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Animal studies could help identify new treatment goals for negative emotions related to pain
Pain is closely related to negative emotional states. Now, while studying rats at the Washington University School of Medicine in St. Louis, researchers have identified circuits in the brain that seem to associate pain with negative emotional states, particularly inhibited motivation and anhedonia. Anhedonia is defined as the inability to experience joy in rewards; Inhibited motivation refers to a lack of interest in rewards.
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Negative emotional states and physical pain are closely related. Numerous people who suffer from chronic, persistent pain also struggle with negative emotions and loss of motivation. Some even eventually become clinically depressed, and doctors sometimes prescribe antidepressants to treat chronic pain, despite poor understanding of the pathways that link pain and mood.
Now, while studying the brain and behavior of rats, a team of researchers at Washington University School of Medicine in St. Louis has identified circuits in the brain that appear to associate pain with negative emotional states, particularly inhibited motivation and anhedonia. Anhedonia is defined as the inability to experience joy in rewards; Inhibited motivation refers to a lack of interest in rewards. The researchers measured this behavior in the rodents, monitored their sucrose consumption and their willingness to pull a lever to earn a sucrose tablet.
The results, published online October 18 in the journal Nature Neuroscience, could lead to treatments that target the emotion-related aspects of pain. Such developments would ideally allow chronic pain patients a better quality of life, even if the pain itself cannot be completely eliminated.
“Pain involves more than just uncomfortable physical sensations; it also has an emotional component, ”said Jose Moron-Concepcion, PhD, one of the study’s lead researchers. “Most research has sought to understand and eliminate the sensory component of pain, while largely ignoring its emotional component and associated comorbidities such as depression, anxiety, and the inability to experience pleasure. By understanding the bigger picture, we can make it easier for people to deal with pain. “
He explained that pain has a sensory component, which is the uncomfortable physical sensation that people experience, and that there is an affective component, which is the negative emotional component of pain, especially persistent pain. Anhedonia is a common aspect of negative emotional pain and, for example, can make a person more susceptible to an opioid use disorder.
Moron-Concepcion, the Henry E. Mallinckrodt Professor of Anaesthesiology, led the study at the Washington University Pain Center with co-senior investigator Meaghan Creed, PhD, an assistant professor of anesthesiology, psychiatry, neuroscience, and biomedical engineering. Her goal was to uncover the brain circuits involved in the relationship between pain and the associated changes in the state of motivation.
Her team was able to identify specific dopamine neurons in a region of the brain called the ventral tegmental region that reduce their activity during pain. Changes in dopamine activity in this brain region are also associated with motivation. And the area of the brain where these neurons are located is part of a pathway associated with reward-motivated behavior, suggesting that changes in the dopamine neurons along that pathway may be important in mediating the negative emotional states associated with pain .
The researchers also found that pain increased the activity of neurons in a region called the rostromedial tegmental core. These neurons deliver a substance called GABA (gamma-aminobutyric acid) to the dopamine neurons in the ventral tegmental area. As the brain’s primary inhibitory neurotransmitter, GABA inhibits the activity of these neurons. The increased GABA levels in painful rats decreased the activity of dopamine neurons, which correlated with a decrease in the motivation for natural rewards.
“It’s like stepping on the brakes in a car,” says Moron-Concepcion, also a professor of neuroscience and psychiatry. “Dopamine is associated with positive emotions, so the GABA of other neurons normally controls dopamine levels; But when there is pain, those dopamine levels can get too low. “
In rats, a major result of such changes in chemical concentrations in the brain has been less reward-seeking behavior. When observed 48 hours after persistent pain began, rats that did not experience pain were less likely to pull a lever that provided a natural reward (in this case, a sugar tablet).
“When the animals feel pain, the brain circulation is dysregulated with dopamine and GABA,” said first author Tamara Markovic, PhD, a doctoral student in neuroscience in Moron-Concepcion’s laboratory. “We correlated lower levels of dopamine neuron activity with less natural reward seeking. The animals were less interested in pulling the lever to get the sucrose tablet, which they normally would if they weren’t feeling the persistent effects of the pain. “
But when the researchers blocked the way in which GABA-producing neurons interfered with dopamine neurons, the rats began to seek rewards on a similar level to rats that are not in pain. By reactivating dopamine production, the researchers were able to essentially restore the rodents’ motivation to receive the reward despite persistent pain sensations.
“We’ve known for years that low dopamine levels are linked to apathy and loss of motivation,” said Creed. “The loss of goal-oriented behavior in these animals is similar to the loss of motivation that many people with chronic pain report. Our work to find out how these brain regions influence each other and cause a loss of motivation could offer new starting points for the treatment of the emotional component of pain. “
The researchers believe that the emotional and behavioral changes that accompany pain may be just as important to quality of life as physical pain signals, which are transmitted to the spinal cord and brain via the peripheral nerves.
“A person’s sense of pain is much more than just the pain signal itself,” said Creed. “Pain can trigger anxiety, depression, anhedonia, and other behaviors. The mental and behavioral changes associated with pain are as real as the physical sensations, and unless we understand how these things work together, we cannot provide real pain relief to people. “
Markovic T, Pedersen C, Massaly N, Vachez Y, Ruyle B, Murphy C, Abiraman K, Shin JH, Garcia J, Yoon HJ, Alvarez VA, Bruchas MR, Creed M, Moron JA. Pain induces adaptations in the dopamine neurons of the ventral tegmental area to promote anhedonia-like behavior. Nature Neuroscience, October 18, 2021.
This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (NIH). Funding numbers DA041781, DA042581, DA042499, DA041883, DA045463, R21 DA047127 and R01 DA049924. Additional support from a NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation, a Whitehall Foundation Grant, a Rita Allen Scholar Award in Pain, and NRSA.
The 1,700 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.