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

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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.