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Migraine is a ubiquitous neurologic disease that afflicts people of all ages. Its molecular pathogenesis involves peptides that promote intracranial vasodilation and modulate nociceptive transmission upon release from sensory afferents of cells in the trigeminal ganglion and parasympathetic efferents of cells in the sphenopalatine ganglion. Experimental data have confirmed that intravenous infusion of these vasoactive peptides induce migraine attacks in people with migraine, but it remains a point of scientific contention whether their site of action lies outside or within the central nervous system. In this context, it has been hypothesized that transient dysfunction of brain barriers before or during migraine attacks might facilitate the passage of migraine-inducing peptides into the central nervous system. Here, we review evidence suggestive of brain barrier dysfunction in migraine pathogenesis and conclude with lessons learned in order to provide directions for future research efforts.
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Migraine is a prevalent neurological disorder that is characterized by recurrent headache attacks of moderate to severe intensity and accompanying symptoms such as nausea, vomiting, photo-, and phonophobia [1]. Its pathogenesis is to be explained within the framework of the trigeminovascular system [2]. This system includes the trigeminal ganglion and its peripheral axonal projections that innervate pain-sensitive intracranial structures, e.g. meninges [3]. In addition, central axonal projections arise from trigeminal ganglion cells and convey nociceptive impulses to second-order trigeminovascular neurons in the brain stem [3]. These neurons, in turn, project to third order trigeminovascular neurons in the thalamus, which then convey nociceptive impulses to a wide array of cortical areas that are involved in pain processing, e.g. the somatosensory cortex [3].
A point of scientific contention is whether the molecular mechanisms that initiate migraine attacks lie outside or within the central nervous system (CNS) [1]. Upon activation, peripheral projections of the trigeminal nerve release neurotransmitters that elicit vasodilation and modulate nociceptive transmission, e.g. calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) [3]. Intravenous administration of these neurotransmitters can induce migraine attacks in individuals with migraine, whereas healthy volunteers most often develop no more than mild headache [4]. Based on this, it becomes a question of key interest whether these neuropeptides can cross the blood-brain barrier (BBB) and initiate migraine attacks from within the CNS. If not, this would favor a peripheral origin of migraine.
In this Review, we examine evidence suggestive of brain barrier dysfunction in migraine. Furthermore, we discuss whether neuropeptides that induce migraine attacks have their site of action within the CNS. Lastly, we review some of the outstanding research questions and provide directions for future research efforts.
The trigeminovascular system is widely considered the anatomical and physiological substrate of migraine pathogenesis [1]. Within this framework, parasympathetic efferents of cells in the sphenopalatine ganglion and sensory afferents of cells in the trigeminal ganglion release, upon activation, various peptides that promote dilation of intracranial arteries and modulate nociceptive transmission [1]. Decades of research have established that intravenous infusion of certain naturally occurring peptides can induce migraine attacks in patients with migraine while healthy volunteers develop most often no more than a mild headache [4]. This raises the question of whether these peptides induce migraine attacks outside or within the CNS.
The following peptides have been implicated in migraine pathogenesis [31]: adrenomedullin (ADM), amylin, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), and vasoactive intestinal polypeptide (VIP). All are potent vasodilators and induce migraine attacks when administered by intravenous infusion to patients with migraine [31, 32]. They mediate their effects via G protein-coupled receptors that, in turn, activate the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway [31]. Preclinical evidence suggests that this pathway results in the opening of ATP-sensitive potassium (KATP) channels, and it has been hypothesized that opening of potassium channels might be the final common pathway in the genesis of a migraine pain [1]. Collectively, the neuropeptides have receptor-binding sites that are expressed at multiple levels of the trigeminovascular system (Table 2) of which the extracerebral vasculature, extracranial vasculature and the trigeminal ganglion is not brain barrier protected.
Direct binding of neuropeptides to Aδ-fibers or neurons in the trigeminal ganglion and subsequent hyperexcitability has been suggested as the pain-initiating mechanism in migraine. However, based on the suggested intracellular pathway with KATP channels as the end station direct binding to nerve fibers would result in hyperpolarization, and thus the vasculature might be a more relevant site of action. Other ganglia without barrier protection may also be involved in migraine pathogenesis, and preclinical data has suggested that activation of the sphenopalatine ganglion causes release of PACAP and VIP from its efferent fibers [1]. This mechanism is bypassed in provoked migraine attacks where the neuropeptides are given intravenously but could play a role in spontaneous attacks. It merits emphasis that ADM, amylin, and CGRP belong to the same family of peptides [33]. The same is also true for PACAP and VIP [34].
The limited brain barrier passage of migraine-inducing neuropeptides suggests a peripheral origin of migraine. However, migraine attacks can also be induced in migraine patients by administration of vasoactive molecules with BBB permeability (e.g. GTN or cilostazol [16, 61, 62]), and several questions concerning migraine origin remain unanswered. One of them is the presence of premonitory symptoms (PS) in migraine which might be suggestive of initial activation of central structures in migraine attacks. The underlying mechanisms of PS are still unclear. Infusion of GTN to migraine patients induced PS in 36% (12/33) of patients prior to triggered migraine attacks [84]. In another study, GTN was found to induce PS in a selected group of patients known to have migraine with PS while PET-scans showed activation in various different brain areas, including hypothalamus [85]. In this study, however, no control group was included, and thus changes may relate to GTN administration rather than migraine. Furthermore, none of these studies compared PS in patients who reported and did not report migraine attacks. A study assessing the incidence of PS in migraine patients after administration of trigeminal signaling molecules reported no PS after CGRP infusion but PS in 48% of patients after PACAP-38 infusion [86]. However, CGRP and PACAP38 did not induce more PS in patients who developed an attack compared to those who did not develop an attack [86], and this aspect must be studied in healthy subjects. Further studies are needed to clarify the presence of a premonitory phase in migraine which may contribute to the discussion of migraine origin.
Additionally, several outstanding questions relate to migraine aura. Although CSD is accepted as the substrate of migraine aura, it is still unknown how CSD arises in a seemingly otherwise healthy cerebral cortex of migraine patients, and how it is related to the headache phase of migraine. The unpredictable and short-lasting nature of migraine aura makes it difficult to study patients during symptoms and thereby answer outstanding research questions on this matter. However, recently a randomized, double-blind, placebo-controlled, crossover study reported that administration of the KATP-channel opener levcromakalim induced aura in 10 of 17 (59%) patients suffering from migraine with aura and migraine attacks in 14 of 17 (82%) the patients [87]. The authors suggest that KATP-channel opening most likely induces CSD and migraine headache via separate pathways since levcromakalim efficiently triggers migraine without aura [65] and this even in some patients who have previously experienced aura symptoms during all their migraine attacks [87]. However, the trigger of migraine aura is still unknown and future research efforts are required to fully understand the initiation CSD and its relation to the headache phase of migraine.
Brain barrier disruption has been hypothesized to play an important role in the genesis of migraine attacks. The current evidence suggests, however, that there is limited experimental data in favor of this hypothesis. Nonetheless, it cannot be excluded that, in particular, CSD might be associated with inflammatory processes within the brain and meninges, ultimately causing transient brain barrier disruption. Further studies are warranted to ascertain whether early transient changes in BBB permeability occur during the early phases of a migraine attack.