Pain is not just a physical sensation – it also has an emotional component. These stresses can turn a temporary injury into a long-lasting ailment. Researchers at the Salk Institute have now identified a brain circuit that gives physical pain its emotional component. They have thus found a new starting point for the treatment of chronic and affective pain conditions such as fibromyalgia, migraine and post-traumatic stress disorder (PTSD). The study, published in the Proceedings of the National Academy of Sciences, 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 signaling pathway challenges textbook knowledge about how pain is processed in the brain and body.
How the Brain Controls Different Dimensions of Pain
“For decades, the prevailing view was that the brain processes sensory and emotional aspects of pain through separate pathways,” says lead author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at the Salk Institute. “However, there has been debate about whether the sensory pain pathway also contributes to the emotional side of pain. Our study provides strong evidence that one branch of the sensory pain pathway directly mediates the affective experience of pain.” The physical sensation of pain allows us to perceive it immediately, assess its intensity and identify its source. The affective part of pain is what makes it so unpleasant. This emotional discomfort motivates us to act and helps us to associate negative feelings with the situation so that we can avoid them in the future.
This is a crucial difference. Most people start to perceive pain at the same stimulus intensity, which means that we all process the sensory side of pain in a fairly similar way. In comparison, our ability to tolerate pain varies greatly. How much we suffer from pain or feel threatened by it is determined by our affective processing. If this becomes too sensitive or lasts too long, it can lead to a pain disorder. It is therefore 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 signaling pathway that sends pain signals from the spinal cord to the thalamus, which then transmits them to sensory processing areas throughout the brain. Affective pain was generally mediated by a second pathway, the so-called spinoparabrachial tract, which transmits pain information from the spinal cord to the brainstem.
However, previous studies using older research methods have suggested that the pain circuitry may be more complex. This long-standing debate inspired Han and his team to re-examine the question using modern research tools. Using advanced techniques to manipulate the activity of specific brain cells, the researchers discovered a new spinothalamic signaling pathway in mice. In this circuit, pain signals are transmitted from the spinal cord to another part of the thalamus that is connected to the amygdala, the emotional center of the brain. 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 the laboratory of Professor Ronald Evans at the Salk Institute.
Treatment Methods for Pain Conditions Such as Fibromyalgia and Migraine
When the researchers “turned off” (genetically silenced) these CGRP neurons, the mice continued to respond to mild pain stimuli such as heat or pressure, indicating that their sensory processing was intact. However, they did not appear to associate any persistent negative feelings with these situations and did not show any learned fear or avoidance behaviors in later trials. In contrast, when the same neurons were “turned on” (optogenetically activated), the mice showed clear signs of stress and learned to avoid this area, even when no pain stimuli were used. “Pain processing is not just about nerves sensing pain, but about the brain deciding how important that pain is,” says first author Sukjae Kang, a research associate in Han’s lab. “Understanding the biology behind these two different processes will help us find treatments for pain that doesn’t respond to conventional drugs.”
Many chronic pain conditions – such as fibromyalgia and migraines – are associated with long, intense and uncomfortable pain experiences, often without a clear physical cause or injury. Some patients also report extreme sensitivity to common stimuli such as light, sound or touch that others would not experience as painful. Han says that overactivation of the CGRP-spinothalamus signaling pathway could contribute to these conditions by causing the brain to misinterpret or overreact to sensory stimuli. Indeed, transcriptome analysis of CGRP neurons showed that they express many of the genes associated with migraine and other pain disorders. Remarkably, several CGRP blockers are already used to treat migraine. This study could help explain how these drugs work and could lead to new, non-addictive treatments for affective pain disorders.
Han also sees potential relevance for psychiatric disorders associated with heightened threat perception, such as PTSD. Increasing evidence from his lab suggests that the CGRP affective pain pathway functions as part of the brain’s broader alarm system, sensing and responding not only to pain but to a variety of unpleasant sensations. Suppressing this pathway with CGRP blockers could offer a new approach to alleviating anxiety, avoidance behavior and hypervigilance in trauma-related disorders. Importantly, however, the link between the CGRP signaling pathway and psychological pain associated with social experiences such as grief, loneliness and heartbreak is still unclear and requires further investigation.