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

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.