mGluR5 promotes oxidative stress and central sensitization in chronic migraine through ERK-mediated phosphorylation of Drp1 to activate mitochondrial fission
Abstract
Chronic migraine (CM) imposes a significant social burden due to its frequent attacks and high disability rate. However, the pathological mechanism remains unclear, and central sensitization was proven to play a crucial role. Various studies have shown that oxidative stress also contributes significantly to chronic migraine. Metabotropic glutamate receptor 5 (mGluR5), a GPCR, is vital in pain modulation. Additional research is required to fully clarify mGluR5's involvement in chronic migraine and its underlying mechanisms. In this work, a chronic migraine model was developed through daily Inflammatory soup (IS) injections into the dura mater for seven consecutive days. Hyperalgesia was quantified via mechanical and thermal pain sensitivity, while central sensitization was evaluated using CGRP and c-Fos expression levels. To ascertain mitochondrial fission, the expression level of phosphorylated dynamin-related protein 1 (Drp1) at Serine 616 (S616) and mitochondrial ultrastructure were examined. Oxidative stress was assessed using malondialdehyde (MDA) content and superoxide dismutase (SOD) activity. Our results indicated that blocking mGluR5 lowered oxidative stress by preventing mitochondrial fission driven by phosphorylated Drp1. Furthermore, blocking the action of phosphorylated Drp1 in mitochondrial fission has the potential to reduce hyperalgesia and central sensitization. ERK may mediate mGluR5's influence on mitochondrial fission. The findings suggest that mGluR5…
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