Objective:To observe the effects of Jieyu Zhitong Prescription on the behavior of migraine-depressed comorbid model rats; To explore its mechanism from the perspective of regulating brain derived neurotrophic factor (BDNF)/ERK1/2/cyclic adenosine responsive element binding protein (CREB) signaling pathway.Methods:Totally 36 SD male rats were divided into blank group, model group, nimodipine group and low-, medium-and high-dose group of Chinese medicine according to random number table method. The migraine-depressive comorbidity model was replicated by intermittent subcutaneous injection of nitroglycerin (10 mg/kg) and chronic unpredictable mild stimulation. Rats in each group were given corresponding drug intervention for 21 days, once a day. The weight of rats in each group before and on the 10th and 21st days after modeling was recorded. The threshold of mechanical pain was detected, and the behavior of rats was evaluated by open field test, forced swimming test, and novelty inhibition feeding test. The protein expressions of BDNF, TrKB, p-ERK1/2 and p-CREB in rat hippocampus were detected by Western blot.Results:On the 10th and 21st day of modeling intervention, compared with model group, the body weight, the scores of horizontal and vertical activity in open field experiment in each dose group of Chinese medicine increased ( P<0.05), and the latent time of novelty inhibition feeding and immobile time of forced swimming were shortened ( P<0.05). On the 7th, 14th and 21st days, compared with the model group at the same time point, the threshold of mechanical pain of rats in each dose group of Chinese medicine increased ( P<0.05). The expression of p-ERK1/2 protein increased in hippocampal tissue in each dose group of Chinese medicine ( P<0.05), and the expression of BDNF, TrkB, and p-CERB protein increased in the low- and high-dose group of Chinese medicine ( P<0.05). Conclusion:Jieyu Zhitong Prescription can significantly improve the symptoms of migraine-depressed comorbid rats, and its mechanism may be analgesic and antidepressant by affecting the expression of proteins in the BDNF/ERK1/2/CREB signaling pathway.