Summary: Pain is more than a physical signal — it carries emotional meaning that shapes how we respond and how the experience is remembered. New research identifies a group of thalamic neurons that link incoming pain signals directly to the brain’s emotional center, revealing a circuit that specifically drives the unpleasant, affective side of pain.
In mice, genetically silencing these neurons reduced fear and avoidance behaviors, while activating them produced distress and learned avoidance even without physical injury. The discovery points to new avenues for treating chronic pain, migraine, and trauma-related disorders by targeting the emotional dimension of pain processing.
Key facts:
- Emotional pain circuit: Researchers mapped a thalamus-to-amygdala pathway that conveys the affective impact of painful stimuli.
- Distinct from sensory detection: Suppressing this circuit reduced suffering and learned avoidance while leaving basic pain detection intact.
- Therapeutic potential: Findings may inform treatments for chronic pain conditions, migraine, and PTSD by addressing affective pain mechanisms.
Source: Salk Institute
Pain is both sensory and emotional. The physical signal alerts us to tissue damage or threat, while the emotional, or affective, component creates the unpleasant feelings that motivate avoidance and learning. When affective processing becomes amplified or prolonged, ordinary sensations can turn into long-term suffering.
Published July 9, 2025, in Proceedings of the National Academy of Sciences, the study from the Salk Institute identifies a subset of thalamic neurons that mediate affective pain in mice. These neurons express CGRP (calcitonin gene-related peptide) and form a previously unrecognized branch of the spinothalamic pathway with direct connections to the amygdala, the brain’s emotional center.
Historically, models separated sensory-discriminative pain (detecting location and intensity) from affective-motivational pain (how unpleasant it feels). The sensory route was attributed to the spinothalamic tract projecting to sensory cortices, while affective pain was thought to travel via the spinoparabrachial pathway to brainstem centers. This new work shows that a thalamic CGRP pathway branches from the spinal cord to directly influence affective responses, challenging that neat separation.
Using modern genetic and optogenetic tools to manipulate cell-type specific activity, the researchers traced dorsal horn inputs to CGRP-positive neurons in the parvicellular subparafascicular nucleus (SPFp) of the thalamus. Calcium imaging showed these CGRPSPFp neurons become active during mechanical, thermal, and inflammatory stimuli.
When researchers genetically silenced CGRPSPFp neurons, mice still detected and reflexively responded to noxious heat or pressure, indicating preserved sensory detection. However, those animals failed to form aversive memories or show avoidance in subsequent tests, demonstrating a loss of the affective component. Conversely, optogenetic activation of the same neurons produced clear distress and avoidance learning even in the absence of painful stimuli.
“Pain processing is not simply about sensing a harmful stimulus; it’s about the brain assigning emotional significance,” says senior author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at Salk. First author Sukjae Kang adds that understanding the separate biological basis of detection versus suffering could enable new treatments for pain that do not rely on traditional analgesics.
The team’s transcriptomic profiling found that CGRPSPFp neurons express several genes linked to migraine and other pain disorders, suggesting these cells could contribute to clinical pain hypersensitivity. CGRP-targeting drugs are already effective for many migraine patients; this circuit-level insight may explain part of their benefit and point to additional, nonaddictive strategies for reducing the emotional burden of pain.
Beyond chronic pain and migraine, the researchers note relevance for psychiatric conditions characterized by heightened threat perception, such as post-traumatic stress disorder (PTSD). Evidence from the lab indicates the CGRP affective pain pathway functions as part of a broader alarm system that responds to a range of unpleasant or threatening sensations. Dampening this pathway could reduce fear, avoidance, and hypervigilance in trauma-related conditions, although its role in social or psychological pain (grief, loneliness) remains to be determined.
The study clarifies a molecular and circuit-level distinction between detecting physical harm and suffering from it. By isolating a thalamic CGRP pathway that specifically mediates affective pain, the work opens a path toward therapies that target suffering while preserving protective sensory responses.
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, all affiliated with the Salk Institute.
Funding: Supported by the National Institutes of Mental Health (BRAINS grant 1R01MH116203) and the Simons Foundation (Bridge to Independence award SFARI #388708).
About this emotion and pain research news
Author: Salk Communications
Source: Salk Institute
Contact: Salk Communications – Salk Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Thalamic CGRP neurons define spinothalamic pathway for affective pain” by Sung Han et al., Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2505889122
Abstract
Thalamic CGRP neurons define spinothalamic pathway for affective pain
Pain combines sensory detection and emotional experience. While many studies have examined peripheral and central mechanisms, the precise circuits linking spinal inputs to brain regions that generate affective pain remain incompletely defined. This work demonstrates that CGRP-positive neurons in the parvicellular subparafascicular nucleus (SPFp) receive projections from the dorsal horn and are activated by mechanical, thermal, and inflammatory stimuli. Genetic silencing of these neurons reduced affective pain behaviors, while optogenetic activation produced aversive memory without changing basic mechanical or thermal thresholds. These results identify a distinct spinothalamic circuit involving CGRPSPFp neurons that mediates affective, but not sensory-discriminative, aspects of pain and suggest new targets for pain therapies with fewer side effects.