Oxidative stress and inflammatory pathways are involved in nitroglycerin (NTG)‐induced migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the Fumaric acid esters (FAEs), dimethyl fumarate (DMF), nuclear factor E2‐related factor 2/antioxidant response element (Nrf‐2/ARE) pathway‐mediated, in regulating the hypersensitivity in a mouse model of NTG‐induced migraine. Mice were orally administered with DMF at the doses of 10, 30 and 100 mg/kg, 5 minutes after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brainand behavioral tests after 4 h by NTG‐migraine induction. The expression of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B‐cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX‐2), Nrf‐2, manganese superoxide dismutase (Mn‐SOD) and heme‐oxygenase‐1 (HO‐1) were detected by Western blot. Tail flick, hot plate, formalin and photophobia tests were used to evaluate neuropathic pain and migraine‐related light sensitivity. DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF‐κB and Nrf‐2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache‐associated neuropathic pain was significantly reduced. These results provide the evidence that DMF has a modulating effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.Support or Funding InformationNo fundingThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.