AsianScientist (Apr. 28, 2022)– Memories of traumatic events such as accidents, natural disasters, sexual violence, and war can continue to haunt a person even when the events have long since passed. This could lead to mental health issues such as anxiety and post-traumatic stress disorder (PTSD) in some people. While there are medications that can help alleviate some of the symptoms, the drugs may not be helpful in effectively managing trauma-induced anxiety. To tackle that problem, some scientists in Japan have been looking into this issue. They previously discovered a synthesized opioid compound that can reduce trauma-induced anxiety in mice. The same researchers have now discerned a likely mechanism of how the opioid works and the biochemical pathway involved in trauma-induced anxiety response. They published their findings in Frontiers in Behavioural Science.
To understand how a drug works, researchers need to first figure out the underlying mechanism of a disease in the body. In the case of anxiety resulting from a traumatic event, it can be difficult to fully discern the mechanism behind the initiation of the anxiety and repeated and prolonged anxiety responses. That is because several complex and interconnected networks are involved in memory retrieval and emotion. But researchers from the Faculty of Pharmaceutical Sciences at Tokyo University of Science have to believe that there are specific regions in the brain that could be involved in both memory retrieval and the subsequent repression of memory, leading to a reduction in anxiety. These regions can be targeted by the synthesized opioid “KNT-127.”
A team co-led by Dr Daisuke Yamada and Ayako Kawaminami conducted some experiments using mice. They exposed the mice to an anxiety-inducing stimulus–a short electric shock to the foot– in a dedicated chamber. An anxious or fear response, identified by the mice freezing in place, was recorded. After 30 minutes, the researchers reintroduced the mice into the chamber and exposed them to the same stressful stimulus to measure the rate of freezing. The re-exposure was done twice, each at 30-minute intervals.
The researchers then administered KNT-127 to specific regions in the brain to observe any changes corresponding with the freezing reaction of the mice.
The brain regions are the basolateral nucleus of the amygdala (BLA), the hippocampus (HPC), and the prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex.
The researchers had earlier discovered that the opioid KNT-127 reduced the freezing response in mice when re-exposed to the electric shocks. But the mice which didn’t get the opioid continued to freeze. The researchers also noted that KNT-127 administered to the BLA and the IL regions of the brain led to the observation of reduction is freezing response, while administering the compound to the HPC and PL did not induce such behaviour.
Having understood the role of KNT-127 in reducing anxiety response and the brain regions associated with that, the researchers started looking for possible biochemical signalling pathways which are involved in reducing the anxious response.
The research team zeroed in on two signalling pathways– MEK/ERK and PI3K/Akt, which are found throughout the mammalian body. The inhibitors of these two pathways were microinjected into the BLA and IL regions of the mice brain after administration of KNT-127. The mice were then re-exposed to the electric shocks to determine if there were any changes to their freezing response.
The researchers found that the MEK/ERK inhibitor reversed the reduced freezing response caused by KNT-127 in the BLA, while the PI3K/Akt inhibitor had the same effect in the IL. The researchers concluded that both pathways must be involved in the retrieval of traumatic memories and can be used as potential targets for further research and drug development.
The researcher say that the discovery of a more targeted and potent medication could be found to help patients fully recover from the devastating after-effects of experiencing trauma.
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Source: Tokyo University of Science; Photo: Freepik
The article can be found at Kawaminami et al. (2022), Selective δ-Opioid Receptor Agonist, KNT-127, Facilitates Contextual Fear Extinction via Infralimbic Cortex and Amygdala in Mice.
