Identifying the Brain Circuit Involved in Fentanyl Abuse and Relapse

Summary: Fentanyl enhances the activity of direct-pathway medium spiny neurons in the striatum. During opioid withdrawal, inhibitory signals from direct-path medium spiny neurons to dopaminergic neurons are enhanced. The increased suppression of dopaminergic neurons contributes to the negative emotions associated with fentanyl withdrawal. Inhibition of the medium spiny neuron direct pathway may reduce withdrawal symptoms and associated anxiety behaviors.

Source: Texas A&M

The ongoing opioid epidemic continues to wreak havoc 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 problem, the neurological mechanisms underlying opioid addiction, withdrawal, and relapse are not fully understood.

A study recently published in Cell reports illuminates the subject. Jun Wang, an associate professor in the Department of Neuroscience and Experimental Therapeutics at Texas A&M University School of Medicine, and members of his lab 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 region of the brain that controls voluntary behaviors and is strongly implicated in drug relapses.

Even after a long period of abstinence from opioids, many people relapse due to the depression, anxiety, and other negative emotions that accompany withdrawal. Removing these negative emotional states could significantly increase a person’s chances of overcoming opioid use disorder.

Opioid addiction is primarily mediated by mu-opioid receptors (MORs), which are expressed in the midbrain and striatum on a type of neuron called direct-pathway medium spiny neurons (dMSNs). Previous studies from the Wang lab have shown that 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. Patch compartments primarily contain MOR-expressing dMSNs and are widely studied for their roles in emotional processing and decision making.

The study aimed to examine how withdrawal from chronic opioid exposure alters the activity of dMSN patches and their outputs to generate the negative emotional states that can cause relapse.

The researchers found that fentanyl enhances the activity of dMSNs in the striatum, and during the early stages of withdrawal, the 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 abstinence from opioids, many people relapse due to the depression, anxiety, and other negative emotions that accompany withdrawal. Image is in public domain

Dopamine neurons play a major role in addiction because they control motivation, rewarding behavior, and emotions. The increased suppression of dopamine neurons likely contributes to the negative emotions that occur during acute fentanyl withdrawal, as researchers have found that inhibiting these dMSNs can reduce withdrawal symptoms and anxiety behaviors.

The results of this research provide new insights into the mechanism underlying opioid-induced negative emotional states and point the way to potential treatments for opioid use disorder. 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 a new understanding of the brain circuitry involved in opioid addiction and withdrawal and could lead to the development of a new treatment for opioid use disorder.

About this Opioid Addiction Research News

Author: Press office
Source: Texas A&M
Contact: Press Office – Texas A&M
Picture: Image is in public domain

Original research: Free access.
“Activation of the striatal μ-opioid receptor triggers direct-pathway GABAergic plasticity and induces a negative effect” by Wei Wang et al. Cell reports


See also

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

Strong points

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


Withdrawal from chronic opioid use often causes hypodopaminergic states and negative effects, which can lead to 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 impacts these MOR-expressing dMSNs and their outflows.

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

In particular, withdrawal from repeated administration of morphine or fentanyl potentiated this GABAergic transmission. In addition, intravenous self-administration of fentanyl enhanced striatonigral GABAergic transmission and reduced midbrain dopaminergic activity.

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

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

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