5 CHAPTER 5 98 line treatment for migraine headaches. Cortical spreading depolarization, the underlying mechanism for the migraine aura, causes COX-2 upregulation potentially leading to increased prostaglandin levels.12, 13 The role of prostaglandins has also been investigated in provocation experiments in migraine subjects, in most cases in those without aura, demonstrating that intravenous infusion of prostaglandin I2 (PGI2) and E2 (PGE2) induces migraine like-attacks in 75% of participants with migraine. 14, 15 Remarkably, subjects with migraine typically developed rapid onset migraine-like attacks, with a median onset of 20 minutes, in 25% (PGI2) and 58% (PGE2) of cases, which is in contrast to provocation with GTN, pituitary adenylate cyclase–activating peptide (PACAP) and CGRP for which the majority of cases develops a delayed onset migraine-like attack after at least a few hours.14, 16 It has been shown that PGE2 is mediated via CGRP release, and vice versa, 10 as evidenced by observations that PGE2 stimulates the release of CGRP in rat trigeminal neurons, 17 trigeminal nucleus caudalis 18, and trigeminal ganglia,19 while CGRP induces secondary release of PGE 2. 20 All the above suggests that PGE2 may be closely upstream of GTN-induced migraine attacks (Figure 2). Figure 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).22 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.23, 24 Additionally, NO on the one hand stimulates COX synthesis and prostaglandin E2 (PGE2) production, 11 and on the other hand stimulates CGRP, independent of the cGMP signaling pathway.8 Subsequently, CGRP has been shown to induce PGE2, 20 and vice versa.17-19 In turn, it has been shown that ONOO− when inducing inflammation-derived hyperalgesia acts via the COX-to-PGE2 pathway, 25 and ONOO− is also implicated along the trigeminovascular migraine pathway associated with CGRP.26 PKG-mediated phosphorylation opens ATP-sensitive potassium channels (K ATP) channels and large (big)-conductance calcium-activated K+ (BK Ca) via the NO/cGMP/PKG pathway. 27, 28 CGRP activates vascular smooth muscle KATP channels and BKCa channels via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) phosphorylation.29, 30 PGE2 can also either increase or decrease the amount of cAMP depending on to which receptor it binds.31 Opening of K ATP and BKCa channels generates outward K+ currents and causes vasodilation,32 and can eventually lead to a migraine-like attack.33, 34 Provocation with PGE2 in subjects with migraine leads to a rapidonset migraine attack,14 which suggests that PGE2 is closely upstream of a migraine-like attack.
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