[32] There is also another interesting explanation, of relevance

[32] There is also another interesting explanation, of relevance for clinical practice, for these results. In the absence of an objective diagnostic marker, CM diagnosis is based on a clinical picture alone. There could be a group of patients with a phenotype mimicking that of CM who are actually suffering from other headaches, either primary or secondary. Even after being

assessed by an experienced headache neurologist and a magnetic resonance imaging has been performed with normal results, other diagnoses, such as tension-type headache in a previous migraineur or psychogenic headache expressing as CM, are still possibilities, which would explain in part the relevant response to placebo in trials with onabotA.[11] This could be an interesting point to be tested in future placebo-controlled clinical trials in CM and is a further example of the necessity of introducing objective markers, such Luminespib as CGRP levels, in CM research to try Ferrostatin-1 to avoid other diagnostic mimics. We still do not have a complete understanding of the pathophysiology of CM

or the real mechanism of action of onabotA in this entity. It is well established, however, that activation of the TVS has a crucial role and leads to afferent and efferent release of neuropeptides, especially CGRP. This facilitates a peripheral inflammatory response and vasodilatory response and causes activation of second-order neurons involved in pain transmission. In most vessels, the release of neuropeptides causes endothelium- and nitric oxide-independent vasodilation through a direct action on smooth muscle cells mediated both by cyclic adenosine monophosphate and by activation of adenosine triphosphate-dependent K + channels.[33, 34] Persistent release of CGRP and possibly other neuropeptides is thought to induce sensitization of central trigeminal neurons, and therefore migraine chronification, by triggering a signaling pathway mediated by brain-derived neurotrophic factor leading those to increased expression of the P2X

receptors. These peptidergic central neurons use L-glutamate as their primary neurotransmitter.[35, 36] CGRP, acting via a unique receptor complex, increases neurotransmitter release at these levels, which could lead to the central sensitization underlying chronic pain states such as CM.[7, 8] Our results, showing high CGRP and VIP levels in CM patients and a significant relationship between increased levels of these neuropeptides and response to onabotA, support, first, a crucial role of these neuropeptides in the pathophysiology of CM in humans, and second, that inhibition of local release of these neuropeptides is the likely mechanism of action of onabotA in CM, as previously had been hypothesized from experimental models.

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