Silencing a specific brain circuit can prevent and reverse chronic pain

A neural circuit hidden in an understudied region of the brain plays a critical role in turning temporary pain into pain that can last months or years, according to new University of Colorado Boulder research.

The animal study, published in the Journal of Neuroscience, found that silencing this pathway, known as the caudal granular insular cortex (CGIC), can prevent or halt chronic pain.

Our paper used a variety of state-of-the art methods to define the specific brain circuit crucial for deciding for pain to become chronic and telling the spinal cord to carry out this instruction. If this crucial decision maker is silenced, chronic pain does not occur. If it is already ongoing, chronic pain melts away."

Linda Watkins, senior author, distinguished professor of behavioral neuroscience, College of Arts and Sciences, University of Colorado Boulder

The study comes amid what first author Jayson Ball calls a "gold rush of neuroscience."

With new tools enabling them to genetically manipulate precise populations of brain cells, neuroscientists are now able to identify, with unprecedented granularity, potential targets for new therapies. Such therapies, including infusions or brain-machine interfaces, could someday provide safer and more effective alternatives to opioids.

"This study adds an important leaf to the tree of knowledge about chronic pain," said Ball, who earned his doctorate in Watkins' lab in May and now works for Neuralink, a California-based startup that develops brain-machine interfaces for human health.

When touch hurts

About one in four adults have chronic pain, according to the Centers for Disease Control, and nearly one in 10 people say chronic pain interferes with their daily life and work.

Those with nerve-related pain often suffer from a condition called allodynia, an extreme sensitivity in which even light touch hurts.

Acute and chronic pain work differently. Acute pain serves as a temporary warning sign, initiated when an injured tissue-like a stubbed toe-sends a signal to the spinal cord and onward to the brain's pain center. Chronic pain is more like a false alarm, in which pain signals persist in the brain for weeks, months or years after the initial tissue injury has healed.

"Why, and how, pain fails to resolve, leaving you in chronic pain, is a major question that is still in search of answers," said Watkins.

Disabling the chronic pain circuit

In 2011, Watkins' lab published a study suggesting that the CGIC-a sugar-cube-sized cluster of cells hidden deep within the folds of a portion of the human brain called the insula-plays an important role in allodynia. Human studies have also shown that chronic pain patients have an over-active CGIC.

But for a long time, the only way to manipulate the CGIC was to remove it-an impractical approach for human treatments.

For the new study, the team used novel fluorescent proteins to observe which cells in the central nervous system light up when a rat sustains a sciatic nerve injury. The team then used cutting-edge "chemogenetic" tools to switch on or off genes inside specific populations of neurons.

The researchers discovered that while the CGIC plays a minimal role in processing acute pain, it plays a vital role in making pain persist.

According to the study, the CGIC signals the brain's pain processing center, or somatosensory cortex, which in turn tells the spinal cord to keep the pain going.

"We found that activating this pathway excites the part of the spinal cord that relays touch and pain to the brain, causing touch to now be perceived as pain as well," said Ball.

When the team turned off cells within this pathway immediately after injury, the rat's pain from injury was short-lived. In animals already experiencing chronic allodynia, disabling this pathway made the pain cease.

"Our research presents a clear case that specific brain pathways can be directly targeted to modulate sensory pain," said Ball.

It's still unclear what prompts the CGIC to start sending chronic pain signals. And more research is necessary before these lessons learned could be applied to help humans.

But Ball imagines a not-too-distant future in which medical professionals treat pain with injections or infusions that target specific brain cells without the systemic side effects and dependency risk that come with opioids. He also believes brain-machine interfaces, either implanted in or attached to the skull, could play a similar role in treating severe chronic pain. Numerous startups are now rushing to get to market first, he said.

 "Now that we have access to tools that allow you to manipulate the brain, not based just on a general region but on specific sub-populations of cells, the quest for new treatments is moving much faster," he said.