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

在P19细胞系实验中，神经细胞黏附分子(NCAM)对m-阿片受体的诱导有影响，提示NCAM可能对吗啡的作用有调节作用。在本研究中，我们研究了NCAM在吗啡镇痛耐受形成中的作用。甩尾法测定小鼠每日注射10 mg/kg吗啡5d后，易形成耐受性。另一方面，反义寡核苷酸(AS-ODN)显著抑制NCAM的耐受性发展。近年来，蛋白激酶C(PKC)磷酸化的阿片受体脱敏作为耐受发生的机制之一已成为研究热点。事实上，在Western印迹分析中，吗啡耐受小鼠中脑区蛋白激酶C同工酶α的磷酸化和表达增加。此外，多次吗啡处理引起的PKCα蛋白表达的改变也可被反义寡核苷酸逆转。这些结果表明，NCAM在吗啡耐受的形成中起重要作用，其机制是通过调节PKCα蛋白的磷酸化和表达来实现的。

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.