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Opioids primarily suppress pain, but chronic opioid use often causes addiction. Treatment options for opioid use disorder (OUD) are limited by an incomplete understanding of opioid-induced neuroplasticity.
Despite the seriousness of the problem, little is known about the neurological processes that underlie opioid addiction, withdrawal, and recurrence.
A new study uncovered a specific brain circuit that characterizes how fentanyl (a synthetic opioid) affects the brain. Scientists, led by Jun Wang, associate professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M University School of Medicine, and members of his laboratory, in particular, looked at the striatum, which is a brain region that controls voluntary behaviors and is heavily implicated in drug relapse.
Many people relapse even after a protracted time of opioid abstinence because of depression, anxiety, and other unpleasant withdrawal symptoms. The likelihood of someone beating opioid use disorder can significantly increase by suppressing these unfavorable emotional states.
Mu-opioid receptors (MORs), expressed in the midbrain and striatum on a type of neuron called direct pathway medium spiny neurons (dMSNs), are the primary mediators of opioid addiction.
Previous research from the Wang group demonstrated that these dMSNs regulate brain “go” processes that support drug-seeking behaviors. The patch and matrix sections are two separate subcompartments of the striatum. The MOR-expressing dMSNs mainly found in the patch compartments are extensively researched for their functions in emotional processing and decision-making.
The research sought to understand how withdrawal from long-term opioid exposure alters patch dMSN activity and outputs to produce unfavorable emotional states that may lead to relapse. Scientists found that fentanyl increases the activity of dMSNs in the striatum and that early withdrawal significantly increases the inhibitory signals from these dMSNs to downstream targets, such as dopaminergic neurons.
Due to their control over motivation, rewarding behavior, and emotions, dopaminergic neurons play a significant part in addiction. As scientists discovered, inhibiting these dMSNs can lessen withdrawal symptoms and anxiety-like behaviors, it is likely that the enhanced suppression of dopaminergic neurons adds to the negative emotions that emerge during acute fentanyl withdrawal.
The findings of this research provide new insights into the mechanism underlying opioid-induced negative emotional states and pave the way for potential treatments for opioid use disorders. By reducing the negative emotional states that accompany withdrawal, it may be possible to reduce the risk of relapse and decrease the number of lives lost to opioids.
The study provides a new understanding of the brain circuits involved in opioid addiction and withdrawal. It could lead to the development of new treatments for opioid use disorders.
- Wei Wang et al. Striatal μ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect. Cell Reports. DOI: 10.1016/j.celrep.2023.112089