Distinct Amygdala Neuronal Populations Control Opioid Use and Withdrawal in Mice.

Study Author Lucas Tortorelli Silva, Ph.D.

Featured Paper of the Month – March 2026

Published in Biological Psychiatry by Lucas Silva Tortorelli and Leandro Vendruscolo et al. of the NIDA IRP Stress and Addiction Neuroscience Unit.

Summary

Background
Opioid use disorder (OUD) is a chronic and recurring psychiatric disorder that is associated with high morbidity and mortality. The central nucleus of the amygdala (CeA) undergoes neuroadaptations in both humans with OUD and opioid-dependent rodents. As part of a heterogeneous microcircuit, the CeA integrates internal and external sensory inputs that drive innate and adaptive behaviors. Key CeA neuronal populations, including protein kinase C-δ (PKC-δ), corticotropin-releasing factor (CRF), and somatostatin (SST) neurons, regulate behaviors that are disrupted in addiction, such as pain, stress, reward function, and anxiety/arousal. We hypothesized that these CeA neuronal populations differentially regulate opioid-related behaviors.

Methods
We used in situ hybridization to characterize the expression of μ opioid receptor (MOR) (Oprm1), and we used behavioral and molecular approaches to assess the functional role of these CeA neuronal populations in opioid-dependent mice.

Results
We identified a decrease in Oprm1 messenger RNA (mRNA) expression in the CeA in opioid-dependent mice that were undergoing withdrawal compared with nondependent mice. In contrast, the expression of PKC-δ (Prkcd), CRF (Crh), and SST (Sst) mRNA levels remained unchanged. The chemogenetic inhibition of CeA^PKC-δ neurons decreased fentanyl vapor self-administration and alleviated fentanyl withdrawal–induced hyperalgesia. The inhibition of CeA^CRF neurons reduced irritability and somatic withdrawal signs. The activation of CeA^SST neurons reduced somatic withdrawal signs.

Conclusions
These findings suggest that distinct CeA neuronal populations uniquely regulate different aspects of opioid use and withdrawal, highlighting cell type–specific targets for potential therapeutic interventions.

Publication Information

Tortorelli, Lucas Silva; Oo, Henry Zin; Hahn, Suyun; Alvarez-Bagnarol, Yocasta; Carrasquillo, Yarimar; Vendruscolo, Leandro F

Distinct Amygdala Neuronal Populations Control Opioid Use and Withdrawal in Mice Journal Article

In: Biol Psychiatry, 2025, ISSN: 1873-2402.

Abstract | Links

@article{pmid40935226,

title = {Distinct Amygdala Neuronal Populations Control Opioid Use and Withdrawal in Mice},

author = {Lucas Silva Tortorelli and Henry Zin Oo and Suyun Hahn and Yocasta Alvarez-Bagnarol and Yarimar Carrasquillo and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/40935226/},

doi = {10.1016/j.biopsych.2025.08.021},

issn = {1873-2402},

year  = {2025},

date = {2025-09-01},

urldate = {2025-09-01},

journal = {Biol Psychiatry},

abstract = {BACKGROUND: Opioid use disorder (OUD) is a chronic and recurring psychiatric disorder that is associated with high morbidity and mortality. The central nucleus of the amygdala (CeA) undergoes neuroadaptations in both humans with OUD and opioid-dependent rodents. As part of a heterogeneous microcircuit, the CeA integrates internal and external sensory inputs that drive innate and adaptive behaviors. Key CeA neuronal populations, including protein kinase C-δ (PKC-δ), corticotropin-releasing factor (CRF), and somatostatin (SST) neurons, regulate behaviors that are disrupted in addiction, such as pain, stress, reward function, and anxiety/arousal. We hypothesized that these CeA neuronal populations differentially regulate opioid-related behaviors.nnMETHODS: We used in situ hybridization to characterize the expression of μ opioid receptor (MOR) (Oprm1), and we used behavioral and molecular approaches to assess the functional role of these CeA neuronal populations in opioid-dependent mice.nnRESULTS: We identified a decrease in Oprm1 messenger RNA (mRNA) expression in the CeA in opioid-dependent mice that were undergoing withdrawal compared with nondependent mice. In contrast, the expression of PKC-δ (Prkcd), CRF (Crh), and SST (Sst) mRNA levels remained unchanged. The chemogenetic inhibition of CeA neurons decreased fentanyl vapor self-administration and alleviated fentanyl withdrawal-induced hyperalgesia. The inhibition of CeA neurons reduced irritability and somatic withdrawal signs. The activation of CeA neurons reduced somatic withdrawal signs.nnCONCLUSIONS: These findings suggest that distinct CeA neuronal populations uniquely regulate different aspects of opioid use and withdrawal, highlighting cell type-specific targets for potential therapeutic interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}