Pain isn't just a physical sensation -- it also carries emotional weight. That distress, anguish, and anxiety can turn a fleeting injury into long-term suffering.

Researchers at the Salk Institute have now identified a brain circuit that gives physical pain its emotional tone, revealing a new potential target for treating chronic and affective pain conditions such as fibromyalgia, migraine, and post-traumatic stress disorder (PTSD).

Published on July 9, 2025, in Proceedings of the National Academy of Sciences, the study identifies a group of neurons in a central brain area called the thalamus that appears to mediate the emotional or affective side of pain in mice. This new pathway challenges the textbook understanding of how pain is processed in the brain and body.

"For decades, the prevailing view was that the brain processes sensory and emotional aspects of pain through separate pathways," says senior author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at Salk. "But there's been debate about whether the sensory pain pathway might also contribute to the emotional side of pain. Our study provides strong evidence that a branch of the sensory pain pathway directly mediates the affective experience of pain."

The physical sensation of pain is what allows you to immediately detect it, assess its intensity, and identify its source. The affective part of pain is what makes it so unpleasant. This emotional discomfort motivates you to take action and helps you learn to associate negative feelings with the situation so you can avoid it in the future.

This is a critical distinction. Most people start to perceive pain at the same stimulus intensities, meaning we all process the sensory side of pain fairly similarly. In comparison, our ability to tolerate pain varies greatly. How much we suffer or feel threatened by pain is determined by our affective processing, and if that becomes too sensitive or lasts too long, it can result in a pain disorder. This makes it important to understand which parts of the brain control these different dimensions of pain.

Sensory pain was thought to be mediated by the spinothalamic tract, a pathway that sends pain signals from the spinal cord to the thalamus, which then relays them to sensory processing areas across the brain.

Affective pain was generally thought to be mediated by a second pathway called the spinoparabrachial tract, which sends pain information from the spinal cord into the brainstem.

However, previous studies using older research methods have suggested the circuitry of pain may be more complex. This long-standing debate inspired Han and his team to revisit the question with modern research tools.

Using advanced techniques to manipulate the activity of specific brain cells, the researchers discovered a new spinothalamic pathway in mice. In this circuit, pain signals are sent from the spinal cord into a different part of the thalamus, which has connections to the amygdala, the brain's emotional processing center. This particular group of neurons in the thalamus can be identified by their expression of CGRP (calcitonin gene-related peptide), a neuropeptide originally discovered in Professor Ronald Evans' lab at Salk.

When the researchers "turned off" (genetically silenced) these CGRP neurons, the mice still reacted to mild pain stimuli, such as heat or pressure, indicating their sensory processing was intact. However, they didn't seem to associate lasting negative feelings with these situations, failing to show any learned fear or avoidance behaviors in future trials. On the other hand, when these same neurons were "turned on" (optogenetically activated), the mice showed clear signs of distress and learned to avoid that area, even when no pain stimuli had been used.

"Pain processing is not just about nerves detecting pain; it's about the brain deciding how much that pain matters," says first author Sukjae Kang, a senior research associate in Han's lab. "Understanding the biology behind these two distinct processes will help us find treatments for the kinds of pain that don't respond to traditional drugs."

Many chronic pain conditions -- such as fibromyalgia and migraine -- involve long, intense, unpleasant experiences of pain, often without a clear physical source or injury. Some patients also report extreme sensitivity to ordinary stimuli like light, sound, or touch, which others would not perceive as painful.

Han says overactivation of the CGRP spinothalamic pathway may contribute to these conditions by making the brain misinterpret or overreact to sensory inputs. In fact, transcriptomic analysis of the CGRP neurons showed that they express many of the genes associated with migraine and other pain disorders.

Notably, several CGRP blockers are already being used to treat migraines. This study may help explain why these medications work and could inspire new nonaddictive treatments for affective pain disorders.

Han also sees potential relevance for psychiatric conditions that involve heightened threat perception, such as PTSD. Growing evidence from his lab suggests that the CGRP affective pain pathway acts as part of the brain's broader alarm system, detecting and responding to not only pain but a wide range of unpleasant sensations. Quieting this pathway with CGRP blockers could offer a new approach to easing fear, avoidance, and hypervigilance in trauma-related disorders.

Importantly, the relationship between the CGRP pathway and the psychological pain associated with social experiences like grief, loneliness, and heartbreak remains unclear and requires further study.

"Our discovery of the CGRP affective pain pathway gives us a molecular and circuit-level explanation for the difference between detecting physical pain and suffering from it," says Han. "We're excited to continue exploring this pathway and enabling future therapies that can reduce this suffering."

Other authors include Shijia Liu, Jong-Hyun Kim, Dong-Il Kim, Tae Gyu Oh, Jiahang Peng, Mao Ye, Kuo-Fen Lee, Ronald M. Evans, and Martyn Goulding of Salk.

The work was supported by the National Institutes of Mental Health (BRAINS grant 1R01MH116203) and the Simons Foundation (Bridge to Independence award SFARI #388708).

