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Mood-Enhancing Drugs Could Also Provide Relief For Chronic Pain

This article is more than 8 years old.

(Photo by Suzanne Kreiter/The Boston Globe via Getty Images)

A class of drugs being studied to treat certain mood disorders may also be able to relieve chronic pain by acting on a gene involved in regulating the body’s reaction to stress. The findings point to a possible new drug target to alleviate chronic pain, which affects 100 million people in the United States--more than the total affected by heart disease, cancer and diabetes combined, according to the Institute of Medicine.

Scientists from University College London were interested in a gene called FKBP5. Variations in this gene have been linked to a higher risk of developing stress-related psychiatric disorders, such as major depression and post-traumatic stress disorder (PTSD). Previous research has shown that people with certain FKBP5 variants also feel greater physical pain after serious trauma, a clue that the gene might also be associated with chronic pain.

To better understand FKBP5’s role in chronic pain, the team genetically engineered mice to lack FKBP51, a variant of the FKBP5 gene. FKBP51 in the brain can prolong the body’s stress response after trauma and also can exacerbate pain response. The researchers observed that the mice without FKBP51 experienced reduced pain from injury and were more mobile compared to their control counterparts, who were also injured. Specifically, the knockout mice appeared to have less pain from nerve damage and arthritic joints.

That led the team to conduct another experiment using a compound called SAFit2, originally designed to block FKBP51 in the brain to treat mood disorders by easing anxiety. But instead of measuring the effects of the investigational drug in the mice’s brains, the U.K. team wanted to know how the compound affected pain. So they injected the compound in the spinal cord of injured mice to selectively block FKBP51 there instead of in the brain. They found that SAFit2, which was developed by scientists at the Max Planck Institute of Psychiatry in Germany, substantially alleviated chronic pain in the injured mice compared to controls. The findings were published Feb. 10 in the journal Science Translational Medicine.

“Targeting FKBP51 in chronic pain states will not only help reduce the pain states by acting on the pain mechanisms at the spinal level but will also reduce stress, which often exacerbates the pain experience, at the level of the brain,” said senior author Dr. Sandrine Géranton, a senior researcher at University College London, in an interview.

Géranton said the findings indicate that FKBP51 has potential for the treatment of chronic pain in humans. Next, Géranton said her team plan to study more clinically relevant models of chronic pain, such as neuropathic pain induced by chemotherapy and diabetes, in rodents.

The U.K. study also shows that an injury can trigger long-term epigenetic changes in spinal cord sensory circuits. Epigenetic changes are those that occur naturally but also can be influenced by factors like age, the environment, lifestyle and disease state. These changes in spinal cord sensory circuits can in turn lead to increased production of FKBP51, which contributes to the body's pain response, according to the study.

A variety of medications already exists to treat pain, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen and opioids. But each of these have drawbacks. Acetaminophen, or Tylenol, as well as some NSAIDs, like aspirin, can be obtained over-the-counter. These drugs can be very effective for treating some types of acute and chronic pain. But when taken for a long period of time or in large quantities, acetaminophen can cause liver failure, and NSAIDs can negatively impact the kidney, blood clotting and gastrointestinal system. Patients taking NSAIDs over the long term also have a higher risk of developing ulcers.

Meanwhile, opioid addiction is a growing problem in the United States and elsewhere. The U.S. Centers for Disease Control and Prevention (CDC) report that while the overall amount of pain that Americans report has not changed since 1999, the amount of prescription painkillers dispensed in the United States has quadrupled since that time. With nearly two million Americans aged 12 or older now abusing or addicted to opioids, it’s no question that alternative pain treatments are sorely needed.

“In terms of replacing opioids, it is still early and tolerance to FKBP51 inhibitors will need to be assessed,” Géranton said. “It is true that FKBP51 inhibitors can be considered as mood enhancers and their abuse potential should therefore be carefully assessed. However, early data seem to indicate that inhibition of FKBP51 does not seem to have the sedative effects seen with morphine or the hyperactivity seen with psychostimulants.”

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