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Acute opioid responses are modulated by dynamic interactions of <i>Oprm1</i> and <i>Fgf12</i>.

Overview

Authors: Paige M Lemen1, Yanning Zuo2, Alexander S Hatoum3, Price E Dickson4, Guy Mittleman5, Arpana Agrawal3, Benjamin C Reiner6, Wade Berrettini6, David George Ashbrook1, Mustafa Hakan Gunturkun1, Xusheng Wang1, Megan K Mulligan1, Caleb J Brown7, Eric J Nestler7, Francesca Telese2, Robert W Williams1, Hao Chen1
ORCID iDs: Paige M Lemen, Alexander S Hatoum, David George Ashbrook, Eric J Nestler, Robert W Williams, Hao Chen
  1. University of Tennessee Health Science Center, Memphis, United States
  2. University of California, San Diego, San Diego, United States
  3. Washington University School of Medicine, St. Louis, United States
  4. Marshall University, Huntington, United States
  5. Ball State University, Muncie, United States
  6. University of Pennsylvania, Philadelphia, United States
  7. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Institutions: University of Tennessee Health Science Center (United States); University of California San Diego (United States); Washington University in St. Louis (United States); Marshall University (United States); Ball State University (United States); University of Pennsylvania (United States); Icahn School of Medicine at Mount Sinai (United States)
Journal: eLife, volume 14, article RP108845
Dates: published online 29 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.7554/elife.108845 · PMID 42525548 · PMCID PMC13421559 · OpenAlex W4416187526
Open access: gold, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: genetics / omics (modality), human (organism), mouse (organism), rat (organism), pain (population), cellular / molecular (subfield)
Methods: Smoothing, state filtering, decompositions, Connectivity, Machine learning
Keywords: Human, Mouse, Rat
MeSH: Analgesics, Opioid*, Morphine*, Receptors, Opioid, mu*, Animals, Epistasis, Genetic, Female, Locomotion, Male, Mice, Mice, Inbred C57BL, Naloxone, Rats (* major topic)
Topic: Fibroblast Growth Factor Research (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NIDA NIH HHS (U01 DA053672); National Institute of Development Administration (U01DA053672)
Citations: not cited yet (Europe PMC); 91 references in the paper

Abstract

We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the µ opioid receptor gene (Oprm1) on chromosome (Chr) 10 with a peak linkage of 12.4 (–logp). The B allele inherited from C57BL/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of locomotion emerged after approximately 100 min. This locus was located on Chr 16 with peak linkage of 10.6 in females and included one compelling candidate, fibroblast growth factor 12 (Fgf12). A strong and transient epistatic interaction existed between the Oprm1 and Fgf12 loci during a short time window (45–75 min). In heterogeneous stock rats, we demonstrated that Oprm1 and Fgf12 were co-expressed in one subtype of Drd1+ medium spiny neuron. A Bayesian network analysis supported an Oprm1-to-Fgf12 network that involves a MAP kinase cascade that modulates FGF12 phosphorylation and locomotor activation. OPRM1 and FGF12 networks in human genome-wide association study (GWAS) data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data and to no code of its authors: see the Data section.

Tracing map

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Data

Datasets cited

Data availability

All behavioral data are available from https://genenetwork.org/ (see Supplementary file 2 for trait IDs). All snRNA-seq data have been deposited into NCBI GEO (accession number: GSE214388 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214388)).

The following dataset was generated:

Zuo Y, Telese F, Chen H. 2023. Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings. NCBI Gene Expression Omnibus. GSE214388

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 17 authors, 3 keywords, 12 MeSH terms, 2 funders, 89 references.

Cite

This paper

Lemen, P. M., Zuo, Y., Hatoum, A. S., Dickson, P. E., Mittleman, G., Agrawal, A., Reiner, B. C., Berrettini, W., Ashbrook, D. G., Gunturkun, M. H., Wang, X., Mulligan, M. K., Brown, C. J., Nestler, E. J., Telese, F., Williams, R. W., & Chen, H. (2026). Acute opioid responses are modulated by dynamic interactions of <i>Oprm1</i> and <i>Fgf12</i>. eLife, 14, RP108845. https://doi.org/10.7554/elife.108845

BibTeX

@article{lemen2026acute,
author = {Lemen, Paige M and Zuo, Yanning and Hatoum, Alexander S and Dickson, Price E and Mittleman, Guy and Agrawal, Arpana and Reiner, Benjamin C and Berrettini, Wade and Ashbrook, David George and Gunturkun, Mustafa Hakan and Wang, Xusheng and Mulligan, Megan K and Brown, Caleb J and Nestler, Eric J and Telese, Francesca and Williams, Robert W and Chen, Hao},
title = {{Acute opioid responses are modulated by dynamic interactions of \<i\>Oprm1\</i\> and \<i\>Fgf12\</i\>}},
journal = {eLife},
year = {2026},
month = jul,
volume = {14},
pages = {RP108845},
publisher = {eLife Sciences Publications, Ltd},
issn = {2050-084X},
doi = {10.7554/elife.108845},
url = {https://doi.org/10.7554/elife.108845},
pmid = {42525548},
pmcid = {PMC13421559}
}

RIS

TY - JOUR
AU - Lemen, Paige M
AU - Zuo, Yanning
AU - Hatoum, Alexander S
AU - Dickson, Price E
AU - Mittleman, Guy
AU - Agrawal, Arpana
AU - Reiner, Benjamin C
AU - Berrettini, Wade
AU - Ashbrook, David George
AU - Gunturkun, Mustafa Hakan
AU - Wang, Xusheng
AU - Mulligan, Megan K
AU - Brown, Caleb J
AU - Nestler, Eric J
AU - Telese, Francesca
AU - Williams, Robert W
AU - Chen, Hao
TI - Acute opioid responses are modulated by dynamic interactions of <i>Oprm1</i> and <i>Fgf12</i>
T2 - eLife
J2 - eLife
PY - 2026
DA - 2026/07/29
VL - 14
SP - RP108845
SN - 2050-084X
PB - eLife Sciences Publications, Ltd
DO - 10.7554/elife.108845
UR - https://doi.org/10.7554/elife.108845
LA - en
ER -

CSL-JSON

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