Figure 7.

The sGC inhibitor, ODQ, inhibits already established NTG-induced basal hypersensitivity. (A) Mice were treated every second day with vehicle (VEH) or NTG (10 mg/kg, IP) for 9 days. Basal responses were significantly decreased in the NTG groups 24h after the final NTG/VEH treatment (day 10, left side). ODQ (1 mg/kg, IP) or vehicle was injected and animals were tested 2h later (post-drug responses). *p<0.05, n=7-8 mice/group. p<0.001 between groups, 1-way ANOVA with Holm-Sidak post-hoc analysis. ODQ significantly attenuated established chronic migraine-associated pain. (B) The sGC pathway is a key regulator of acute and chronic migraine. The sGC stimulator, VL-102 produces acute and chronic migraine-associated pain, comparable to NTG. In contrast, the sGC inhibitor, ODQ, completely blocks NTG-induced hyperalgesia. These results indicate that NTG-associated pain is critically mediated by the sGC pathway. ODQ also effectively blocks already established chronic migraine-associated pain, indicating that an upregulation of the sGC pathway enforces migraine chronification, potentially through adaptations of endogenous nitric oxide synthases (NOS). Our work indicates that inhibitors or negative modulators of the sGC pathway could be effective migraine treatments.