Objective To investigate the association between small conductance calcium-activated potassium channel SK3 and migraine in rats, and to provide an experimental basis for the research on the pathogenesis of migraine and discovery of new therapeutic targets.Methods A total of 40 adult female Sprague-Dawley rats were randomly divided into control group with 8 rats, model group with 16 rats, and intervention group with 16 rats, and the latter two groups were further divided into acute episode group and interictal period group, with 8 rats in each group. The Cristina Tassorelli method was used to establish a rat model of migraine. The control group was treated with normal saline to establish the model. The rats in the intervention group were given flunarizine 2 ml (0.5 mg/kg) by gavage every day, and those in the control group were given normal saline 2 ml by gavage every day. The rats in the acute episode group were decapitated at 3 hours after the fifth time of modeling, and those in the interictal period group were decapitated at 4 days after the fifth time of modeling; the brain stem was collected. RT-PCR and Western blot were used to measure the mRNA and protein expression of SK3 in the brain stem.Results Compared with the control group, the model group and the intervention group had significant reductions in the mRNA and protein expression of SK3 (P<0.05), and the acute episode groups had significantly lower mRNA and protein expression of SK3 than the corresponding interictal period groups (P<0.05). There were no significant differences in the mRNA and protein expression of SK3 between the acute episode group in the model group and that in the intervention group, as well as between the interictal period group in the model group and that in the intervention group (P>0.05).Conclusions Reduced expression of SK3 in the brain stem may be associated with the development and progression of migraine. The mechanism of action of flunarizine in the prevention and treatment of migraine may not be realized through its effect on the expression of SK3 in the brain stem.