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Fentanyl-Induced Rapid Cortical Damage and Cardiopulmonary Arrest Linked to Atypical Dynamics of Apoptosis and Immune Response in a Mouse Model [miRNA]

ABSTRACT: The rapid onset of fentanyl impairs cardiopulmonary and neurological function, often outpacing clinical intervention. To understand its tissue-specific molecular effects, we administered three escalating doses of fentanyl (HNLD, LD10, and LD50) to SKH-1 mice and collected cortex, heart, and lung samples at 0h, 6h, 24h, and 7d post-injection. This study employed miRNA-seq to uncover conserved regulatory signatures underlying apoptosis and immune response networks. Using a machine-learning pipeline, we identified phylogenetically conserved miRNA-mRNA axes with translational potential, such as miR-877-3p in cortex and miR-146b-5p in lungs, providing early leads for therapeutic intervention in fentanyl overdose.

ORGANISM(S): Mus musculus

PROVIDER: GSE296604 | GEO | 2026/04/15

REPOSITORIES: GEO

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Project description:Background: The “loss of control” over drug consumption, known as escalation of intake in opioid use disorder (OUD), is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, influence fentanyl intake trajectories. Moreover, it is unclear if distinct escalation phenotypes are driven by genetic markers predictive of OUD susceptibility. Methods: Male and female Sprague-Dawley rats (n=72) were trained in a sucrose reinforcement task using a progressive ratio schedule. Individual differences in responsivity to sucrose were hypothesized to predict escalation of fentanyl intake. Rats underwent daily 1-h acquisition sessions for i.v. fentanyl self-administration (2.5 µg/kg; FR1) for 7 days, followed by 21 6-h escalation sessions, then tissue from prefrontal cortex was collected for RNA sequencing and qPCR. Latent growth curve and group-based trajectory modeling were used, respectively, to evaluate the association between sucrose reinforcement and fentanyl self-administration and to identify whether distinct escalation phenotypes can be linked to gene expression patterns. Results: Sucrose breakpoints did not predict fentanyl acquisition nor change during escalation, but did predict fentanyl intake on the first day of extended access. Permutation analyses found no associations between behavior and single gene expression, either overall or within our ascertained phenotypes. However, weighted genome correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) determined several gene modules linked to escalated fentanyl intake, including genes coding for voltage-gated potassium channels, calcium channels, and excitatory synaptic signaling. Transcription factor analyses identified EZH2 and JARID2 as potential transcriptional regulators associated with escalated fentanyl intake. Further, genome-wide association study (GWAS) term categories positively associated with terms relating to substance use disorders. Discussion: Escalation of opioid intake largely differs from motivation for natural rewards like sucrose. Further, the gene networks associated with fentanyl escalation suggest that engagement of select molecular pathways were associated with “addiction prone” behavioral endophenotypes, potentially representing druggable targets for OUD. Our extended in silico identification of SNPs and transcription factors associated with the “addiction prone” high escalating rats highlights the importance of integrating findings from translational preclinical models, supporting patient-centered treatment options for OUD.

Dataset Information

Fentanyl-Induced Rapid Cortical Damage and Cardiopulmonary Arrest Linked to Atypical Dynamics of Apoptosis and Immune Response in a Mouse Model [miRNA]

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