Medications which reinforce the effect of natural brain opioids could be an improved way to reduce anxiety compared to receptor-binding opioid drugs like morphine, which have major side effects, says new research from the University of Sydney.

The study reveals the role of natural brain opioids in regulating critical brain circuits affecting fear and anxiety. Fear and anxiety help defend us against harm, and are largely controlled via neural circuits of interconnected nerve cells and synaptic activity in the brain’s amygdala that allow neurons to pass electrical or chemical signals to each other.

Specialized neural circuits control these emotions, but disturbances in the circuits can cause prolonged and disabling emotional responses that are out of proportion to threatening events. These disturbances are thought to underlie many anxiety disorders such as phobias and post-traumatic stress disorder.

Endogenous Opioids

Anxiety currently affects about one in 13 people, or 7.3 percent, around the world. The mood disorder is poorly managed by commonly prescribed medications such as benzodiazepines and serotonin reuptake inhibitors, says the University of Sydney’s Associate Professor Elena Bagley, who led the research:

“These drugs weren’t developed to treat anxiety but they’re widely used because of chance findings suggesting their clinical usefulness Many experts agree that better anxiety treatments will come when science uncovers how the neural circuits and endogenous or naturally occurring opioids regulate fear and anxiety.

The precise action of these natural opioids in the brain is poorly understood, but better insights are critical because these opiods control how we acquire and store fear memories and regulate our emotional responses once a threat has passed."

Experiments in mice have shown that ‘deleting’ the natural opioid enkephalin, which is heavily expressed in the brain’s amygdala, increases their fear, anxiety and aggressiveness. By contrast, increasing enkephalin or reducing its breakdown reduces these behaviors.

Effects Depends On Receptor

While this effect of enkephalin suggests that it is anxiety-inhibiting, when it binds to different receptors in the amygdala, it exerts opposing effects, depending on which one it binds to. For example, when it binds to the mu-opioid receptor, enkephalin promotes anxiety, but when it binds to the delta-opioid receptor, it inhibits it.

“Given this complexity, understanding the cellular actions of natural opioids at these two receptors is critical if we hope to use opioid-related medications for emotional issues,” says Dr Bagley. “Our findings show that opioids produced and released by our own brain cells strongly regulate these critical neural circuits that are important for fear responses. We also show that we could boost the actions of these endogenous opioids using a novel pharmacological approach."

The work was supported by grants from the National Health and Medical Research Council, Bosch Institute Bishop Fellowship and USYD Thompson Fellowship, and the National Institutes of Health.

Winters, B. L. et al. Endogenous opioids regulate moment-to-moment neuronal communication and excitability Nat. Commun. 8, 14611 doi: 10.1038/ncomms14611 (2017)

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