The Stress-Pain Connection

The Stress-Pain Connection

A stress-related protein called FKBP51 drives chronic pain, a new study in mice shows. Researchers found that the protein was expressed [i.e., present] in the neurons of the dorsal horn, a part of the spinal cord that processes sensory information, including pain signals.
[Credit: C. Bickel / Science Translational Medicine (2016)]

A gene called FKBP51 is known to play a role in the brain’s response to stress. For instance, in people, variations in the gene affect the severity of musculoskeletal pain following a car crash or sexual assault, and have also been linked to depression and posttraumatic stress disorder. Now, new research in mice suggests that FKBP51 is also important for the development and maintenance of chronic pain, and that blocking the gene is an effective way to reduce this pain.

The findings were published February 10 in the journal Science Translational Medicine.

“This is a very thorough, very exciting paper. [Based on these results], I think it’s definitely worthwhile to see if blocking FKBP51 can reduce chronic pain in humans,” says Moshe Szyf, McGill University, Montreal, Canada, who was not involved in the new study.

The current team of researchers, led by Sandrine Géranton, University College London, UK, had previously examined gene expression changes—alterations in which genes are turned on, and which genes are turned off—in the spinal cord in response to chronic pain, in an animal study. They found that levels of FKBP51 were highly increased within two hours of initiating painful inflammation of the rat ankle joint (a common animal model that researchers use to study pain). This finding suggested a link between FKPB51 and pain, but the nature of the association was unclear.

In the new study, the researchers looked to see whether FKBP51 could directly contribute to the development and maintenance of chronic pain, using mice that were genetically engineered to lack FKBP51—so-called “knockout animals.”

“Right away, we could clearly see that the knockout animals [missing FKBP51] were not as sensitive as their wild-type littermates [i.e., mice that still had FKBP51] under chronic pain conditions,” Géranton tells RELIEF.

In particular, compared to wild-type animals, the FKBP51 knockout mice were not as sensitive to mechanical stimulation with thin filaments used to poke an animal’s paw (a technique used in many research studies to assess pain) after inflammation of either the ankle joint or hind paw.

In addition, in the spared nerve injury model of neuropathic pain, in which portions of the sciatic nerve are severed, the knockout animals were again less sensitive to mechanical stimulation, compared to wild-type mice.

The researchers also found that injection of SAFit2, a recently developed drug that inhibits FKBP51, into the spinal canal three days after inflammation reduced sensitivity to mechanical stimulation. That result raises the possibility that similar drugs could someday be used to treat chronic pain in humans.

The investigators also determined that FKBP51 eased pain by acting specifically in the spinal cord, rather than in the brain. And, in a final set of experiments, they found that FKBP51 alleviated pain by changing the activity of the glucocorticoid receptor. This receptor is a molecule to which glucocorticoids bind; glucocorticoids are hormones that are involved in the body’s response to stress. Thus, the researchers had discovered a link between stress, FKBP51, and pain.

Overall, the results suggest that drugs that inhibit FKBP51 may be effective in treating chronic pain in people. Géranton emphasized that such an approach would lead to two different responses in the body. When a drug that inhibits FKBP51 is administered into the circulatory system so that it goes throughout the body, it blocks pain in the spinal cord. But it also works in the brain to reduce the stress that is associated with chronic pain. “Since we know that both of these conditions [stress and pain] exacerbate each other, I think that blocking FKBP51 will be able to alleviate chronic pain much quicker [than existing therapies],” she says. —Allison Marin.

To read about the research in more detail, see the related Pain Research Forum news story here.

Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.