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

Researchers have uncovered the complex interplay between two genes, Oprm1 and Fgf12, in modulating the body's response to acute opioid injections, such as morphine. Their study involved analyzing time-series data from 105 mice, representing 64 diverse strains, after a single morphine injection. By mapping variations in locomotor responses, they discovered that the Oprm1 gene, located on chromosome 10, played a significant role, with the B allele from C57BL/6J strain associated with up to 60% higher activity.

This effect peaked at 75 minutes but subsided by 160 minutes. A second major modulator, Fgf12, located on chromosome 16, emerged after about 100 minutes. The interaction between Oprm1 and Fgf12 displayed a transient epistatic relationship during a short window (45–75 minutes), suggesting a potential mechanism for modulating drug response in mammals.

Furthermore, the researchers found co-expression of Oprm1 and Fgf12 in a specific subtype of Drd1 + medium spiny neurons in rats. The findings were supported by a Bayesian network analysis, which revealed a MAP kinase cascade network involving FGF12 phosphorylation, contributing to locomotor activation. Importantly, these networks were also found to be enriched in human genome-wide association study (GWAS) data, linking them to substance use disorders.

This study marks the first demonstration of a time-dependent epistatic interaction in modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.