Ohtani M, Kotaki H, Nishitateno K, Sawada Y, Iga T
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, Japan.
J Pharmacol Exp Ther. 1997 Apr;281(1):428-33.
The respiratory depression induced by buprenorphine and its active metabolite, norbuprenorphine (NBN), was evaluated in rats by measurement of changes in respiratory rate and arterial pCO2 levels. After i.v. bolus administration of buprenorphine no effects were noted over the dose range 0.008 to 3 mg/kg; by contrast, the respiratory rate after rapid i.v. administration of NBN decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg, and the arterial pCO2 levels also varied in relation to the change in respiratory rate. The minimum respiratory rate was observed 15 min after NBN administration. Judging by the respiratory depressive effect after i.v. infusion, NBN was approximately 10 times more potent than the parent drug. In spite of the similarity of NBN concentrations in the brain after i.a. and after i.v. administration of NBN (3 mg/kg), neither the respiratory rate nor the arterial pCO2 levels after i.a. administration changed compared with the control levels. Moreover, the NBN concentration in the lungs after i.v. administration was approximately 4-fold higher than that after i.a. administration. NBN-induced depression was rapidly reduced after i.v. administration of naloxone and beta-funaltrexamine, but ICI 174864 was without effect. These results suggest that the respiratory depression induced by NBN may be mediated by opioid mu receptors in the lung rather than in the brain.
通过测量呼吸频率和动脉血二氧化碳分压水平的变化，在大鼠中评估丁丙诺啡及其活性代谢物去甲丁丙诺啡（NBN）引起的呼吸抑制作用。静脉推注丁丙诺啡后，在0.008至3mg/kg的剂量范围内未观察到任何影响；相比之下，快速静脉注射NBN后，在1至3mg/kg的剂量范围内，呼吸频率呈剂量依赖性下降，且动脉血二氧化碳分压水平也随呼吸频率的变化而改变。在注射NBN后15分钟观察到最低呼吸频率。根据静脉输注后的呼吸抑制作用判断，NBN的效力约为母体药物的10倍。尽管腹腔注射和静脉注射NBN（3mg/kg）后大脑中的NBN浓度相似，但腹腔注射后与对照水平相比，呼吸频率和动脉血二氧化碳分压水平均未改变。此外，静脉注射后肺部的NBN浓度比腹腔注射后高约4倍。静脉注射纳洛酮和β-氟纳曲胺后，NBN引起的抑制作用迅速减弱，但ICI 174864无效。这些结果表明，NBN引起的呼吸抑制可能是由肺部而非大脑中的阿片μ受体介导的。
