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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).

Barriers of vaccination for PWUD in this study can be classified into 5 main categories: Vaccine hesitancy, low health literacy and knowledge, low social capital, limited access to vaccine and finally, fear and worry caused by previous experiences.

Stereotyped beliefs

Stereotyped beliefs were identified as one of the barriers to COVID-19 vaccination among the participants in this study.

These beliefs consist of stereotypes—oversimplified and often inaccurate ideas that lack scientific basis and increase people’s risk of infection. A stereotype is a simplified, uncritical, and sometimes incorrect judgment about a particular subject. Below, the subcategories of stereotypical beliefs are explained:

Believing that PWUD will not become infected with COVID-19

Most participants in this study believed that they were immune to COVID-19 infection because of the resistance created in their bodies built up by their use of drugs.

Participant 9 in this regard stated: “Addicts do not get infected with coronavirus…who said addicts get sick?”

Participant 7 also stated: “PWUD don’t get any disease because of the substances in their blood.”

Ineffectiveness of COVID-19 vaccine

Some participants believed that COVID-19 vaccine is not effective, and the use of face masks is more effective than vaccination in preventing COVID-19. Some people viewed the free COVID-19 vaccination with suspicion, arguing that it seemed strange to offer vaccines for free while there was a severe shortage of alcohol and face masks, and everything else had to be paid for.

Participant 21 in this regard stated: “They say that even if you get vaccinated, you still need to wear a mask, which means that a mask can prevent this infection, but a vaccine cannot.”

Participant 3 added: “In Iran, you have to pay for everything. In this tough economic condition, is it possible to vaccinate everyone only for altruism purposes?”

Negative effect of vaccine on underlying diseases

One of the stereotypes beliefs about the vaccination was related to its negative effect on underlying diseases, which believed by the participants to increase the mortality rate. Considering the fact that most PWUDs have various underlying diseases, participants in this study, were less willing to get vaccinated.

Participant 3 stated: “We (the addicts) have hundreds of diseases, some of which we don’t even know about. I think that if I get vaccinated, it will have a bad effect on my health and my condition gets worse. If I’m going to die, let me die a little later.”

Lack of trust in the healthcare system and the type of vaccine

A number of participants had a problem with the type of vaccine and stated that they would be willing to get vaccinated if they receive European or American vaccines.

Participant 2 stated: “They put us in the priority list for vaccination and think we are laboratory rats. They receive Pfizer vaccine, but when it is our turn, they suggest Sinopharm or Barekat vaccines for us.”

Low health literacy and knowledge

High health knowledge makes people to prioritize their health. It also helps them to distinguish between important facts and issues and false news and information. This category includes the following subcategories:

Neglecting health and underestimating the disease

Some drug users refused to receive vaccination because they did not prioritize health and underestimated the risks of diseases. These people may not pay enough attention to side effects and consequences of the disease because of their addiction and think that diseases are not a serious threat to them. This attitude can increase their risk of diseases and other health problems. Also, based on the results of this study, some of the drug users, contrary to the observations, believed that they have not been sick in the past few years despite their living conditions and substance use.

Participant 19 stated: “I’m healthy and I don’t get sick. Even if I get sick, COVID-19 is nothing compared to diseases I have had in the past. If we get sick, we’ll get rid of it quickly by taking some more substances.”

Participant 5 also stated: “As far as I can remember, influenza has always existed. It is a seasonal disease and will end when the weather gets hotter.”

Participant 17 added: “We (the addicts), who sleep, eat and use substances together, and do not follow the protocol, nor the physical distance. We never got infected. It’s all propaganda.”

Not prioritizing the health

A number of drug users, especially psychedelic drug users and homeless people, referred to their high substance consumption and behaviors such as gambling and theft as the reasons for not getting vaccinated.

Participant 7 in this regard stated: “We are all either looking for money or taking substance. Who has a time to go for vaccination?”

Participant 6 also stated: “Do you think I should give up gambling and business, and not take substances for two hours just to go for vaccination?”

Low health literacy

Although there were people with high education among the drug users, lack of health literacy seemed to be one of the barriers of vaccination among them.

Participant 12 in this regard stated: “People say that the vaccine causes infertility. I don’t want that to happen to me. Maybe one day I withdraw substance use, and want to have a child.”

