Alternation of Signal Transduction by Repeated Morphine Treatment in the Presence of Chronic Pain.

本研究旨在探讨慢性疼痛对调控吗啡耐受形成的G蛋白和PKC活性变化的影响。来准备一份。建立小鼠慢性疼痛模型，左后爪背侧注射2%福尔马林。在这些小鼠中，吗啡耐受性的形成被显著阻止，而根据甩尾试验，反复暴露于吗啡导致对照组动物在不注射福尔马林的情况下止痛性减少。在每日注射吗啡的耐受小鼠中，μ阿片受体选择性激动剂DAMGO刺激的GTPγS结合量明显低于生理盐水对照组。然而，在福尔马林和U-50,488H(一种选择性γ-阿片受体激动剂)处理的小鼠中，[&lt；35&gt；S]GTP与κ-S的结合增加，表明抑制吗啡耐受的发展。此外，κ阿片受体反义寡核苷酸的治疗逆转了对吗啡耐受的抑制和对福尔尼林处理小鼠[&lt；35&gt；^S]GTPyS结合量的增加。另一方面，同时使用吗啡和选择性PKC抑制剂组织磷脂酶C也阻碍了耐受性的发展，提示PKC参与了吗啡耐受性。事实上，在吗啡耐受小鼠中脑中有大量阿片受体的区域，PKC活性增加。然而，在福尔马林处理的小鼠中没有观察到这种PKC活性的增加。这些结果提示，慢性疼痛可通过增加G蛋白和PKC活性来阻止吗啡耐受的形成，而*阿片受体可能在调节0蛋白活性中起重要作用。

In the present study, the influence of chronic pain on the change of G-protein and PKC activity regulating the development of morphine tolerance was examined. To prepare an. animal model suffered from chronic pain, 2% formalin was injected into the dorsal part of hind left paw in mice. In these mice, the development of morphine tolerance was prevented significantly, while repeated exposure to morphine leads to analgesic reduction in control animals without formalin injection as evaluated by tail-flick test. In the tolerated animals made by daily injection of morphine, DAMGO (a selective μ-opioid receptor agonist)-stimulated [<35>^S] GTPγS binding was reduced significantly as compared with control mice treated saline instead of morphine. However, [<35>^S] GTPγS binding was increased in the formalin and U-50, 488H (a selective κ-opioid receptor agonist) treated mice showing that the inhibition of the development of morphine tolerance. Furthermore, the treatment of antisense oligodeoxynucleotides for κ-opioid receptors reversed the inhibition of morphine tolerance and the increase of [<35>^S] GTPyS binding in fornialin-treated mice. Orr the other hand, concomitant treatment with morphine and caiphostin C, a selective PKC inhibitor, was also impeded the tolerance development suggesting the involvement of PKC in morphine tolerance. Indeed, PKC activity in the midbrain region, which has a lot of *-opioid receptors, increased in morphine tolerated mice. However, this increase of PKC activity was not observed in formalin treated mice. These results suggest that chronic pain could prevent the development of morphine tolerance mediating by the increase of G-protein and PKC activity and that *-opioid receptors might play an important role in the regulation of 0-protein activity.