Read more …How a hidden brain circuit fuels fibromyalgia, migraines, and PTSD

For people with Type 1 diabetes, developing hypoglycemia, or low blood sugar, is an ever-present threat. When glucose levels become extremely low, it creates a life-threatening situation for which the standard treatment of care is injecting a hormone called glucagon.

As an emergency backup, for cases where patients may not realize that their blood sugar is dropping to dangerous levels, MIT engineers have designed an implantable reservoir that can remain under the skin and be triggered to release glucagon when blood sugar levels get too low.

This approach could also help in cases where hypoglycemia occurs during sleep, or for diabetic children who are unable to administer injections on their own.

"This is a small, emergency-event device that can be placed under the skin, where it is ready to act if the patient's blood sugar drops too low," says Daniel Anderson, a professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. "Our goal was to build a device that is always ready to protect patients from low blood sugar. We think this can also help relieve the fear of hypoglycemia that many patients, and their parents, suffer from."

The researchers showed that this device could also be used to deliver emergency doses of epinephrine, a drug that is used to treat heart attacks and can also prevent severe allergic reactions, including anaphylactic shock.

Siddharth Krishnan, a former MIT research scientist who is now an assistant professor of electrical engineering at Stanford University, is the lead author of the study, which was published on July 9 in Nature Biomedical Engineering.

Emergency response

Most patients with type 1 diabetes use daily insulin injections to help their body absorb sugar and prevent their blood sugar levels from getting too high. However, if their blood sugar levels get too low, they develop hypoglycemia, which can lead to confusion and seizures, and may be fatal if it goes untreated.

To combat hypoglycemia, some patients carry preloaded syringes of glucagon, a hormone that stimulates the liver to release glucose into the bloodstream. However, it isn't always easy for people, especially children, to know when they are becoming hypoglycemic.

"Some patients can sense when they're getting low blood sugar, and go eat something or give themselves glucagon," Anderson says. "But some are unaware that they're hypoglycemic, and they can just slip into confusion and coma. This is also a problem when patients sleep, as they are reliant on glucose sensor alarms to wake them when sugar drops dangerously low."

To make it easier to counteract hypoglycemia, the MIT team set out to design an emergency device that could be triggered either by the person using it, or automatically by a sensor.

The device, which is about the size of a quarter, contains a small drug reservoir made of a 3D-printed polymer. The reservoir is sealed with a special material known as a shape-memory alloy, which can be programmed to change its shape when heated. In this case, the researcher used a nickel-titanium alloy that is programmed to curl from a flat slab into a U-shape when heated to 40 degrees Celsius.

Like many other protein or peptide drugs, glucagon tends to break down quickly, so the liquid form can't be stored long-term in the body. Instead, the MIT team created a powdered version of the drug, which remains stable for much longer and stays in the reservoir until released.

Each device can carry either one or four doses of glucagon, and it also includes an antenna tuned to respond to a specific frequency in the radiofrequency range. That allows it to be remotely triggered to turn on a small electrical current, which is used to heat the shape-memory alloy. When the temperature reaches the 40-degree threshold, the slab bends into a U shape, releasing the contents of the reservoir.

Because the device can receive wireless signals, it could also be designed so that drug release is triggered by a glucose monitor when the wearer's blood sugar drops below a certain level.

"One of the key features of this type of digital drug delivery system is that you can have it talk to sensors," Krishnan says. "In this case, the continuous glucose-monitoring technology that a lot of patients use is something that would be easy for these types of devices to interface with."

Reversing hypoglycemia

After implanting the device in diabetic mice, the researchers used it to trigger glucagon release as the animals' blood sugar levels were dropping. Within less than 10 minutes of activating the drug release, blood sugar levels began to level off, allowing them to remain within the normal range and avert hypoglycemia.

The researchers also tested the device with a powdered version of epinephrine. They found that within 10 minutes of drug release, epinephrine levels in the bloodstream became elevated and heart rate increased.

In this study, the researchers kept the devices implanted for up to four weeks, but they now plan to see if they can extend that time up to at least a year.

"The idea is you would have enough doses that can provide this therapeutic rescue event over a significant period of time. We don't know exactly what that is -- maybe a year, maybe a few years, and we're currently working on establishing what the optimal lifetime is. But then after that, it would need to be replaced," Krishnan says.

Typically, when a medical device is implanted in the body, scar tissue develops around the device, which can interfere with its function. However, in this study, the researchers showed that even after fibrotic tissue formed around the implant, they were able to successfully trigger the drug release.

The researchers are now planning for additional animal studies and hope to begin testing the device in clinical trials within the next three years.

"It's really exciting to see our team accomplish this, which I hope will someday help diabetic patients and could more broadly provide a new paradigm for delivering any emergency medicine," says Robert Langer, the David H. Koch Institute Professor at MIT and an author of the paper.

Other authors of the paper include Laura O'Keeffe, Arnab Rudra, Derin Gumustop, Nima Khatib, Claudia Liu, Jiawei Yang, Athena Wang, Matthew Bochenek, Yen-Chun Lu, Suman Bose, and Kaelan Reed.

The research was funded by the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, a JDRF postdoctoral fellowship, and the National Institute of Biomedical Imaging and Bioengineering.

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