Attenuation of the morphine-induced rewarding effect under chronic inflammatory pain-like state in rats: Implication of the activation of endogenous k-opioid system

Recent clinical studies have demonstrated that when opioids are used to control pain, tolerance is not a major concern and patients rarely show any withdrawal sign. However, little information is available regarding changesin fun ction at the supraspinal level under chronic pain state. Therefore, the present study was designed to investigate the opioid-induced place preference and the effect on the extracellular dopamine release by opioid in the nucleus accumbens (N.Acc), and its mechanism under inflammatory pain-like state in rats. In the present study, the paw pressure thresholds were significantly decreased maximally on day 1 after 2.5% formalin injection and gradually recovered over at least 11 days, using the Randall-Selitto test. The decrease in paw pressure threshold obviously indicated the developmentof mechanical hyperalgesia under inflammatory pain-like state. Under inflammatory painstate,we investigated theopioid-induced place preference in rats. Results of the study showed that the opioid-induced place preference was significantly attenuated by chronic inflammation. These findings suggest that pain can suppress the development of psychological dependence on opioids. In the present study, we also demonstrated that morphineinduced extracellular dopamine release in the N.Acc was significantly reduced under inflammatory pain-like state. In order to elucidate the mechanism of this attenuation, the effects of pretreatment with c5- and «-opioid receptor antagonists, naltrindole (NTI) and nor-binaltorphimine (nor-BNI) on the development of the morphine-induced place preference under chronic inflammatory pain-like state were conducted in rats. We demonstrated that the attenuation of the morphine-induced place preference under chronic inflammatory pain-like state was effectively suppressed by pretreatment with δ-and κ-opioid receptor antagonist, nor-BNI but not the c5-opioid receptor antagonist, NTI. In conclusion, the present results suggest that the suppression of the opioid-induced place preference under inflammatory pain-like state may result from the activation of the endogenous κ-opioid systems and may implicate the reduction in extracelullar dopamine release in the N.Acc. These findings imply that psychological dependence is not a major concern for patients receiving opioids and opioid treatment is highly recommendedfor pain relief