Opioids, such as the often-prescribed analgesic oxycodone, are widely known for their significant risk of addiction. In 2022, the Centers for Disease Control reported that approximately 85,000 individuals succumbed to opioid overdoses in the United States. Despite this alarming statistic, the prescription of opioids continues, especially in Southern states, largely due to the absence of alternative treatments (1^✔ ✔Trusted Source
A master regulator of opioid reward in the ventral prefrontal cortex

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Researchers at the Medical University of South Carolina (MUSC) and other institutions are studying the brain to understand the addictive properties of certain drugs and to develop non-addictive pain relief medications. Alexander Smith, Ph.D., an assistant professor at MUSC, made a significant discovery about opioid mechanism of action during his post-doctoral training with Paul Kenny, Ph.D., at the Icahn School of Medicine at Mount Sinai.

Contradicting the Current Belief- Opioid Receptors and not Dopamine Responsible for Opioid Action

Smith and his team found that the dorsal peduncular nucleus, a brain region that has received limited attention in research concerning aversion, exhibits a significant responsiveness to opioids. The opioid receptors located in this area demonstrate a distinct reaction to opioids, challenging the common belief that opioids primarily exert their effects through dopamine pathways in the brain. This finding opens up a promising new avenue for research. This study was published in June 7 issue of Science.

“This is potentially a nondopaminergic mechanism for opioid reward, which is something people have been looking for a long time,” said Smith.

Dopamine-releasing cells are typically in an active state. However, their activity is regulated by another type of cell known as an inhibitory neuron, which prevents the release of dopamine. These inhibitory neurons possess mu opioid receptors, a specific category of opioid receptors. When opioids attach to these receptors, they inhibit the function of the inhibitory neuron, thereby permitting the dopamine-releasing cell to inundate the brain with the neurotransmitter that enhances mood. This phenomenon is referred to as disinhibition.

What Causes Pleasurable and Addictive Properties of Opioids

The research team, under the guidance of Smith and his mentor Paul Kenny, discovered a high concentration of mu opioid receptors on the cells located in the dorsal peduncular nucleus. These opioid receptors in this specific area do not cause disinhibition; instead, they are situated directly on the cells that send projections to a brain region associated with aversive emotions. When opioids attach to these cells, they exert an inhibitory effect. Eliminating these negative emotions results in a sense of reward, a phenomenon known as negative reinforcement. This mechanism plays a significant role in the pleasurable and addictive properties of opioids.

“We found the mu opioid receptor in a part of the brain that no one expected it to be, and that really goes against all the dogma,” Smith said. “This is a population of cells that are directly responsive to opioids, which is not the way things usually work.”

For many years, a significant number of addiction researchers have concentrated their efforts on examining four key regions of the brain: the extended amygdala, the ventral tegmental area, the nucleus accumbens, and the prefrontal cortex.

“Studying those four regions hasn’t gotten us very close to developing an actual therapeutic to treat opioid use disorder,” explained Smith. “So, we are trying to take a more holistic view and look at what else might be happening in the brain.”

When Smith got his early results back showing that the dorsal peduncular nucleus was the most significantly affected region by opioids, he had to look up what this brain region did.

“When I found out that it was in the prefrontal cortex, which is part of the brain I’ve looked at thousands of times, I was very surprised,” shared Smith. “I couldn’t believe I never noticed that.”

While recognizing the importance of the dorsal peduncular nucleus in response to opioids, they determined this brain region’s function by stimulating it. This showed that the dorsal peduncular nucleus is required for aversion. They also found that when they deleted the opioid receptor from this brain region, opioids were no longer rewarding. In fact, they became aversive without the opioid receptors in the dorsal peduncular nucleus.

Region in Brain Controls Rewarding and Aversive Behavior of Opioids

Smith calls this his most exciting piece of data; he had never seen opioids switch from rewarding to aversive before. When mice without opioid receptors in the dorsal peduncular nucleus were made dependent on opioids, they showed worse withdrawal symptoms. These findings suggest that this brain region is not only involved in the rewarding properties of opioids but also the aversive aspects of opioid withdrawal. This further supports their finding that the opioid receptors in this brain region are critical for the development of opioid addiction.

Smith hopes that in the future, scientists will find ways to target this brain region to help people with substance use disorders by preventing the return to use (relapse) and reducing craving and withdrawal. He also hopes this discovery will lead to the development of nonaddictive painkillers.

Reference:

1. A master regulator of opioid reward in the ventral prefrontal cortex – (https://www.science.org/doi/10.1126/science.adn0886)

Source-Eurekalert