Neuroscientists have found a possible new approach to treating patients with chronic pain. As they discovered, there are certain nerve cells in our brainstem that can maintain or suppress pain signals depending on the situation. By specifically activating this neuronal junction, the pain stimuli in the rest of the brain could be kept in check, as the team reports in “Nature”. Possible medications and behavioral therapies are now being developed to calm down the hyperactive neurons.
When we stub our toe, a brief, sharp pain shoots through our foot. This acute and temporary pain stimulus warns us of a possible injury and at the same time teaches us to avoid dangers such as an edged chair leg. Sometimes it can also happen that the pain and its trigger persist for so long that the pain becomes chronic and continues even after the original trigger has disappeared. After an accident or an operation, for example, those affected suffer from leg pain for years, even though the original injury has now healed. In these cases, the nervous system sounds an excessive and persistent alarm, even though the actual danger has passed. “It’s a brain input that has become sensitized and hyperactive,” says senior author J. Nicholas Betley of the University of Pennsylvania.
Hunger trumps pain
A team led by Betley and lead author Nitsan Goldstein has now investigated how this hyperactivity of the nervous system can be curbed using mouse models. Using various techniques, they visualized the different types of nerve cells in the brain to find out which cells are active when pain signals are received. The result: In the lateral parabrachial nucleus (LPBN) of the brainstem there is a special group of nerve cells that carry the Y1 receptor (Y1R) on their surface. These neurons, which are distributed in a mosaic pattern in the LPBN, are activated when someone is hungry, afraid or thirsty – and also when someone has acute or chronic pain. The neurons act like a filter to ensure that the incoming signals are sorted, dampened if necessary, and only the most urgent needs are passed on to other brain regions.
When someone is hungry, thirsty or afraid, this vital need signal trumps even severe pain, as the team found in the animal experiments. This suggests that these Y1R nerve cells act like a switching point and can either constantly fire up or switch off chronic pain. If the Y1R neurons have become hyper- and permanently active due to overstimulation, they ensure that the pain persists – regardless of the nerve stimuli at the original site of injury. However, if they are distracted by another, more acute stimulus, they switch and the pain fades. “There are circuits in the brain that can reduce the activity of neurons that transmit the pain signal,” the researchers write.
New approach to pain therapy
Goldstein and his colleagues also discovered how this pain suppressor works at the molecular level. According to this, neuropeptide Y (NPY) is released by other types of neurons throughout the brain when acute threats such as hunger or fear take precedence. This signaling molecule binds to the Y1 receptors on the neurons in the LPBN of the brainstem and thus inhibits incoming pain signals. “It’s like the brain has this built-in override switch,” Goldstein explains. “When you are starving or facing a predator, you cannot afford to be overwhelmed by persistent pain.”
These findings could be used in the future to better diagnose and treat chronic pain. On the one hand, doctors could measure how active the Y1R neurons are and thus objectively check whether the chronic pain stimulus is (still) present. On the other hand, the Y1R neurons could be specifically activated by drugs and distracted from the pain stimulus in order to alleviate it. It is possible that the nerve cells in this newly discovered brain switching point can be calmed down again over time and returned to a resting state through exercise or meditation. “We have shown that this circuit is flexible; it can regulate pain up or down,” says Betley. “So the future is not just about developing a pill. It’s also about asking how behavior, training and lifestyle can change the way these neurons encode pain.”
Source: Nitsan Goldstein (University of Pennsylvania) et al.; Nature, doi: 10.1038/s41586-025-09602-x