Nociceptin agonist mitigates PTSD-like symptoms in traumatized mice

In recent years, post-traumatic stress disorder (PTSD) has attracted a great deal of attention, largely because of its effects on Iraq and Afghanistan war veterans. Consequently, efforts to understand PTSD's underlying molecular mechanisms have increased. Emotion centers in the brain such as the amygdala and insula are thought to be the seat of those mechanisms. Researchers led by Dr. Kerry Ressler, from the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, recently found that the amygdala-specific dysregulation of the opioid receptor-like 1 gene (Oprl1 in mice; OPRL1 in humans) – a gene that encodes an opioid receptor-related protein implicated in pain perception – is associated with PTSD-like symptoms in traumatized C57BL/6J (B6J, 000664) mice and humans (Andero et al. 2013). An agonist for that receptor significantly mitigates PTSD symptoms in the mouse model and could treat or prevent PTSD in humans.

Post-traumatic stress disorder

PTSD typically develops after a person experiences one or more traumatic events, such as a violent crime or combat, sexual assault, serious injury or a near-death experience. The trauma appears to disrupt the brain's mechanisms for processing fear, blurring its ability to distinguish between safe and dangerous situations. Typical PTSD symptoms include anxiety, irritability, insomnia, nightmares, disturbing flashbacks of the traumatic event, depression, paranoia, difficulty focusing, apathy, avoiding people and circumstances reminiscent of the traumatic event, and forgetting or unwilling to talk about the event. Women are more likely to develop PTSD than men, and children, especially those under 10, are less likely to experience PTSD than adults.

Traumatized mice exhibit PTSD-like behaviors

The Ressler team found that traumatizing B6J mice by securing them to a wooden board for two hours impairs their long-term spatial memory and increases their anxiety – two PTSD-like symptoms. If these mice are later conditioned to fear a mild electric shock, they exhibit more freezing behavior than previously untraumatized mice. In fact, they freeze as much before and in between being shocked as they do when they are actually shocked, suggesting that, as in people with PTSD, trauma has compromised their ability to distinguish between safe and dangerous situations.

Traumatizing mice dysregulates the Oprl1 gene

The Ressler team compared gene expression patterns in the amygdala of mice shocked after being traumatized and mice shocked without being previously traumatized. They found that one gene, Oprl1, is significantly up-regulated in both groups of mice. After the shock, however, Oprl1 is down-regulated in the untraumatized mice but not in the previously traumatized mice. Because Oprl1 encodes the nociceptin receptor (NOP-R), which is activated by nociceptin (NOP), a peptide implicated in pain perception, the Ressler team hypothesized that aberrant fear processing in traumatized mice is due to trauma-induced amygdala-specific Oprl1 dysregulation.

Nociceptin agonist mitigates PTSD-like symptoms in traumatized mice

To find out if a drug could ameliorate the PTSD-like symptoms in previously traumatized mice, Ressler and his team turned their attention to SR-8993, a newly developed and highly selective NOP agonist that robustly activates NOP-R. SR-8993 passes common drug-likeness criteria, is not predicted to be toxic, has a half-life of only several hours, and is stable in human and mouse liver. Ressler and his colleagues found that, whether injected systemically or directly into the central amygdala, either 30 minutes before or immediately after the mice are shocked, SR-8993 prevents aberrant fear processing in previously traumatized mice. It was not found to affect normal mouse activities, cause anxiety, or affect reactions to the mild shock.

An OPRL1 SNP is associated with PTSD symptoms in humans

To determine if dysregulation of OPRL1 is associated with human PTSD, the Ressler team performed an association study in 1,847 highly traumatized people. They found a significant association between an OPRL1 SNP – rs6010719 – and increased PTSD symptoms in individuals who had been moderately to severely abused as children. These individuals were found to be unable to discriminate between safe and dangerous stimuli, and the women were found to have greater functional connectivity between the amygdala and posterior insula – two fear-processing brain regions.

In summary, the Ressler team demonstrated that dysregulation of the Oprl1 gene in mice and the orthologous OPRL1 gene in humans is associated with PTSD-like defects in fear processing. An SNP in the human gene appears to be responsible for the dysregulation. SR-8993, a nociceptin agonist, mitigates the aberrant fear processing in mice and may do the same in humans. SR-8993's potential use in humans is particularly attractive because it does not appear to have the undesirable side effects – dependency, addiction, tolerance, gastrointestinal symptoms, and respiratory impairment – associated with pain-mitigating opiods.