Schwartz, Malenka and their associates looked at lab mice enduring chronic paw pain due either to persistent inflammation or to nerve damage. The mice also happened to be hungry. The scientists trained the mice to poke their noses into a hole to get a food pellet. At first, a single nose poke earned a pellet. But over time, the number of nose pokes required for a reward was increased. In essence, the researchers were asking these mice: How hard are you willing to work for food? Will you poke your nose into that hole once to satisfy your hunger? Ten times? Even 150 times?

Fading motivation

Within a week after the onset of chronic pain, the animals grew increasingly less likely to work hard for food than pain-free control animals were. The researchers next explored three possible explanations: Were the mice unable to work because their pain was too severe? Did something about being in pain cause them to not value the food reward as much? Or was their failure to seek food due simply to a lack of motivation? Additional tests showed that the mice had no movement problems. “Like other research groups, we found that they can scamper around just fine,” said Malenka. Also, when the mice were given free access to food, they ate just as much as the animals who weren’t in pain — so they still valued the food. But they were less willing to put in an effort to obtain food than mice who’d suffered no pain.

There's no escape from it. You want it to end, but it doesn't.

Moreover, the difference didn’t disappear even when the scientists relieved the mice’s pain with analgesics. “They were in demonstrably less pain, but they were still less willing to work,” Malenka said.

The Stanford scientists then focused on the nucleus accumbens, a brain structure known to be involved in computing the behavioral strategies that prompt us to seek or avoid things that can affect our survival. They found that chronic pain permanently changed certain connections to the nucleus accumbens, causing an enduring downshift in the excitation transmitted by them. Importantly, Malenka’s group showed that a particular brain chemical called galanin plays a critical role in this enduring suppression of nucleus accumbens excitability.

Galanin is a short signaling-protein snippet secreted by certain cells in various places in the brain. While its presence in the brain has been known for a good 60 years or so, galanin’s role is not well-defined and probably differs widely in different brain structures. There have been hints, though, that galanin activity might play a role in pain. For example, it’s been previously shown in animal models that galanin levels in the brain increase with the persistence of pain.

Possible therapies?

Schwartz, Malenka and their peers identified receptors for galanin on a set of nerve cells in the nucleus accumbens and demonstrated that disabling galanin’s signaling via this receptor prevented the long-term suppression of motivation seen in mice — and people — with chronic pain. This suggests that therapeutic compounds with similar effects could someday be developed, although they would have to be carefully targeted so as to not disrupt galanin signaling in other important brain circuits.

“There’s no reason to think this finding won’t generalize to people,” said Fields of UCSF. “Our brains have galanin, and a nucleus accumbens, just as mouse brains do. However, before jumping from mice to humans it would be wise to test other animal species. If the same things happen in a non-rodent species that happen in mice, then it’s probable they happen in humans, too.”

The study was funded by a Banting postdoctoral fellowship and the National Institutes of Health (grant DA008227). Additional co-authors were postdoctoral scholars Paul Temkin, PhD, and Jai Polepalli, PhD; former postdoctoral scholars Sandra Jurado, PhD (now at the University of Maryland), and Byung Kook Lim, PhD (now at UC-San Diego); and anesthesiology instructor Boris Heifets, MD, PhD.

Information about Stanford’s Department of Psychiatry and Behavioral Sciences, which also supported this work, is available at www.psychiatry.stanford.edu/.