Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We collected plasma samples from mice undergoing acute or chronic morphine or saline injections and analyzed them using targeted GC–MS-based metabolomics to profile approximately 80 metabolites involved in the central carbon, amino acid, nucleotide, and lipid metabolism. Our findings reveal distinct alterations in plasma metabolite concentrations in response to acute or chronic morphine intake, and these changes were linked to the development of tolerance to morphine’s analgesic effects. We identified several metabolites that had been differentially affected by acute versus chronic morphine use, suggesting that metabolic changes may be mitigated by prolonged exposure to the drug. Morphine-tolerant mice showed a restoration of amino acid and glycolytic metabolites. Additionally, we conducted reconstructed metabolic network analysis on the first 30 VIP-ranked metabolites from the PLSDA of the saline, acute, and morphine-tolerant mice groups, which uncovered four interaction networks involving the amino acid metabolism, the TCA cycle, the glutamine-phenylalanine-tyrosine pathway, and glycolysis. These pathways were responsible for the metabolic differences observed following distinct morphine administration regimens. Overall, this study provides a valuable resource for future investigations into the role of metabolites in morphine-induced analgesia and associated effects following acute or chronic use in mice.