INSERM U705, CNRS UMR8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Toxicology. 2013 Mar 8;305:99-108. doi: 10.1016/j.tox.2013.01.013. Epub 2013 Jan 29.
While most deaths from asphyxia related to buprenorphine (BUP) overdose have been reported in males, higher plasma concentrations of BUP and its toxic metabolite norbuprenorphine (NBUP) have been observed in females. We previously demonstrated that P-glycoprotein (P-gp) modulation at the blood-brain barrier (BBB) contributes highly to BUP-related respiratory toxicity, by limiting NBUP entrance into the brain. In this work, we sought to investigate the role of P-gp-mediated transport at the BBB in gender and strain-related variability of BUP and NBUP-induced respiratory effects in mice. Ventilation was studied using plethysmography, P-gp expression using western blot, and transport at the BBB using in situ cerebral perfusion. In male Fvb and Swiss mice, BUP was responsible for ceiling respiratory effects. NBUP-related reduction in minute volume was dose-dependent but more marked in Fvb (p<0.01 at 1mg/kg NBUP and p<0.001 at 3 and 9mg/kg NBUP) than in Swiss mice (p<0.001 at 9mg/kg NBUP). Female Fvb mice were more susceptible to BUP than males with significantly increased inspiratory time (p<0.05) and to NBUP with significantly increased expiratory time (p<0.01). Following BUP administration, plasma BUP concentrations were significantly higher (p<0.01) and plasma NBUP concentrations significantly lower (p<0.001) in Fvb mice compared to Swiss mice. Plasma BUP concentrations were significantly higher (p<0.05) and plasma NBUP concentrations significantly lower (p<0.01) in male compared to female Fvb mice. In contrast, following NBUP administration, comparable plasma NBUP concentrations were observed in both genders and strains. No differences in P-gp expression or BUP and NBUP transport across the BBB were observed between male and female Fvb mice as well as between Swiss and Fvb mice. Our results suggest that P-gp-mediated transport across the BBB does not play a key-role in gender and strain-related variability in BUP and NBUP-induced respiratory toxicity in mice. Both gender- and strain-related differences in respiratory effects of BUP could be attributed to BUP itself rather than to its metabolite, NBUP.
虽然大多数与丁丙诺啡（BUP）过量有关的窒息死亡报告都发生在男性中，但女性的 BUP 及其有毒代谢物去甲丁丙诺啡（NBUP）的血浆浓度更高。我们之前的研究表明，P-糖蛋白（P-gp）在血脑屏障（BBB）的调节作用极大地导致了 BUP 相关的呼吸毒性，通过限制 NBUP 进入大脑。在这项工作中，我们试图研究 BBB 中 P-gp 介导的转运在性别和品系相关的 BUP 和 NBUP 诱导的呼吸效应中的作用。使用 plethysmography 研究通气，使用 Western blot 研究 P-gp 表达，使用原位脑灌注研究 BBB 中的转运。在雄性 Fvb 和瑞士小鼠中，BUP 引起呼吸上限效应。NBUP 相关的分钟通气量减少与剂量呈依赖性，但在 Fvb 中更为明显（1mg/kg NBUP 时为 p<0.01，3mg/kg 和 9mg/kg NBUP 时为 p<0.001），而在瑞士小鼠中不明显（9mg/kg NBUP 时为 p<0.001）。雌性 Fvb 小鼠比雄性小鼠对 BUP 更敏感，吸气时间显著增加（p<0.05），对 NBUP 更敏感，呼气时间显著增加（p<0.01）。给予 BUP 后，Fvb 小鼠的血浆 BUP 浓度明显升高（p<0.01），血浆 NBUP 浓度明显降低（p<0.001），而瑞士小鼠的血浆 BUP 浓度明显升高（p<0.01），血浆 NBUP 浓度明显降低（p<0.001）。相比之下，给予 NBUP 后，两性和两品系的血浆 NBUP 浓度相似。雌雄 Fvb 小鼠以及瑞士和 Fvb 小鼠之间的 P-gp 表达或 BUP 和 NBUP 穿过 BBB 的转运均无差异。我们的结果表明，P-gp 介导的 BBB 转运在小鼠 BUP 和 NBUP 诱导的呼吸毒性的性别和品系相关变异性中不起关键作用。BUP 引起的呼吸效应的性别和品系差异可能归因于 BUP 本身，而不是其代谢物 NBUP。
