Science: Chronic Pain Rewires Motivational Circuits in Mouse Brains

Chronic pain can alter neural circuits in the brain that control motivation, according to a new study in mice. The finding could help explain why people suffering from chronic pain become less active and often feel unmotivated.

The report in the 1 August issue of Science suggests that chronic pain unleashes a small signaling molecule called galanin, which helps remodel neurons in a part of the brain called the nucleus accumbens that controls motivated behaviors.

Galanin's effect can be prevented, the Science authors discovered, and they say the molecule could be a possible target in future treatments for chronic pain.

The study may also help researchers better understand how other known "de-motivators" such as addictive drugs could rewire the brain and lead to a reduction in the ability to function and complete tasks, said Neil Schwartz of the Stanford University School of Medicine.

Chronic pain keeps some neurons in the mouse brain from receiving the molecular signals that lead to motivated behavior. | V. Altounian/Science

Schwartz and colleagues looked for a connection between chronic pain and motivation in neurons taken from mice that were subjected to two kinds of chronic pain. One set of mice received irritating, inflammatory injections in their hind paws, and a second set received an injury to their sciatic nerves.

The researchers tested the rodents' levels of motivation in an experiment where the mice had to poke their nose into a port inside a box to receive a food reward. The rewards became more difficult to earn as the experiment progressed, requiring an increasing number of nose pokes. The mice that persisted in the nose-poking task were considered to be more motivated than their companions.

The mice sought out the food reward at the same rate before and after their pain treatments when the number of pokes to receive a treat was low. But, after the treatment they were much less likely to keep poking their noses into the port as the challenge became more difficult. In fact, there was a 40% drop in the number of nose pokes after seven to 21 days of pain, and the mice remained unmotivated even after they were given pain relief.

Schwartz and colleagues then examined neurons from a part of the brain called the nucleus accumbens, where motivational neural circuitry is located. In mice with chronic pain, the signaling molecule galanin alters some of the neurons in this circuit, making them less responsive to other molecules that prompt motivation.

By blocking galanin's effect, the researchers could prevent this change in the neural circuitry. And, mice with their galanin receptors blocked did not experience a loss of motivation in the food experiment, even though they were in chronic pain. The researchers were also able to keep motivation levels high in the mice by altering another protein in the motivational neural circuit affected by galanin.

"Although we did not test it, my guess is that the galanin receptor has to be knocked down early, even before many of the other symptoms develop," Schwartz said.

The longer the pain lasts, he added, the more difficult it might be to reverse galanin’s effect. “Other changes will impact the motivational circuitry, even in rodents, with prolonged exposure to chronic or persistent pain.”