Emerich D F, Snodgrass P, Pink M, Bloom F, Bartus R T
Preclinical R and D, Alkermes, Inc., 64 Sidney Street, Cambridge, MA 02139, USA.
Brain Res. 1998 Aug 10;801(1-2):259-66. doi: 10.1016/s0006-8993(98)00571-x.
The bradykinin analog, Cereport (RMP-7), was designed to increase permeability of the blood brain barrier (BBB). Over the past several years it has been developed primarily as a means of increasing permeability of the blood brain tumor barrier, where early evidence indicated a particularly robust and reliable effect. The present series of experiments were intended to determine whether Cereport might also be used to increase delivery of pharmacological agents across the normal (i.e., non-tumor) BBB. This was accomplished by testing the ability of Cereport to enhance delivery of the peripherally acting opiate agonist, loperamide, to the brain, as evidenced by induction of a centrally mediated analgesic effect. Intravenous administration of a combination of Cereport and loperamide produced a significant analgesic effect (2-fold increase in response times) when animals were tested on a hotplate apparatus. Loperamide alone did not produce analgesia. An analysis of the time course of analgesia revealed a graded onset of analgesia which peaked at 30 min, maintained asymptote at 60 min, and began to diminish by 120 min following Cereport and loperamide administration. Finally, the analgesic effects of combining Cereport and loperamide were completely blocked when animals were pre-treated with the opiate antagonist naloxone, demonstrating that the analgesia was mediated through opiate receptors. Collectively, these results suggest that Cereport was able to increase delivery of loperamide across the BBB, allowing it to gain access to opiate receptors in the CNS to produce a centrally mediated analgesic effect. They therefore provide clear evidence that safe and well-tolerated doses of Cereport can increase permeability of the normal (i.e., non-tumor) BBB. Moreover, they provide the first evidence of a pharmacological effect specifically enabled by controlled (i.e., receptor-mediated) modulation of the BBB.
缓激肽类似物Cereport（RMP - 7）旨在增加血脑屏障（BBB）的通透性。在过去几年中，它主要被开发作为一种增加血脑肿瘤屏障通透性的手段，早期证据表明其具有特别强大且可靠的效果。本系列实验旨在确定Cereport是否也可用于增加药理剂穿过正常（即非肿瘤）血脑屏障的递送。这是通过测试Cereport增强外周作用的阿片类激动剂洛哌丁胺向脑内递送的能力来实现的，其证据是诱导出中枢介导的镇痛作用。当在热板装置上对动物进行测试时，静脉注射Cereport和洛哌丁胺的组合产生了显著的镇痛效果（反应时间增加了2倍）。单独使用洛哌丁胺未产生镇痛作用。对镇痛时间进程的分析显示，镇痛作用呈分级起效，在30分钟时达到峰值，60分钟时保持稳定，在给予Cereport和洛哌丁胺后120分钟开始减弱。最后，当动物用阿片类拮抗剂纳洛酮预处理时，Cereport和洛哌丁胺联合使用的镇痛作用被完全阻断，表明镇痛作用是通过阿片受体介导的。总体而言，这些结果表明Cereport能够增加洛哌丁胺穿过血脑屏障的递送，使其能够进入中枢神经系统中的阿片受体以产生中枢介导的镇痛作用。因此，它们提供了明确的证据，即安全且耐受性良好的Cereport剂量可以增加正常（即非肿瘤）血脑屏障的通透性。此外，它们提供了第一个证据，证明通过对血脑屏障进行可控（即受体介导）调节可产生药理作用。
