A PTSD Painkiller

In the late 1990s, child psychiatrist Glenn Saxe launched a study of children with burn injuries, who are known to have a high risk of developing post-traumatic stress disorder. The researchers gave psychological interviews to two dozen children admitted to the Shriners Burns Hospital in Boston and then followed their progress for six months.

Saxe’s team tracked everything they could about the kids’ cases — severity of injury, length of hospital stay, pain ratings, heart rate, medications and surgeries, parental stress, even how much they smiled around other people — hoping to find patterns that could predict which children would develop the frightening memories, anxiety, guilt, and heightened state of arousal that are characteristic of childhood PTSD.

A predictive variable popped out of the analysis that was wholly unexpected: morphine. Children who received higher doses of this common painkiller while in the burn unit showed less severe PTSD symptoms six months later. “It dramatically reduced the PTSD risk,” says Saxe, who’s now director of the NYU Child Study Center.

Saxe published those findings in 2001. Since then, other studies have found a similar link. For example, in 2010 researchers reported that among a group of nearly 700 U.S. soldiers who had been injured in combat in Iraq, those who took morphine shortly after trauma were less likely to develop PTSD than were those who didn’t get the drug.

Opioids — a family of drugs that includes morphine, heroin, and endorphins — are famous for relieving pain. Less well known are a handful of rodent studies showing that opioids also seem to dial down the brain’s response to fear and stress. This latter research is bolstered by a study out today Science Translational Medicine.

With experiments in mice and people, neuroscientist Kerry Ressler and his colleagues have uncovered a candidate drug for PTSD that acts on an opioid receptor in the brain.

“It’s a pretty elegant study,” says Saxe, who was not involved in the work. Although the opioid-PTSD connection has been talked about for years, “a study like Ressler’s takes the discussion to a much, much deeper level, by really looking at the pathways in animals and humans.”

Ressler didn’t begin the new study with the intention of looking at opioid receptors. His question was more open-ended: After an animal experiences severe stress, what genes are turned on (or turned off) in its amygdala? The amygdala is an almond-shaped nub of brain tissue that is activated during stress, fear, and other emotions.

The researchers exposed mice to a terribly stressful experience: being strapped on a wooden board — belly down, limbs restrained — for two hours. Then they tested how the animals learned to anticipate fear. For this common test, the animals first learn to associate a certain sound with a mild foot shock. After this link is cemented in their brains, they’ll freeze upon hearing the sound, even when there is no shock.

In Ressler’s experiment, the mice that had been exposed to the stressful event froze after hearing the sound but also during non-danger periods, indicating a heightened sense of fear and arousal. They also had high anxiety and long-term memory problems. All of these are similar to the symptoms of PTSD.

Two hours after these fear tests, the researchers examined the expression of genes in the animals’ amygdalae. Why two hours? “Our goal is to understand these underlying processes that transition a memory from a transient, labile state to a more permanent, structurally consolidated state,” Ressler says.

His team found that in mice exposed to the stressful immobilization, a gene called Oprl1 (opioid receptor-like 1) is switched on, pumping out bits of RNA that code for a protein called the nociceptin receptor. Mice that were not exposed to stress, in contrast, show far less RNA expression of the Oprl1 gene.

“We don’t yet fully understand what the difference in gene expression after trauma means,” Ressler says. For example, the data don’t necessarily mean that Oprl1 is switched off in normal mice. In fact, he suspects it’s the opposite: The nociceptin receptor could be helping to turn off the fear response in normal mice. If that’s the case, then the control animals would have less Oprl1 RNA because it was being activated made into the protein. That would also mean that activating the nociceptin receptor in the stressed-out mice might alleviate some of their PTSD-like symptoms.

And that’s exactly what the study showed. Collaborating with scientists at the University of Miami and the Scripps Research Institute, Ressler turned to a compound, called SR-8993, which selectively activates the nociceptin receptor. That means the drug doesn’t have much of an effect on other opioid receptors, including those that are thought to trigger the pain relief and euphoria that come after exposure to morphine, heroin, or endorphins. Compared with controls, mice given SR-8993 shortly after a stressful experience were less likely to hold on to fear memories days later.

No one knows yet whether this drug or others like it would be safe or effective in people with PTSD. But Ressler’s study offers some promising human data. The researchers looked for common genetic blips in Oprl1 in nearly 2,000 people enrolled in the Grady Trauma Project, all of whom were exposed to high levels of violence and trauma. The study found an interesting gene-environment interaction: Participants who were abused as children and carry certain Oprl1 variants tend to have more severe PTSD symptoms than those who were abused but don’t carry the variants.

There are lots of reasons to be excited about these findings. Human and mouse data seem to agree, for one thing, and the previous studies showing the beneficial effects of morphine on traumatized individuals lend credence to the whole idea. But Ressler, who’s been studying the devastating effects of PTSD for a long time, isn’t read to beat the drum for SR-8993. “Until replication studies are performed I don’t want to be overly enthusiastic,” he says.

He also doesn’t want people to forget about the already available treatments for PTSD, namely psychotherapy, which has been proven to help many people with the disorder. “It is important for people to know that PTSD is understandable as a brain illness and is treatable,” he says.