effects of hunger on inflammatory pain were reversed. And when hungry mice were either given access to food, or subjected to acute pain, AgRP neuronal activity was significantly reduced.

“Together, these data suggest that acute thermal pain can influence behavior by suppressing activity in AgRP neuron circuits,” the authors state. “Importantly, this neural circuit can be manipulated to inhibit potentially maladaptive inflammatory pain without compromising adaptive responses to painful stimuli that may acutely threaten survival. Through developing a mechanistic understanding of the influence of hunger on nociception, these experiments provide novel targets for the development of pain management therapies, which is of utmost importance in the search for non-addictive analgesics.”

“We don't want to shut off pain altogether,” Dr. Alhadeff notes, “there are adaptive reasons for pain, but it would be great to be able to target just the inflammatory pain.”

The researchers aim to try and map out how the brain processes inflammatory pain, with the hope of identifying additional targets. They also plan to continue investigating how different survival behaviors integrate in the brain and how the brain processes and prioritizes them.

“We've initiated a new way of thinking about how behavior is prioritized,” Dr. Betley says. “It's not that all the information is funneled up to your higher thinking centers in the brain but that there's a hierarchy, a competition that occurs between different drives, that occurs before something like pain is even perceived.”

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