Brain Circuit Involved in Fentanyl Abuse and Relapse Identified

Summary: Fentanyl enhances direct pathway medium spiny neurons activity in the striatum. During withdrawal from the opioid, inhibitory signals from direct pathway medium spiny neurons to dopaminergic neurons become enhanced. The enhanced suppression of dopaminergic neurons contributes to the negative emotions associated with fentanyl withdrawal. Inhibiting the direct pathway medium spiny neurons can reduce withdrawal symptoms and associated anxiety behaviors.

Source: Texas A&M

The ongoing opioid epidemic continues to take a heavy toll on American communities, with more than 80,000 opioid-related deaths reported in 2021, according to the National Institutes of Health. Despite the severity of this issue, the neurological mechanisms underlying opioid addiction, withdrawal and relapse are not fully understood.

A study recently published in Cell Reports sheds light on the subject. 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 have identified a specific brain circuit that characterizes how fentanyl (a synthetic opioid) affects the brain. Specifically, they looked at the striatum, which is a brain region that controls voluntary behaviors and is heavily implicated in drug relapse.

Even after a long period of abstaining from opioids, many people relapse as a result of the depression, anxiety and other negative emotions that accompany withdrawal. Suppressing these negative emotional states could greatly increase a person’s chance of overcoming opioid use disorder.

Opioid addiction is mainly mediated by mu-opioid receptors (MORs), which are expressed in the midbrain and the striatum on a type of neuron called direct pathway medium spiny neurons (dMSNs). Previous studies from the Wang lab showed these dMSNs control “go” actions in the brain that promote drug-seeking behaviors.

The striatum contains two distinct sub-compartments, the patch and matrix compartments. The patch compartments primarily contain MOR-expressing dMSNs and are widely studied for their roles in emotional processing and decision-making.

The study aimed to look at how withdrawal from chronic opioid exposure alters the activity of patch dMSNs and their outputs to generate the negative emotional states which may cause relapse.

The researchers discovered that fentanyl enhances the activity of dMSNs in the striatum, and during the early stages of withdrawal, inhibitory signals from these dMSNs to downstream targets, such as dopaminergic neurons, were significantly enhanced.

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Even after a long period of abstaining from opioids, many people relapse as a result of the depression, anxiety and other negative emotions that accompany withdrawal. Image is in the public domain

Dopaminergic neurons play a major role in addiction as they control motivation, rewarding behavior and emotions. The enhanced suppression of dopaminergic neurons likely contributes to the negative emotions that arise during acute fentanyl withdrawal, as the researchers found that inhibiting these dMSNs can reduce withdrawal symptoms and anxiety-like behaviors.

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.

In summary, the study provides new understanding of the brain circuits involved in opioid addiction and withdrawal and could lead to the development of new treatment for opioid use disorders.

About this opioid addiction research news

Author: Press Office
Source: Texas A&M
Contact: Press Office – Texas A&M
Image: The image is in the public domain

Original Research: Open access.
Striatal μ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect” by Wei Wang et al. Cell Reports


Striatal μ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect


  • Repeated morphine and fentanyl injections potentiate IPSCdMSN→GPh transmission
  • Repeated fentanyl administration potentiates IPSCdMSN→SNc transmission
  • Fentanyl administration recruits striatal neurons that encode contextual memory
  • Striatal MOR+ neurons drive fentanyl withdrawal-induced negative affect


Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain μ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs.

Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons.

Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity.

Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR+ neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors.

These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.

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