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

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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.