COMPARATIVE ANALYSIS OF BUPRENORPHINE AND -ITS METABOLITE INDUCED ANALGESIC EFFECTS AND RESPIRATORY DEPRESSION

Abstract

The relationships between plasma or brain concentrations and analgesic effects of both buprenorphine (BN) and its metabolite, norbuprenorphine (NBN), were investigated in rats. Maximal analgesic effects were obtained at 10 and 30 min after iv administration of BN (8 μg/kg) and NBN (100 μg/kg) administration. No correlation was observed between analgesic effect and the early plasma BN or NBN concentrations. However, a good correlation was found between the estimated specific binding concentration of BN in the brain and the analgesic effects. Further, it was suggested that the intrinsic analgesic activity of NBNwas one-fourth that of BN. We concluded that the remarkabley weak analgesic effect of NBN after iv administration may be due not only to the low permeability of NBN into the brain but also to its small intrinsic analgesic effect.
Further, the toxicodynamics of BN and NBN on respiratory depression was studied. Although the respiratory rate after iv bolus administration of BN did not change within the range of 1-3 mg/kg dose, that after administration of NBN was decreased dose-dependently. The action of respiratory depression of NBN was approximately 10 times more potents than that of the parent drug. The respiratory rate was not influenced after directly injection of NBN into 3 different brain regions. The respiratory depression induced by NBN was rapidly reduced after supplement of naloxon and β-FNA. These results suggest that the respiratory depression by NBN may be mediated by opioid μ-receptors in the peripheral tissue, probably in the lung, rather than in the brain.