Alternation of Signal Transduction and Desensitization by Repeated Morphine Treatment in the Presense of Chronic Oain.

在慢性疼痛的情况下通过重复吗啡治疗来改变信号转导和脱敏。

• 批准号: 14572163
• 负责人: TOKUYAMA Shogo
• 金额: $ 1.92万
• 依托单位: Kobe Gakuin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572163/
• 关键词: chronic pain; pain stimulation; morphine; tolerance; neuronal cell adhesion molecule; NCAM; PKC; 細胞内情報伝達; κオピオイド受容体; μオピオイド受容体

It has been reported that induction of m-opioid receptors is affected by neuronal cell adhesion molecule (NCAM) in the experiment used by P19 cell line, suggesting that morphine action might be modulated by NCAM. In the present study, involvement of NCAM in the development of tolerance to morphine analgesia was examined. The tolerance was easily developed by daily injection of 10 mg/kg morphine on mice for 5 days, as evaluated by tail-flick method. On the other hand, treatment of antisense oligodeoxynucleotides (AS-ODN) for NCAM significantly inhibited its tolerance development. Recently, desensitization of opioid receptor phosphorylated by protein kinase C (PKC) as one of the mechanisms of tolerance development has been focused. In fact, phosphorylation and expression of PKCα, one of the PKC isozymes, protein was increased in the midbrain region of morphine tolerant mice in the Western blot analysis. Furthermore, the change in PKCα protein caused by multiple treatment of morphine was also reversed by AS-ODN for NCAM. These results obtained in this study demonstrate that NCAM plays an important role in the development of tolerance to morphine mediated through the regulation of phosphorylation and expression of PKCα protein.

在P19细胞实验中发现神经细胞粘附分子（neuronal cell adhesion molecule，NCAM）对m阿片受体的诱导有影响，提示NCAM可能参与吗啡作用的调节。在本研究中，NCAM参与吗啡镇痛耐受性的发展进行了研究。小鼠每天注射吗啡10 mg/kg，连续5 d，用甩尾法观察，可容易地产生耐受性。另一方面，反义寡核苷酸（AS-ODN）处理NCAM显着抑制其耐受性的发展。近年来，蛋白激酶C（PKC）磷酸化阿片受体的脱敏作为耐受发生的机制之一受到了广泛关注。事实上，在Western blot分析中，吗啡耐受小鼠中脑区域的PKC同工酶之一PKCα蛋白的磷酸化和表达增加。此外，NCAM反义寡核苷酸还能逆转吗啡多次处理引起的PKCα蛋白表达的变化。这些结果表明NCAM通过调节PKCα蛋白的磷酸化和表达在吗啡耐受的形成中起重要作用。