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Objective:To observe the tolerance and the dependence of endomorphin-1 (EM-1) in rats and the possible mechanisms.Methods :Sixty Sprague-Dawley rats were randomly allocated into saline, acute EM-1-treated and chronic EM-1-treated groups.The rats were intracerebroventricularly injected with saline, acute EM-1 10 μg/kg 30 min prior to sacrifice,and chronic EM-1 by daily administration at 8:00 A.M. and 15:00 P.M. from 10 pg/kg on the 1st day to 50 μg/kg on the 9th day, respectively. In chronic EM-1-treated group, the median antinociceptive dose (AD50) and the catatonic median effective dose (ED50) were determined by the improved Dixons method. Natural withdrawl test was used to assess the dependence of EM-1. Maximal binding capacity (Bmax) and dissociation constant (Kd) of 3H-DAMGO, binding to mu-opioid receptor (MOR) in brain tissue, was measured by Scatchard analysis. Gene expression of MOR was measured by reverse transcription-polymerase chain reaction(RT-PCR).Results:Tolerance of the antinociceptic and catatonic effects on the 3rd day (3.1-fold and 1.9-fold) and the 9th day (28.4-fold and 8.5-fold) were observed in chronic EM-1-treated group (P ＜ 0.05). Jumping times and withdrawal scores of rats were significantly higher in the chronic EM-1-treated group than those in saline group on the 9th day (P ＜ 0.05). Bmax and mRNA expression of MOR in cortex, midbrain and striatum were lower in chronic EM-1-treated group on the 9th day than the other two groups(P ＜ 0.05),but Kd had no significant difference (P ＞ 0.05). AD50,ED50,Bmax,Kd and gene expression of MOR were recorded. Conclusion:EM-1 possesses the tolerance and the dependence. After a long-term treatment, EM-1 down regulates the binding capacity and mRNA of MOR, which somewhat accounts for the dependence.