Researchers have found that an experimental compound works in the amygdala to quell the pain of arthritis in rats

Pain is an alert that something is wrong — unfortunately, the pain does not go away while the problem remains, and finding a resolution is not always possible.

Volker E. Neugebauer, Ph.D., who headed the research at the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine, says that “[Pain] is not just a sensation that lets you know where it hurts and how intense the pain feels. It also causes anxiety, impairs quality of life, and causes depression.”

While most pain studies look at other parts of the body, including the spinal cord, Neugebauer explains that “We’re studying the brain because all of those things reside there.”

The study reveals a new understanding of the amygdala’s role in pain relief using an arthritis pain model.

“Our unique area of expertise is really understanding that changes in the brain contribute to the persistence, intensity, and other side effects of pain,” says Neugebauer.

The key compound LY379268

Neugebauer’s study appears in the journal Neuropharmacology.

In it, the researchers describe their investigation into the properties of an existing experimental anxiety reducing compound called LY379268.

Many experts believe that compounds, such as LY379268, interact with the spinal cord and other nervous system components outside the brain. This is why doctors typically target the spinal cord when introducing drugs to relieve pain.

However, much uncertainty remains as to how these compounds work, as well as where they work in the body.

To try to answer these questions, the researchers introduced LY379268 systemically into rats, allowing it to circulate throughout the body in the hopes of determining where it went and what it did.

When it proved to have an analgesic effect in the rats, the team turned their attention to group II metabotropic glutamate receptors (II mGluRs) in the amygdala.

The researchers knew that LY379268 is an agonist for these receptors — an agonist is a substance that causes a physiological response when combined with a compatible receptor — and wondered if they were the source of LY379268’s inhibitory effect on pain.

Basically, the entire pain relieving effect of the drug can be explained by an action in the brain, not in the spinal cord

Basically, the entire pain relieving effect of the drug can be explained by an action in the brain, not in the spinal cord

The role of the amygdala

The amygdala comprises almond-shaped clusters of neurons located deep in the center of the brain’s temporal lobe. It is part of the brain’s limbic system, which is involved with motivation, emotions, and fear, as well as anxiety, addiction, and pain.

To test whether they were involved in the pain relief offered by LY379268, the researchers blocked the receptors to see if this would switch off the pain relieving effect of the compound.

“And it did, actually,” says Neugebauer. “So imagine you inject this drug systemically, you block the receptors only in the amygdala, and the analgesic, or pain relieving, effect of the drug is gone.”

The team’s results may have significant implications for future research.

“It means the effect of the compound has not really been through an action in the spinal cord, but through an action in the area of interest in the brain, which is the amygdala,” summarizes Neugebauer.

Researchers have found that an experimental compound works in the amygdala to quell the pain of arthritis in rats.

 

scientist looking through microscope
Experiments in rodents suggest that pain relief in arthritis originates in the brain.

 

Pain is an alert that something is wrong — unfortunately, the pain does not go away while the problem remains, and finding a resolution is not always possible.

Volker E. Neugebauer, Ph.D., who headed the research at the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine, says that “[Pain] is not just a sensation that lets you know where it hurts and how intense the pain feels. It also causes anxiety, impairs quality of life, and causes depression.”

While most pain studies look at other parts of the body, including the spinal cord, Neugebauer explains that “We’re studying the brain because all of those things reside there.”

The study reveals a new understanding of the amygdala’s role in pain relief using an arthritis pain model.

“Our unique area of expertise is really understanding that changes in the brain contribute to the persistence, intensity, and other side effects of pain,” says Neugebauer.

The key compound LY379268

Neugebauer’s study appears in the journal Neuropharmacology. In it, the researchers describe their investigation into the properties of an existing experimental anxiety reducing compound called LY379268.

Many experts believe that compounds, such as LY379268, interact with the spinal cord and other nervous system components outside the brain. This is why doctors typically target the spinal cord when introducing drugs to relieve pain.

However, much uncertainty remains as to how these compounds work, as well as where they work in the body.

To try to answer these questions, the researchers introduced LY379268 systemically into rats, allowing it to circulate throughout the body in the hopes of determining where it went and what it did.

When it proved to have an analgesic effect in the rats, the team turned their attention to group II metabotropic glutamate receptors (II mGluRs) in the amygdala.

The researchers knew that LY379268 is an agonist for these receptors — an agonist is a substance that causes a physiological response when combined with a compatible receptor — and wondered if they were the source of LY379268’s inhibitory effect on pain.

The role of the amygdala

The amygdala comprises almond-shaped clusters of neurons located deep in the center of the brain’s temporal lobe. It is part of the brain’s limbic system, which is involved with motivation, emotions, and fear, as well as anxiety, addiction, and pain.

Scientists know that II mGluRs in the amygdala serve two opposing functions. On the one hand, they can increase pain by triggering an excitatory response. On the other, they can trigger an inhibitory response that reduces pain.

To test whether they were involved in the pain relief offered by LY379268, the researchers blocked the receptors to see if this would switch off the pain relieving effect of the compound.

“And it did, actually,” says Neugebauer. “So imagine you inject this drug systemically, you block the receptors only in the amygdala, and the analgesic, or pain relieving, effect of the drug is gone.”

The team’s results may have significant implications for future research.

“[It] means the effect of the compound has not really been through an action in the spinal cord, but through an action in the area of interest in the brain, which is the amygdala,” summarizes Neugebauer.

Although LY379268 does affect the spinal cord, the effect is not a direct one, and it is not involved in the reduction of pain.

LY379268 and aging

The TTUHSC study suggests that LY379268 deserves further exploration as a painkiller for humans. “When it’s given systemically, it works, and now we know it works in the brain,” says Neugebauer.

“It produces pain relieving effects and also eases anxiety, so it could prove to be a very good pain medication.”

Firstly, however, Neugebauer wants to find out whether LY379268 would prove as successful in older mice as it has been for the younger animals studied.

If it does, “it may open up new avenues for investigating chronic pain, long term pain from arthritis, and other similar conditions.”

It is an area Neugebauer plans to explore, saying, “In the context of aging, there is really a big knowledge gap, so that’s a direction I think we’re going to go.”