INSIGHT - OPIOID USE DISORDER - Identifying new targets in the fight against opioids

Sep 29, 2026

Uploaded by Ben

Insight piece on opioid use disorder describing research that uncovers time-dependent epistatic interactions affecting mouse responses to opioids. It highlights two genetic modulators: Oprm1 and Fgf12, both enriched in neurons tied to dopamine DRD1 reward circuits. The work proposes a MAP kinase pathway and links a voltage-gated sodium channel, Nav1.2, to opioid sensitivity through protein interactions. Findings emphasize a dynamic molecular network and translational relevance to human GWAS signals.

LanguageEnglish

CategoryHealthcare

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OPIOID USE DISORDER

Identifying new targets in the fight against opioids

Key genetic modulators and neural circuit context

MAPK/Nav1.2 network model

Time-dependent epistatic interaction and translational relevance

INSIGHT OPIOID USE DISORDER Identifying new targets in the fight against opioids Experiments reveal that a time-dependent epistatic interaction influences how mice respond to opioids, and that intracellular fibroblast growth factors also influence opioid sensitivity. FERNANDA LAEZZA Copyright Laezza. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Related research article Lemen PM, Zuo Y, Hatoum AS, Dickson PE, Mittleman G, Agrawal A, Reiner BC, Berrettini W, Ashbrook DG, Gunturkun MH, Wang X, Mulligan MK, Browne CJ, Nestler EJ, Telese F, Williams RW, Chen H. 2025. Acute opioid responses are modulated by dynamic interactions of Oprm1 and Fgf12. eLife 14:108845 . doi: 10.7554/ eLife.108845 O pioid use disorder is a global public health crisis that continues to have devastating consequences for individuals and society (Mathis et al., 2025) . Despite its prevalence, the mechanisms underlying this disorder remain poorly understood, perpetuating stigma and limiting effective treatments. At its core, opioid use disorder is a chronic brain disorder marked by dysregulation of reward circuits, which traps individuals in a cycle of compulsive drug seeking and impaired ability to abstain. Current therapies are limited to preventing overdoses, and there is a lack of therapeutics that can modify the mechanisms underlying the disorder. Now, in eLife, Hao Chen, Robert Williams and co-workers – including Paige Lemen of the University of Tennessee Health Science Center (UTHSC) as first author – report a major advance in our understanding of the molecular architecture of opioid use disorder (Lemen et al., 2025) . Using a systems genetics approach in mouse models, Lemen et al. generated high-resolution time-series data for morphine-induced behaviors, and then mapped these traits to specific genetic loci. Two key modulators emerged: a gene on chromosome 10 called Oprm1, which codes for a well-known opioid receptor; and a gene on chromosome 16 that codes for a signaling protein called fibroblast growth factor 12 (Fgf12), which has not previously been linked to opioid use disorder. Complementary studies revealed that both genes are highly expressed in neurons that express a dopamine receptor called DRD1: these neurons are critical components of the reward circuit in the central nervous system. Lemen et al.– who are based at UTHSC and other institutions across the US – also applied a computational network analysis, which supported a model involving enzymes called MAP kinases, and a voltage-gated sodium channel called Nav1.2 (Figure 1) . These enzymes regulate neuronal activity and interact with Fgf12 (Schoorlemmer and Goldfarb, 2001), while the Nav1 .2 sodium channel controls neuronal excitability and is a known binding partner of Fgf12 (Wildburger et al., 2015) . Moreover, mutations in Fgf12 lead to dysfunction of Nav1.2, and have been linked to epilepsy and a number of encephalopathies (Siekierska et al., 2016; Trivisano et al., 2020; Pierret et al., 2025; Seiffert et al., 2022) . This model is intriguing as it reveals the central role of Oprm1, and the importance of interactions between proteins that are involved in the regulation of neuronal excitability (that is, between MAP kinases and the Nav1 .2 sodium channel) . Laezza. eLife 2026;14:e109920. DOI: [https://doi.org/10.7554/eLife.109920](https://doi.org/10.7554/eLife.109920) 1 of 3 Insight Opioid Use Disorder | Identifying new targets in the fight against opioids Figure 1. The Oprm1–Fgf12 network in opioid use disorder. Lemen et al. identified two genes that are associated with opioid use disorder: Oprm1, which is located chromosome 10 and codes for a well-known opioid receptor; and Fgf12 on chromosome 16, which codes for a signaling protein with no previously known links to opioids. The influence of morphine on

FAQs

What does the study reveal about how mice respond to opioids over time?

It shows a time-dependent epistatic interaction that changes which genetic factors dominate opioid-related behaviors as time after morphine administration progresses.

Which two genes are identified as key modulators of opioid use disorder in the research?

The research highlights Oprm1 on chromosome 10 and Fgf12 on chromosome 16 as major modulators influencing opioid sensitivity.

How is the proposed molecular mechanism linked to neuronal excitability?

The proposed model involves MAP kinases and the sodium channel Nav1.2, with interactions between these components and Fgf12 helping regulate neuronal activity that underlies opioid sensitivity.

Sep 29, 2026

Uploaded by Ben