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Background: According to the previous studies, the exact mechanism of dependence on opioids and withdrawal syndrome has not been fully understood but one of the most important mechanisms is the increase of pro-inflammatory cytokines in CNS. On the other way, previous studies showed that natural honey (NHO) has anti-inflammatory properties. This study was aimed to evaluate the effects of chronic administration of natural honey on the development of morphine dependence in male rats. Methods: Honey was prepared from Tarom Oliya region in Zanjan province. Experiments were performed on male Wistar rats weighing 225-275 g, randomly divided into 6 groups (n=8). The study groups included morphine group, the three doses of morphine plus honey group (at doses of 200,400 and 800 mg/kg, i.p.), the morphine plus vehicle group, and the saline group. The subcutaneous injections of additive doses of morphine were used for 9 days to create morphine dependency. On the 9th day, one hour after the morning dose of morphine, naloxone (4 mg/kg, i.p.) was injected, and symptoms of withdrawal syndrome were assessed for 60 minutes. Then, blood samples were taken to measure TNF-α. One-way ANOVA and Tukey tests were used to compare the results. P- Value of <0.05 was considered as statistically significant. Results: The results of this study showed that intraperitoneal injection of honey at 3 doses (200, 400 and 800 mg/kg with p <0.001) could significantly decrease the total score of the symptoms compared to the morphine-vehicle control group. Natural honey (NHO) could significantly decrease TNF-α at dose of 400 mg/kg. Conclusion: The results indicated that chronic administration of NHO had beneficial effects in reducing symptoms of morphine withdrawal syndrome, and this effect is probably due to the anti-inflammatory effect caused by the polyphenolic compounds in honey.<br />