Pharmacokinetic analysis of morphine-3-glucuronide after acute morphine intravenous bolus administration to rats with traumatic brain injury.

This study investigates the effects of traumatic brain injury (TBI) on the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), and their influence on neuroinflammation and systemic inflammation. We hypothesized that disruptions in the blood-brain barrier (BBB) due to TBI would enhance M3G exposure to the brain, which could potentially trigger inflammatory responses. We implemented a rat model of controlled cortical impact (CCI) injury to assess systemic pharmacokinetics of morphine and M3G over 24 hours postintravenous bolus administration. To gain an understanding of relative levels in the brain, we measured the drug and metabolite concentrations in both brain tissue and plasma at the systemic maximum concentration, which occurred at 1 hour post-CCI. While this study was designed to conduct a thorough acute pharmacokinetic analysis, the design also afforded an early examination of potential pharmacodynamic effects. Markers of neuroinflammation and systemic inflammation were measured in plasma and cerebrospinal fluid at 24 hours post-CCI. Results showed a 2-fold increase in systemic M3G exposure and doubled concentrations of both morphine and M3G in the brain. Notably, only M3G demonstrated a significant increase in the brain/plasma ratio at 1 hour. Despite these pharmacokinetic changes following a single bolus, there were limited morphine-induced or M3G-induced increases in markers of neuroinflammation or systemic inflammation at 24 hour post-CCI. This study highlights that TBI significantly alters the pharmacokinetics of morphine and M3G, increasing their brain penetration without worsening acute inflammation. Future research will need to explore the implications of extended and repeated dosing on these pharmacokinetic and inflammatory outcomes after TBI. SIGNIFICANCE STATEMENT: To our knowledge, this is the first pharmacokinetic analysis of morphine and its metabolite morphine-3-glucuronide (M3G) following traumatic brain injury (TBI). This research provides the first evidence that morphine and M3G show increased systemic and brain concentrations following experimental TBI, with an acute rise in M3G's brain/plasma ratio. Although no exacerbation of acute TBI-induced inflammation was observed with either morphine or M3G, the impact of longer, more frequent dosing needs evaluation because its longer administration could exacerbate TBI's neuroinflammatory response.