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. 2022 Dec 28;13:100112. doi: 10.1016/j.ynpai.2022.100112

Fig. 2.

Fig. 2

Pathway relevant to nitroglycerin (GTN)-induced migraine-like headache. Nitroglycerine (GTN) liberates nitric oxide (NO) in peripheral and cerebral structures. NO subsequently, by binding to soluble guanylyl cyclase (sGC), increases cyclic guanosine monophosphate (cGMP) (Arnold et al., 1977). Furthermore, NO can interact with superoxide to form peroxynitrite. Peroxynirite (ONOO−) is a proinflammatory compound and has been implicated in the pathophysiology of not only stroke, but also pain and is gaining interest in the migraine field (Bredt, 1999, Taffi et al., 2005). Additionally, NO on the one hand stimulates COX synthesis and prostaglandin E2 (PGE2) production (Mollace et al., 2005), and on the other hand stimulates CGRP, independent of the cGMP signaling pathway (Bellamy et al., 2006). Subsequently, CGRP has been shown to induce PGE2 (Kress et al., 1999), and vice versa (Jenkins et al., 2001, Jenkins et al., 2004, Neeb et al., 2011). In turn, it has been shown that ONOO− when inducing inflammation-derived hyperalgesia acts via the COX-to-PGE2 pathway (Ndengele et al., 2008), and ONOO− is also implicated along the trigeminovascular migraine pathway associated with CGRP (Akerman et al., 2021). PKG-mediated phosphorylation opens ATP-sensitive potassium channels (KATP) channels and large (big)-conductance calcium-activated K+ (BKCa) via the NO/cGMP/PKG pathway (Murphy and Brayden, 1995, Schubert and Nelson, 2001). CGRP activates vascular smooth muscle KATP channels and BKCa channels via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) phosphorylation (Hosokawa et al., 2010, Miyoshi and Nakaya, 1995). PGE2 can also either increase or decrease the amount of cAMP depending on to which receptor it binds (Markovič et al., 2017). Opening of KATP and BKCa channels generates outward K+ currents and causes vasodilation (Chrissobolis and Sobey, 2003), and can eventually lead to a migraine-like attack (Al-Karagholi et al., 2021, Al-Karagholi et al., 2019). Provocation with PGE2 in subjects with migraine leads to a rapid-onset migraine attack (Antonova et al., 2012), which suggests that PGE2 is closely upstream of a migraine-like attack.