Genetic Variation Raises Risk of Post-Traumatic Pain

By Pat Anson, Editor

If you have chronic pain because of an accident, injury or assault, it could be because you have a genetic variation that makes you more likely to develop post-traumatic pain.

That’s the key finding behind a new study published in the Journal of Neuroscience. Researchers at the University of North Carolina studied over 1,500 people who were admitted to emergency rooms for trauma after a motor vehicle collision.

In addition to genotyping the patients, the researchers assessed their distress immediately after the accident, as well as their pain and post-traumatic stress symptoms six weeks later. Participants with a particular variant in the gene FKBP5 reported more severe pain and distress at follow up.

FKBP5 is a critical regulator of the stress response and affects how we respond to environmental stimuli. Previous studies have shown that certain variants of the gene play a role in the development of neuropsychiatric disorders such as post-traumatic stress disorder, depression, suicide risk and aggressive behavior.

UNC School of Medicine researchers were the first to show an association between FKBP5 and post-traumatic chronic pain. A 2013 study found that people with a particular variation of the gene are likely to experience more pain after exposure to trauma compared to people who don't have the variant.

The new study by the same research group builds on that discovery by showing that the variation inhibits the regulation of cortisol, a stress hormone that sensitizes peripheral nerves. People with high levels of cortisol are likely to experience more pain.

"In our current study, we showed that the reason this variant affects chronic pain outcomes is because it alters the ability of FKBP5 to be regulated by a microRNA called miR-320a," said lead author Sarah Linnstaedt, PhD, a professor of anesthesiology and an investigator in the UNC Institute for Trauma Recovery.

"In other words, it does not negatively regulate FKBP5, thus causing FKBP5 to be over-expressed. High levels of FKBP5 can be detrimental because it alters natural feedback mechanisms that control circulating cortisol levels."

Linnstaedt says the findings suggest there could be new therapeutic approaches to treating traumatic pain, such as medication that inhibits the activity of FKBP5 or gene editing that alters the variation.

Funding for the UNC study was provided by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, The Mayday Fund, a Future Leaders in Pain Grant from The American Pain Society, and the National Human Genome Research Institute.

Scientists Building a Safer Opioid

By Pat Anson, Editor

Researchers at the University of North Carolina believe they’ve found a way to create a new type of opioid medication that relieves pain without risky side effects.

Currently, opioid painkillers bind to several opioid receptors on the surface of brain cells, triggering a wide range of side effects -- from nausea, numbness and constipation to anxiety, addiction and potentially fatal respiratory depression.

The UNC researchers report in the journal Cell that they have created a new drug compound that only activates the kappa opioid receptor – the brain receptor that is the key to pain relief.

"To create better opioids, we need to know the structure of their receptors," said senior author Bryan Roth, MD, a professor in the Department of Pharmacology at UNC School of Medicine.

"Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids."

The compound was created in cell cultures in Roth's lab, and still needs to be tested in animal models. But knowing the detailed structure of the kappa opioid receptor (KOR) has opened the door to developing other drug-like compounds that are highly selective for specific opioid receptors.

KAPPA OPIOID RECEPTOR (unc IMAGE)

"Tens of thousands people who take opioids die every year, and so we need safer and more effective drugs for treating pain and related conditions," Roth said in a news release. "One of the big ideas is to target KORs because the few drugs that bind to it don't lead to addiction or cause death due to overdose. Those side effects are mainly related to actions at the mu opioid receptor."

Drugs that bind to KORs can still have side effects, such as hallucinations and dysphoria - a state of unease or dissatisfaction with life related to anxiety and depression. That is why scientists say it’s important to know how this receptor is activated – so they can figure out a way to bind a compound to KORs so that it only relieves pain.

"Now we have a much better understanding of the direction we have to explore in order to create a selective drug to activate only kappa opioid receptors," said corresponding author Daniel Wacker, PhD, UNC School of Medicine.

The UNC research was funded by the National Institutes of Health, the Mayday Fund, and the Peter F. McManus Trust.