慢性疼痛下におけるモルヒネ依存の修飾とその機序

抄録

Clinical studies have demonstrated that when opiates are used to control cancer pain, psychological dependence and analgesic tolerance are not a major concern. The present study was, therefore, designed to investigate the modulation of rewarding effects of opiates under inflammatory chronic pain in SD rats. Formalin (2.5%, 50 μl) or carrageenan (1%, 100 μl) was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9 to 13 days. Rewarding effect of morphine was evaluated by conditioned place preference paradigm. Morphine produced a significant place preference. This effect was significantly attenuated in inflamed groups as compared with the respective non-inflamed groups. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. On the other hand, we found that κ-opioid receptor agonists markedly inhibit rewarding effect of μ-opioid receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with κ- and δ-opioid receptor antagonists, nor-binaltorphimine (nor-BNI) and naltrindole (NTI), on the development of the morphine-induced place preference under inflammation were examined. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. The morphine-induced increase in dopamine turnover in the limbic forebrain was suppressed under inflammation, and the suppression was abolished by the pretreatment with nor-BNI. These results suggest that endogenous κ-opioid systems may be activated by chronic inflammatory nociception, resulting in the suppression of the development of rewarding effects produced by morphine.