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at the same time, changes in intracellular Ca 2+ lead to the opening of neuronal pannexin 1 channels to open and activate cystatinase 1, followed by the release of high mobility group box-1 protein and the activation of nuclear factor kappa-B signaling pathway in astrocytes (Karatas et al., 2013), which triggers substantial inflammatory response, producing a variety of inflammatory cytokines such as interleukin (IL)-1 (Ghaemi et al., 2018), IL-6 (Ghaemi et al., 2018) and tumor necrosis factor (TNF)- (Ghaemi et al., 2018) as well as Toll-like receptor (Ghaemi et al., 2016) production, which prolongs trigeminal nerve stimulation, leading to sensitization of the dura mater and triggering of headache (Figure 1B)