Abstract
[Backgrounds] Benzimidazoles are a synthetic opioid subclass recently emerging on the illicit drug market. Although we have found opioid-related behavioral toxicities of some benzimidazoles in mice, their detailed mechanism of action and pharmacokinetics, especially in the brain, are still unknown. This study aimed to reveal the distribution of a benzimidazole analog, metonitazene (MNZ), in mouse brains. [Methods] Eight-week-old male C57BL/6J mice were i.p. injected with MNZ at 10 mg/kg and sequentially sacrificed at 0, 5, 15, 60, 90, 240, and 480 min after the injection. While the sera and portions of the brains were analyzed by LC-MS/MS, the remaining brains were dissected and prepared for sagittal cryosections, followed by image analysis using DESI-MSI. [Results & Discussion] MNZ concentrations in the sera and brains were highest at 5 and 15 min after injection, respectively, with peak values of 1.13 µg/mL and 2.63 µg/g brain, and then rapidly decreased. In the DESI-MSI analysis, MNZ signals visualized with a product ion at m/z 100.11 were observed throughout the brain, but strong signals were detected in the brainstem (midbrain, pons, and medulla), thalamus, and hypothalamus, which are the regions where μ–opioid receptors localize and regulate analgesia, respiratory depression, and the formation of drug dependence. Combined with our previous studies with behavioral observation tests and a conditioned place preference test, these results strongly suggest that the induction of neurological toxicities of MNZ in mice is indeed mediated by μ–opioid receptors.
