Scientists in the U.K. and Japan say they have identified how the brain's natural painkilling system could be used as a possible alternative to opioids for the effective relief of chronic pain, which affects as many as one in three people at some point in their lives. 

The team, led by the University of Cambridge, pinpointed an area of the brain that is important for endogenous analgesia—the brain's intrinsic pain relief system. They believe their study (“The Control of Tonic Pain by Active Relief Learning”), published in eLife, could lead to the development of pain treatments that activate the painkilling system by stimulating this area of the brain, but without the dangerous side effects of opioids. 

“Tonic pain after injury characterizes a behavioural state that prioritizes recovery. Although generally suppressing cognition and attention, tonic pain needs to allow effective relief learning to reduce the cause of the pain. Here, we describe a central learning circuit that supports learning of relief and concurrently suppresses the level of ongoing pain. We used computational modelling of behavioural, physiological and neuroimaging data in two experiments in which subjects learned to terminate tonic pain in static and dynamic escape-learning paradigms,” write the investigators.

“In both studies, we show that active relief-seeking involves a reinforcement learning process manifest by error signals observed in the dorsal putamen. Critically, this system uses an uncertainty ('associability') signal detected in pregenual anterior cingulate cortex that both controls the relief learning rate, and endogenously and parametrically modulates the level of tonic pain. The results define a self-organizing learning circuit that reduces ongoing pain when learning about potential relief.”

Opioid drugs such as oxycodone, hydrocodone, and fentanyl hijack the endogenous analgesia system, which is what makes them such effective painkillers. However, they are also highly addictive, which has led to the opioid crisis in the United States, where drug overdose is now the leading cause of death for those under 50, with opioid overdoses representing two-thirds of those deaths. 

“We're trying to understand exactly what the endogenous analgesia system is: why we have it, how it works, and where it is controlled in the brain,” said Ben Seymour, Ph.D., of Cambridge's department of engineering, who led the research. “If we can figure this out, it could lead to treatments that are much more selective in terms of how they treat pain.”

“Pain can actually help us recover by removing our drive to do unnecessary things—in a sense, this can be considered 'healthy pain'. So why might the brain want to turn down the pain signal sometimes?”

Dr. Seymour and his colleagues thought that sometimes this “healthy pain” could be a problem, especially if we could actively do something that might help—such as try and find a way to cool a burn. In these situations, the brain might activate the pain-killing system to actively look for relief. To prove this, and to try and identify where in the brain this system was activated, the team designed a pair of experiments using brain-scanning technology.

In the first experiment, the researchers attached a metal probe to the arm of a series of healthy volunteers and heated it up to a level that was painful, but not enough to physically burn them. The volunteers then played a type of gambling game where they had to find which button on a small keypad cooled down the probe. The level of difficulty was varied over the course of the experiments—sometimes it was easy to turn the probe off, and sometimes it was difficult. Throughout the task the volunteers frequently rated their pain, and the researchers constantly monitored their brain activity.

The results found that the level of pain the volunteers experienced was related to how much information there was to learn in the task. When the subjects were actively trying to work out which button they should press, pain was reduced. But when the subjects knew which button to press, it wasn't. The researchers found that the brain was actually computing the benefits of actively looking for and remembering how they got relief and using this to control the level of pain. 

Knowing what this signal should look like, the researchers then searched the brain to see where it was being used. The second experiment identified the signal in a single region of the prefrontal cortex, called the pregenual cingulate cortex. 

“These results build a picture of why and how the brain decides to turn off pain in certain circumstances, and identify the pregenual cingulate cortex as a critical 'decision center' controlling pain in the brain,” said Dr. Seymour. 

This decision center is a key place to focus future research efforts. In particular, the researchers are now trying to understand what the inputs are to this brain region, if it is stimulated by opioid drugs, what other chemical messenger systems it uses, and how it could be turned on as a treatment for patients with chronic pain.








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