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

Wei Wang1, Xueyi Xie2, Xiaowen Zhuang2

  • 1Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA; Interdisciplinary Faculty of Toxicology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.

Cell Reports
|February 16, 2023
PubMed

Insights

Chronic opioid use alters brain pathways, leading to withdrawal symptoms like anxiety and physical discomfort. Targeting specific brain cells (MOR+ neurons) can alleviate these opioid withdrawal effects and reduce relapse risk.

Area of Science:

  • Neuroscience
  • Neuropharmacology
  • Addiction Research

Background:

  • Chronic opioid use is linked to hypodopaminergic states and negative affect, contributing to relapse.
  • Medium spiny neurons (dMSNs) expressing μ-opioid receptors (MORs) in the striatum are implicated in opioid effects, but their role during withdrawal is unclear.

Purpose of the Study:

  • To investigate the impact of chronic opioid exposure and withdrawal on MOR-expressing dMSNs and their neural outputs.
  • To elucidate the role of striatal MOR+ neurons in opioid withdrawal symptoms and relapse behaviors.

Main Methods:

  • Electrophysiological recordings of GABAergic transmission in striatopallidal and striatonigral pathways.
  • Intravenous fentanyl self-administration and subsequent behavioral assessments.
  • Chemogenetic manipulation of striatal MOR+ neurons in rodent models.

Main Results:

  • Acute MOR activation suppressed GABAergic striatopallidal transmission; withdrawal potentiated this transmission.
  • Fentanyl self-administration enhanced striatonigral transmission and reduced midbrain dopamine activity.
  • Inhibition of striatal MOR+ neurons ameliorated fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors.

Conclusions:

  • Chronic opioid use induces plasticity in GABAergic striatopallidal and striatonigral pathways.
  • This plasticity contributes to a hypodopaminergic state, negative emotions, and potential relapse.
  • Targeting striatal MOR+ neurons offers a potential therapeutic strategy for opioid withdrawal and addiction.
Keywords:
CP: Neurosciencedirect-pathway medium spiny neurons, dMSNsdopaminergic neuronsfentanylhabenula-projecting globus pallidus neurons, GPhmorphinenegative emotional statestriatumstriosome and matrix compartmentssubstantia nigra pars compacta, SNcμ-opioid receptor, MOR

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