Published September 3, 2020
General anesthetics used in surgeries cause loss of consciousness. This sedative effect has long been thought to underlie the analgesic (pain-relieving) actions of these drugs. But a new study in mice now poses a strong challenge to this conventional wisdom.
Research led by Fan Wang, Duke University Medical Center, Durham, US, now shows that analgesia caused by the general anesthetics isoflurane and ketamine is independent from the sedative effects of these drugs.
Instead, the researchers show that these anesthetics directly suppress pain via an extremely potent “pain-off” switch in a brain region called the central amygdala.
A number of experiments also showed that the nerve cells that make up this switch can ease pain when they are activated. And, these cells were responsible for the pain-relieving effects of isoflurane and ketamine.
“This is a great advance in understanding the pharmacology of anesthetics,” said Fusao Kato, a pain researcher at Jikei University School of Medicine, Tokyo, Japan, who was not part of the study.
“They have many effects on the CNS [central nervous system],” Kato continued, “yet we didn’t know why they exert such a strong analgesic effect. This paper clearly shows that CeA [central amygdala] neurons activated by general anesthetics are the most important players for reducing pain in this circumstance.”
The research was published in the July 2020 issue of the scientific journal Nature Neuroscience.
Isoflurane activates neurons in the central amygdala
Previously, Wang’s group showed that general anesthesia causes sedation by activating a set of neurons in the hypothalamus, a brain structure that makes hormones that regulate body temperature, sleep, appetite, thirst and many other bodily functions.
“Classically, we think that humans and animals do not perceive pain under general anesthesia because the brain is largely shut down and that analgesia is a consequence of loss of consciousness,” said Thuy Hua, co-first author of the new study along with Bin Chen, both from Duke.
But the group was keen to distinguish the analgesic effects of anesthetics from the sedative ones. They hypothesized that perhaps these drugs actively suppressed pain, possibly by tapping into a system in the brain that is not involved with sedation. In this scenario, pain relief from anesthetics would not simply be a passive outcome of sedation.
To test that idea, the authors measured the activity of brain cells in response to isoflurane. This anesthetic is commonly used in patients undergoing surgery.
The researchers identified three clusters of neurons that became activated in response to the drug. One cluster was in the amygdala; another in a brain region called the bed nucleus of the stria terminalis; and a third cluster of sleep-promoting neurons in the hypothalamus that were the focus of Wang’s earlier work.
The investigators turned their attention to the neurons activated by general anesthesia in the central amygdala. That’s because the central amygdala has a well-known role in endogenous pain modulation, which refers to the body’s own ability to ease or ramp up pain.
The scientists used a method that allowed them to study the activity of nerve cells in live mice. They confirmed that central amygdala neurons were active in mice that were anesthetised with isoflurane.
A “pain-off” switch
The group’s experiments so far had shown that anesthetics activate a population of neurons in the central amygdala. The authors had a strong hunch that these cells could modulate pain in mice, based on what pain researchers had already learned about how the amygdala regulates pain.
To learn if that was the case, the authors turned to optogenetics to manipulate the activity of nerve cells in the central amygdala. Optogenetics is a method in which light is used to activate or suppress activity in specific neurons of interest, in genetically engineered animals.
By using optogenetics to turn central amygdala neurons on or off during painful stimulation of the body, the authors could now test how these cells regulated pain in mice.
The researchers found that activating the neurons profoundly reduced sensitivity to painful stimulation of the body in the animals. This showed that these cells can turn off pain when they are stimulated.
Conversely, using optogenetics to inhibit the neurons increased the sensitivity of the mice to pain.
“This is an important finding,” Hua said, “and shows that…central amygdala neurons [activated by general anesthesia] have the bidirectional capability of enhancing and suppressing pain, if silenced or activated, respectively.”
The “pain-off” switch is always in action
Because silencing the central amygdala neurons increased pain, the investigators thought that these neurons might continuously dampen down pain, even in the absence of painful stimuli.
They reasoned that if the cells were silenced when the animals were placed in an innocuous environment – one that posed no threat to the mice – the animals would not like being in that environment.
And that’s exactly what they found. In this case, they saw that mice tended to avoid the side of a chamber in which the central amygdala neurons were silenced using light. Instead, the animals preferred the other side of the chamber, where they were not exposed to optogenetic manipulation.
On the other hand, the animals preferred the side of a chamber where light was used to turn on the neurons.
Together, the findings showed that ongoing activity of the central amygdala neurons keeps pain in check.
But what happens during chronic pain? Would activation of central amygdala neurons provide relief?
To find out, the team tested whether activation of the neurons could improve pain in a mouse model of neuropathic pain (that is, pain resulting from an experimental nerve injury); in this model, the mice show pain hypersensitivity in the face.
Lo and behold, activation of the central amygdala neurons dramatically lessened the animals’ pain hypersensitivity. It also decreased behaviors such as face wiping, which mice also show in response to painful stimuli.
Going the distance
The authors next traced where the central amygdala neurons sent their axons – long, slender projections from the center of the cells. They wanted to learn which brain regions the projections went to, especially areas that regulate pain.
The projections were extensive, going to many brain regions known to be involved in pain, but also to regions that had not been previously implicated in pain.
“I did not fully expect central amygdala neurons [activated by general anesthesia] to have such widespread projections,” Wang said.
She also stressed that the study helps the pain field understand the fundamental workings on the brain’s pain system.
“I think this work advances basic science about the brain’s role in pain. It brought new insights into likely a common and an active mechanism through which general anesthetics exert profound analgesia,” she said.
Fred Schwaller, PhD, is a freelance science writer based in Germany.
This story first appeared on the IASP Pain Research Forum and has been lightly edited for RELIEF.