Identification of Plasma Metabolites Responding to Oxycodone Exposure in Rats

Oxycodone has an elevated abuse liability profile compared to other prescription opioid medications. However, many human and rodent metabolomics studies have not been specifically focused on oxycodone.

Investigating metabolomics changes associated with oxycodone exposure can provide insights into biochemical mechanisms of the addiction cycle and prognosis prediction.

Plasma samples from 16 rats at pre-exposure and intoxication time points were profiled on the Metabolon platform. A total of 941 metabolites were characterized. We employed a k-Nearest Neighbor imputation to impute metabolites with low levels of missingness and binarized metabolites with moderate levels of missingness, respectively.

Of the 136 binarized metabolites, 6 showed differential abundance (FDR < 0.05), including 5 that were present at pre-exposure but absent at intoxication (e.g., adenine), while linoleamide (18:2n6) exhibited the opposite behavior. Among the 798 metabolites with low levels of missingness, 364 showed significant changes between pre-exposure and intoxication (FDR < 0.01), including succinate, oleamide, and sarcosine. We identified four pathways, including tryptophan metabolism, that were nominally enriched among the metabolites that change with oxycodone exposure (p < 0.05). Furthermore, we identified several metabolites that showed nominal correlations with the Addiction Index (composite of oxycodone behaviors): 17 at pre-exposure and 8 at intoxication. In addition, the changes in abundance between pre-exposure and intoxication time points of 9 metabolites were nominally correlated with the Addiction Index, including sphingomyelins, methylhistidines, and glycerols.

In summary, not only were we able to capture oxy-induced changes in metabolic pathways using easily accessible blood samples, but we also demonstrated the potential of blood metabolomics to better understand addiction liability.