Mechanism of opioid dependence and interaction between opioid receptors

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. Formalin or carrageenan was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9-13 days. The 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 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. We also found that kappa-receptor agonists markedly inhibited the rewarding effect of mu-receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with kappa- and delta-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 (DA) 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 kappa-opioid systems may be activated by chronic inflammatory nociception, and then the activation of kappa-opioid system may inhibit DA release in nucleus accumbens, resulting in the suppression of the development of rewarding effects produced by morphine.