Salk Institute researchers discover pathway from pain to suffering

Last Updated on July 24, 2025

The La Jolla scientists found a key neural circuit in mice that transforms pain into an emotional response, with implications for pain-related conditions.

According to new research from the Salk Institute for Biological Studies, pain carries emotional weight, which can turn short-term injury into long-term suffering.

In a July 9 study published in Proceedings of the National Academy of Sciences, the Salk scientists identified a group of neurons in a central brain area called the thalamus that appears to contribute to the emotional or affective side of pain in mice, giving pain an emotional tone.

The findings challenge the textbook understanding of how pain is processed and may lead to a new potential target for treating chronic and affective pain conditions such as fibromyalgia, migraines and post-traumatic stress disorder (PTSD).

From left: Sukjae Kang and Sung Han
Salk Institute

“For decades, the prevailing view was that the brain processes sensory and emotional aspects of pain through separate pathways,” study senior author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at Salk, said in a press release. “Our study provides strong evidence that a branch of the sensory pain pathway directly mediates the affective experience of pain.”

Pain’s associated physical sensation of pain is what allows for detection and assessment of its source; the affective component, or emotional discomfort, is what motivates action and future avoidance.

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 the signals 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.

CGRP-expressing neurons (green) in the parvocellular subparafascicular nucleus (SPFp) of the thalamus.
Salk Institute

Using advanced techniques to manipulate the activity of specific brain cells, the Salk 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 calcitonin gene-related peptide (CGRP), a neuropeptide originally discovered in Salk professor Ronald Evans’ lab.

When the researchers “turned off,” or 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” or 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,” said 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.”