A c-Fos activation map in NTG/levcromakalim-induced chronic migraine mice

Abstract Background Chronic migraine is a common and disabling disorder. Functional MRI has established that abnormal brain region activation is present in chronic migraine. Drugs targeting the calcitonin gene-related peptide (CGRP) or its receptor have been reported to be efficient for treating chronic migraine. The CGRP signaling pathway has been documented in two types of preclinical migraine mouse models. However, it remains unclear how an active specific brain region develops migraine-like pain and whether CGRP receptor antagonists can alter specific brain region activation and relieve migraine-like pain. Therefore, we sought to investigate brain activation and the effect of olcegepant treatment on brain activation in two chronic migraine models and provide a reference for future research on neural circuits. Methods Repeated administration of nitroglycerin (NTG) or levcromakalim(LEV) was conducted to establish two types of preclinical migraine mouse models to stimulate human migraine-like pain. Mechanical hypersensitivity was evaluated using the von Frey filament test. Then, we evaluated the activation of different brain regions using c-Fos and NeuN staining. Olcegepant, a CGRP receptor-specific antagonist, was administered to explore its countering effect on brain region activation and mechanical hyperalgesia. Results After treatment with NTG and LEV, acute and chronic basal mechanical hyperalgesia was observed in the migraine models. Olcegepant, a CGRP receptor selective antagonist, significantly alleviated mechanical hyperalgesia in both models. In NTG-induced chronic migraine mice, the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and caudal part of the spinal trigeminal nucleus (Sp5c) showed a significant increase in c-Fos expression, while olcegepant reduced c-Fos expression. No change in c-Fos expression was found in the paraventricular thalamic nucleus (PVT) and ventrolateral periaqueductal gray (vlPAG). In LEV-induced migraine mice, mPFC, PVT and Sp5c showed a significant increase in c-Fos expression and olcegepant reduced c-Fos expression. No change in c-Fos expression was found in vlPAG and ACC. Conclusions Our study demonstrated activation of the medial prefrontal cortex and caudal part of the spinal trigeminal nucleus in both chronic migraine models. Olcegepant may alleviate hyperalgesia of the hind paw and periorbital area by attenuating brain activation in chronic migraine.