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SUPRESSION OF MORPHINE TORELANCE

抑制吗啡耐受

基本信息

批准号：
10671874
负责人：
MATSUMOTO Ken
金额：
$ 2.05万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

We demonstrated in this study that calcium channels, especially N-type, in brain cortex increased not only the quantity but the functional calcium influx on morphine tolerant stage. Analgesic effect of intracerebroventricular administration of ψ-conotoxin (ψ-CTx) GVIA, an N-type voltage-sensitive calcium channel blocker, in morphine-or clonidine-tolerant mice was examined. The effects of ψ-CTx GVIA and other ψ-toxins (ψ-agatoxin IV A and ψ-CTx MVILA) on 45Ca uptake into synaptosomes prepared from brain cortex of these tolerant mice were also examined. In both tolerant mice, the analgesic effect of ψ-CTx GVIA was significantly decreased, and K+-stimulated 45Ca uptake into these cortical synaptosomes significantly increased, compared with control mice. 45Ca uptake into the synaptosomes of control mice was reduced by not only ψ-CTx GVIA but also other_-toxins, and the inhibition of 45Ca uptake by these toxins was attenuated in both tolerant mice. These results suggest that N-type calcium channels play some important roles for antinotiception, and are concerned with the development of morphine or clonidine tolerance through the increase of presynaptic calcium influx as well as the upregulation of opioid receptor.We also examined the interaction between morphine and nitric oxide (NO). Peroxynitrite induced cell death accompanied by DNA fragmentation in human neuroblastoma SH-SY5Y cell cultures. Morphine prevented the cell death induced by peroxynitrite. The protective effect of morphine was concentration-dependent, but was not antagonized by naloxone. The selective ligands for opioid receptor subtypes did not prevent the cell death induced by peroxynitrite. Tease results suggest that morphine prevent peroxynitrite-induced cell damage through its direct scavenging action.

本研究表明，吗啡耐受期大鼠大脑皮层钙通道，尤其是N型钙通道不仅增加了数量，而且增加了功能性钙内流。研究了侧脑室注射N型电压敏感性钙通道阻滞剂--芋螺毒素（GVIA）对吗啡或可乐定耐受小鼠的镇痛作用。还检查了β-CTx GVIA和其它β-毒素（β-agatoxin IV A和β-CTx MVILA）对从这些耐受小鼠的脑皮层制备的突触体中~（45）Ca摄取的影响。在这两种耐受小鼠中，与对照小鼠相比，GVIA的镇痛作用显著降低，并且K+刺激的45 Ca摄取到这些皮质突触体中显著增加。对照组小鼠突触体对~（45）Ca的摄取不仅被α-CTx GVIA所减少，而且也被其它α-毒素所减少，在两种耐受小鼠中，这些毒素对~（45）Ca摄取的抑制作用减弱。这些结果表明，N型钙通道在镇痛中起重要作用，并通过增加突触前钙内流和上调阿片受体参与吗啡或可乐定耐受的形成。过氧亚硝酸盐诱导人神经母细胞瘤SH-SY 5 Y细胞培养物中的细胞死亡伴随DNA片段化。吗啡可阻止过氧亚硝基阴离子诱导的细胞死亡。吗啡的保护作用呈浓度依赖性，但不被纳洛酮拮抗。阿片受体亚型的选择性配体不能阻止过氧亚硝基阴离子诱导的细胞死亡。提示吗啡通过其直接的清除作用防止过氧化亚硝酸盐引起的细胞损伤。