Participant 16 added: “We need to know who has made these vaccines, how they have been made, and whether the manufacturer is valid or not.”

Believing in self-treatment and traditional medicine

Some drug users believed in self-medication through traditional and herbal medicines.

Participant 18 stated: “Whenever I feel sick, I drink tea with candy.”

Participant 9 also stated: “We put harmful substances and chemicals into our bodies every day. So why would we want to get vaccinated? It feels like solving one problem but creating a hundred more.”

Available rumors

The increase of rumors without scientific basis among drug users, especially those with a lower level of literacy, was found to be another barrier of vaccination. Rumors can spread quickly among people’s network, and when their frequency increases, people began to believe them.

Participant 18 in this regard said: “It’s true, we don’t want to be alive, but why should we die because of a vaccine? You know why—because they say everyone who gets the vaccine will die within two years, and if they don’t, they’ll end up with a whole bunch of diseases.”

Participant 16 also said, “Don’t they say that if more people get vaccinated, herd immunity will be achieved? So, go get vaccinated so we can all benefit from it. God bless you.”

Low social capital

Social capital gives meaning to life and makes life simpler and more enjoyable. Considering the issue of CIVID-19, the role of social capital was important for the participants. This category has several subcategories as follow:

Inhibitory social networks

The peer social network of PWUD and their negative impact on each other was one of the reasons for encouraging and persuading drug users not to get vaccinated. The noteworthy point in this regard was the lack of correct information provision to homeless people by radio and local trustees. So, in the absence of such information provision, drug users were trusting their peers more than the media.

Participant 20 in this regard said: “Anyone who watches the video clip will immediately know how much of a lie it is.”

Participant 21 added: “Those who received the vaccine, their body become magnet and got covered by blistered”.

Lack of social responsibility

Most of the participants did not feel an obligation towards the society, and did not feel the need to comply with the preventive measures and collective safety. Responsibility is one of the main components of social capital.

Participant 10 stated: “I have no moral sense and I don’t think it is necessary for me and people like me to get vaccinated.”

Structural and experiential barriers

One of the issues raised in the interviews was discrimination in the distribution of medical services, in a way that it denies drug users a fair access to healthcare services without social stigmatization.

Lack of access to vaccine

According to the participants in this study, the distance and long queues for vaccination were the most important obstacles to COVID-19 vaccination for them. It seemed that access to vaccine in a place close to their hangout was one of the main drivers of COVID-19 vaccination for them.

Participant 15 in this regard stated: “In the beginning, when the number of centers was few and far away from us, we did not feel like going to get vaccinated.”

Participant 14 added: “The queues were so crowded and long, we couldn’t deal with it. We also didn’t have the patience to wait for our turn.”

Unpleasant past experiences in relation with the vaccination

Some drug users were not well-groomed in terms of cleanliness and appearance due to their condition, illness and lifestyle, and also, they had experienced stigma and discrimination in utilizing health services. They had encountered the unpleasant experience of not receiving health services. That was why they did not have any trust in the health system.

Participant 1 in this regard stated: “When we go to healthcare centers, they cover their noses, they stay away from us and think they will become substance addicts or get AIDS. How do they want us to go there and get vaccinated? It’s better for us to stay away from them, so that they don’t humiliate us.”

Fear and worry caused by previous experiences

The previous observations and experiences of drug users were the cause of their fear, anxiety and worry about vaccination, and prevented them from receiving the vaccination.

Death or illness of close friends/relatives who had been vaccinated

If previous experiences in relation to a particular subject are stressful and unpleasant, the desire to repeat it, is minimized. The experience of infection or death of close friends/relatives after getting vaccinated was one of the barriers of vaccination for the participants.

Participant 2 in this regard stated: “We heard about and saw many people who got sick or died after getting vaccinated.”

Participant 4 also stated: “Many of my acquaintances received the vaccine for several times, but still got infected with COVID-19.”

Fear of the vaccine

A number of participants believed that injecting the vaccine itself could be harmful and believed that the vaccine might have some side effects.

Participant 2 stated: “Many people in our family have been vaccinated, and yet two of them began to show symptoms of COVID-19, and two more got infected with COVID-19. Do you think it is wise to get vaccinated? I don’t think so.”

Participant 3 added: “I think these vaccines are doing more harm than good.”