Researchers at Duke University have identified a region in the central amygdala – more often thought of as a processing hub for emotions – that could suppress pain when activated.

The work, which was published in the May 18, 2020, issue of Nature Neuroscience, gives new insights into the relationship between analgesia and anesthesia, and might help clarify the molecular underpinnings of the placebo effect.

The studies that led Fan Wang and her team to discover the analgesic effects of stimulating the amygdala were “a premeditated adventure,” Wang told BioWorld.

Wang, Morris N. Broad Distinguished Professor of neurobiology in the Duke University School of Medicine, described herself as “very interested in general anesthesia,” and its relationship to analgesia.

Anesthetic drugs are a structurally diverse bunch, but they have two effects in common. In addition to their anesthetic effect, “at low doses, they are all analgesics,” Wang pointed out.

To find the brain structure that Wang hypothesized was behind those convergent effects, she and her team anesthetized mice with two different classes of anesthesia, isoflurane and ketamine, and used neuronal activity markers to map which brain areas were active under both.

Both drugs activated a cluster of neurons in the central amygdala – a finding that initially puzzled the researchers, since the amygdala is better known for processing than preventing pain, and even more so, fear.

But labeling experiments demonstrated that the neurons activated by anesthesia were not the same ones involved in fear and pain processing.

While Wang and her team were not able to find a common marker expressed by the anesthesia-activated cells, such cells mostly did not express somatostatin, prodynorphin, neurotensin or CGRP-receptor, as amygdala neurons that process fear and pain do.

The researchers then tested whether activation of the anesthesia-activated cells could itself lead to analgesia.

They found that activating the cells via optogenetics did not lead to fear-like behaviors, but could prevent the animals from feeling pain in response to normally noxious stimuli.

Activating the neurons identified by Wang and her team could ultimately be a new strategy for inducing analgesia. Wang noted that such activation of a single, compact brain region might be easier and have fewer side effects than trying to inhibit the multiple pathways that have evolved to sense pain.

Additionally, she pointed out, “in preliminary studies, we don’t see activating these circuits have addictive properties.”

For the time being, however, what specific activators of the newly identified region would look like is unclear.

The neurons identified in the study use GABA as their transmitter. GABA is the most common inhibitory neurotransmitter, making it challenging to develop specific drugs.

Wang said that the team wants to study the neurons in greater detail, which could identify unifying characteristics that might be targeted pharmacologically. Another possibility, she said, could be to look at their connections for targeting possibilities.

Wang also said that studying the analgesia neurons might enable new insights into two separate phenomena, namely stress and the placebo effect.

Stress, she said, is “a double-edged sword.” Low-level stress can aggravate pain, as well as anxiety.

But “under life-threatening situations, you have to ignore the pain,” suggesting that extreme stress has a way to silence pain pathways.

Wang and her team are also trying to see whether or not the neurons they have identified are involved in the placebo effect.

“Placebo is such a vague thing,” Wang said. But there are clearly brain circuits underlying the phenomenon. Understanding those circuits could potentially lead to ways to activate them – or to keep them under control in clinical trials, where placebo effects have at times doomed promising medicines.

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