Once access to heroin was stopped, these neurons became more excitable. The
by blocking the protein kinase A (PKA) enzyme. Inhibiting this enzyme also reduces opioid-seeking behavior.
Professor of Neuroscience, Ph.D. Jacqueline McGinty and Saurabh Kokane, Ph.D., a postdoctoral scientist in McGinty’s lab, recently published their team’s findings in the journal Neuroscience.
The risk of opioid overdose may increase after returning to drug-seeking and use, or relapse may occur after abstinence or abstinence from the drug.
Innovations in Opioid Relapse and Overdose Prevention
“Relapse prevention is key to the successful development of effective treatments for substance use disorders,” Kokane said.
“After decades of research on opioid use disorder, there are three FDA-approved medications, but they only reduce the severity of detoxification symptoms and do not stop relapse. So more treatment options are definitely needed,” he said. .
“Currently, we do not have a comprehensive understanding of how opioids, such as heroin, affect the neurons that drive relapse. A better understanding of these changes may lead to additional treatment options.”
The McGinty Lab at MUSC has identified specific types of pyramidal neurons that contribute to relapse. They found that these neurons in a certain brain region prelimbic prefrontal cortex undergoes molecular and functional changes during heroin withdrawal, a commonly used opioid that disrupts function.
The prelimbic cortex is one of the areas of the brain involved in decision-making and behavioral control. Opioids can disrupt normal function in this part of the brain, and in someone with opioid use disorder, this interference can lead to compulsive drug-seeking.
Importantly, researchers in this preclinical study show that restoring the normal activity of these neurons by inhibiting the main enzyme can prevent drug seeking in a rodent model during heroin withdrawal.
Substance use disorders are chronic, treatable illnesses from which people can recover. These disorders are defined in part by continued use of substances despite negative consequences, as well as periods of abstinence followed by return to use or relapse.
One type, cue-induced relapse, can occur when a person with a substance use disorder encounters a “cue” or “trigger” that may cause that person to crave the drug.
For example, a person with an alcohol use disorder may want to drink when they hear a champagne cork popping, or a person with an opioid use disorder may want heroin when they see someone using drugs on television.
“These cravings can lead people with opioid use disorder to relapse, even if they don’t want to,” Kokane said.
“The problems with compulsive drug use are the loss of ability to decide between different behavioral options and the lack of resistance to environmental stimuli reminiscent of taking opioids such as heroin,” McGinty said.
Changes in several areas of the brain are responsible for cue-induced relapse and make it difficult for a person with a substance use disorder to control their drug cravings. In this study, Kokane and the McGinty Lab focused on two of these regions: the nucleus accumbens and the prelimbic cortex.
“The nucleus accumbens is a brain region that receives input from the prelimbic cortex and dopamine-releasing pathways that are associated with the desire to take the substance again, which is associated with all addictive drugs, including opioids,” Kokane explained. Abnormal functioning of these pathways during abstinence is a major contributor to relapse-induced relapse.
In general, the prelimbic cortex and other cortical regions are responsible for deciding to act on a feeling or desire. Thanks to their connections with nuclear accumbens the prelimbic cortex either prompts us to stop acting or prompts us to act, Kokane said.
The unique changes in the function of these brain regions caused by opioids make stopping opioid use much more difficult.
“Changes in the brain of someone recovering from a substance use disorder lead to relapse when environmental drug cues are overwhelming, but the exact types of changes that occur are not fully understood,” McGinty said.
Using a rodent model, the MUSC team found that neurons connecting the prelimbic cortex with the nucleus accumbens increase their activity during periods of withdrawal from heroin. Instead of hitting the brakes increased activity of these neurons may contribute to nucleus accumbens relapse.
Drug use can continue unchecked, despite negative social and psychological consequences in most cases.
Kokane and McGinty believe that restoring normal activity to neurons in the prelimbic cortex may prevent cue-induced relapse, but more research is needed.
“We need to better understand the changes in neurons during heroin withdrawal and determine how they lead to relapse,” Kokane said.
The MUSC study also found that the PKA enzyme is more active during withdrawal from heroin. In the prelimbic cortex, where abstinence increases neuronal activity, the researchers found that blocking PKA locally returned neuronal activity to normal levels.
This finding led to a new idea for the MUSC researchers: Perhaps PKA inhibition could restore control.
“When we infused a PKA inhibitor into the prelimbic cortex during heroin withdrawal, we saw a reduction in relapse,” Kokane said.
By blocking PKA, the researchers discovered a way to restore control of the prelimbic cortex during opioid withdrawal in a rodent model. Importantly, the restoration of control within the brain also led to better behavioral control, as heroin-seeking decreased.
A promising path: new approaches to prevent opioid relapse
“Our findings provide a new molecular target for the development of future pharmacotherapies,” said Kokane. “We are in the very early stages of this research, but it has potential. Our results suggest that research should be focused on the development of pharmacotherapies that target the functional changes that develop during withdrawal from heroin, such as the prelimbic cortex.”
Until then, the team is excited to continue their preclinical studies to shed light Prelimbic control over opioid seeking and relapse and detect additional targets.
“It is important to understand that the brain is constantly adapting to the environment, and that the changes we have documented in the prefrontal cortex during heroin withdrawal, while lasting, are not necessarily permanent and subject to reversal,” McGinty said.
- Increased excitability and synaptic plasticity of Drd1- and Drd2-expressing prelimbic neurons are reversed by cue-induced relapse and protein kinase A inhibition that projects to the nucleus accumbens after heroin abstinence – (https://www.jneurosci.org/content/early/2023/04/05/JNEUROSCI.0108-23.2023.long)