Liver and Kidney Tissues Under Opioid Exposure: Rewriting and Old Story Through Proteomics and MALDI-MSI.

A proteomic analysis of rat liver and kidney was performed following exposure to morphine (10 mg/kg, 10 days) versus untreated controls. Our data revealed alterations in numerous protein expression. Differences were observed in pro- and antiapoptotic signaling, oxidative stress response, transport mechanisms, nucleic acid metabolism, and regulators of alternative splicing, among others. Liver tissue exhibited primarily adaptive changes, including upregulation of metabolic enzymes and subtle markers of oxidative stress. In contrast, the kidneys displayed a broader spectrum of proteomic alterations, affecting a wider array of functional pathways, suggesting that this organ may be more susceptible to morphine-induced toxicity or that of its metabolites. We employed also MALDI-MSI to examine lipidomic alterations: while no significant changes were detected in liver tissue, important lipidomic alterations were observed in the kidneys, further supporting their increased vulnerability to morphine exposure. Our results should be regarded as preliminary; however, they highlight a promising direction for identifying early stage protein markers of toxicity using proteomic approaches. Monitoring such markers could prove valuable in multidrug therapies, particularly for patients with a history of hepatic or renal impairment, contributing to the development of safer therapeutic strategies. Data are available via ProteomeXchange under the identifiers: PXD067999 (DDA) and PXD068084 (DIA).