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CeAga Neurons Play an Important Role in Chronic Pain Suppression

By: Sai Srihaas Potu

Pain is a complex sensory and emotional experience that can vary widely between people and even within an individual depending on the context and meaning of the pain and the psychological state of the person. Cognitive and emotional factors have a surprisingly important influence on pain perception. A negative expectation can completely reverse the analgesic effect of a clinical dose of an opioid, whereas the expectation of pain relief is an important component of placebo analgesia.


Clinical and experimental studies show that even a simple psychological manipulation, such as distraction, can have a powerful effect on our perception of pain. Our emotional state also has an enormous influence on pain; a negative emotional state increases pain, whereas a positive state lowers pain. Not surprisingly, complex emotional states such as empathy, which incorporate emotional and cognitive factors, alter the way an individual feels pain. Brain imaging studies have allowed us to examine the neural basis of psychological modulation of pain. These studies reveal that activity in afferent pain pathways is altered by the attentional state, positive and negative emotions, empathy, and the administration of a placebo.


Recently, a group of researchers from Duke University has discovered a small area of the brain in mice that can profoundly control the animals' sense of pain. According to this research, the brain can turn pain off, not on. This small complex is located in an area where few people would have thought to look for an anti-pain center, the amygdala, which is often considered the home of negative emotions and responses, like the fight or flight response and general anxiety.


"People do believe there is a central place to relieve pain, that's why placebos work," said senior author Fan Wang, the Morris N. Broad Distinguished Professor of neurobiology in the School of Medicine. "The question is where in the brain is the center that can turn off pain."


The researchers found that general anesthesia also activates a specific subset of inhibitory neurons in the central amygdala, which they have called the CeAga neurons. Mice have a relatively larger central amygdala than humans, but Wang said she had no reason to think we have a different system for controlling pain.


Using technologies that Wang's lab has pioneered to track the paths of activated neurons in mice, the team found that the CeAga was connected to many different areas of the brain, "which was a surprise," Wang said.


By using technology such as optogenetics, which uses light to activate a small population of cells in the brain, the research team found that they could turn off the self-caring behaviors a mouse exhibits when it feels uncomfortable by activating the CeAga neurons.


Ultimately, the researchers concluded that the inhibition of CeAga activity exacerbated pain, produced strong aversion, and canceled the analgesic effect of low-dose ketamine. CeAga neurons have widespread inhibitory projections to many affective pain-processing centers. Their study points to CeAga as a potentially powerful therapeutic target for alleviating chronic pain.


Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache, and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga, and cognitive behavioral therapy. The neural mechanisms underlying the modulation of pain by cognitive and emotional states are important components of mind-body therapies.


The Duke research team proved that CeAga not only can help alleviate chronic pain but is also a better treatment source when compared to what is out there in the market. Previous studies proved that chronic pain can alter brain circuitry suggesting that controlling pain becomes increasingly difficult as the pain becomes chronic. This new study helps display the significance of CeAga activity in the brain as it can exacerbate pain. Subsequent research and evidence can help solidify this claim and ultimately help the millions of people who suffer from chronic pain in our world today.



References:

1. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005.

2. Bingel U, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011.

3. Thuy Hua, Bin Chen, Dongye Lu, Katsuyasu Sakurai, Shengli Zhao, Bao-Xia Han, Jiwoo Kim, Luping Yin, Yong Chen, Jinghao Lu, Fan Wang. General anesthetics activate a potent central pain-suppression circuit in the amygdala. Nature Neuroscience, 2020.

4. Villemure C, Bushnell MC. Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain. 2002.

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