Acute opioid responses are modulated by dynamic interactions of Oprm1 and Fgf12

eLife

卷:14

Genetics and Genomics

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 

[1] University of California, San Diego, San Diego, United States

[2] University of Tennessee Health Science Center, Memphis, United States

[3] Washington University School of Medicine, St. Louis, United States

[4] Ball State University, Muncie, United States

[5] Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States

[6] University of Pennsylvania, Philadelphia, United States

[7] Marshall University, Huntington, United States

关键词: Oprm1;    Fgf12;    epistasis;    locomotion;    QTL;    quantitative trait loci;    Human;    Mouse;    Rat;   

DOI  :  10.7554/eLife.108845

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2025, Lemen et al

【 图 表 】

Fig. 8