Blood and Spinal Fluid in Migraines

Paola Sarchielli

Flemming W. Bach

No biological markers of migraine have been identified as yet and migraine diagnosis remains primarily clinical. Many neurotransmitter pathways have been investigated because they are believed to underlie the susceptibility to attacks and to be involved in the induction and maintenance of the pain phase in migraine.

Research carried out in the peripheral blood concerned markers of the serotonergic, sympathetic, opioid, and dopaminergic systems, based on the assumption that modifications of their levels in the serum/plasma or in blood elements (platelets, lymphocytes) can mirror similar changes in the central pathways both in the headache-free phase and during attacks. Cerebrospinal fluid (CSF) investigations concerned several neurotransmitters whose changes are believed to better reflect analogous changes of the same pathways in the central nervous system (CNS) rather than in the peripheral blood.

Further investigations were aimed at measuring the biochemical markers of activation of the trigeminovascular system in jugular venous blood, and more recently, to verify the involvement of nitric oxide (NO), indicated as a key molecule in migraine. Excitatory amino acids, markers of NO metabolism, and recently, some neurotrophins, also are involved in chronic migraine (CM) on the basis of findings in the CSF, but their changes have been considered more as markers of chronic pain per se rather than as specific of migraine chronicity.

This chapter deals with the biochemical and neurotransmitter alterations in migraine demonstrated both in the blood and CSF.

PERIPHERAL BLOOD

Serotonin

From the first observation of Sicuteri et al. (95) of an increased urinary excretion of the serotonin (5-hydroxytryptamine; 5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in migraine patients during attacks, studies focused on the platelet-free plasma and serum levels of this neurotransmitter in the peripheral blood of migraineurs (Table 34-1). The most relevant finding was increased blood concentrations during attacks, which corresponded with a reduction in platelet 5-HT levels compared with the interictal period. Reduced plasma 5-HT levels in the interictal period suggested increased turnover in the headache-free period, whereas its increase during an attack had been ascribed to release from activated platelets by a hypothetical releasing factor, or else normalization of turnover. If the latter, this might invoke compensatory mechanisms to counteract reduction in biologically active serotonin.

The majority of studies on serotonin metabolism in platelets have been based on the assumption of functional and structural analogies with serotonergic neurons. Results also supported reduced turnover between attacks and release during attacks (Table 34-2). The normalization of serotonin turnover during attacks was also confirmed by reduction in the activity of the enzymes intervening in its degradation.

Contrasting results have been obtained for urinary concentrations of 5-HIAA. Some studies reported increased levels during a migraine attack (95), and others showed reduced levels or no change. Discrepancies in the results could be caused in part by methodologic differences, difference in urine collection (24-hour, diurnal, or nocturnal samples), sample acidification, and expression of the results (absolute values or values expressed per mol of creatinine).

Functional impairment of serotonergic pathways and intracellular transduction mechanisms emerged in the platelet model in CM patients; upregulation of 5-HT_2A receptors, decreased serotonin content, and dilatation of the canaliculi system, implying excessive 5-HT release may produce a hyposerotonergic state, particularly with analgesic abuse (98,99).

Sympathetic System Markers

Studies of plasma and urinary levels of noradrenaline have provided contradictory results, possibly because they failed to account for circadian rhythms. Increased
dopamine-betahydroxylase was first reported by Gotoh et al. (48), but could not be confirmed subsequently (37). On the contrary, a reduction in its activity suggested functional derangement rather than sympathetic hyperactivity in migraine. Another study investigated peripheral levels of neuropeptide Y (NPY), a neurotransmitter widely distributed in the sympathetic system where it is stored together with noradrenaline (43). Unlike noradrenaline, however, NPY is responsible for more marked and prolonged vasoconstriction, by the interacting with specific receptors on vascular smooth muscle involving increase of extracellular calcium. In child and adolescent migraine patients assessed while headache free, NPY reduction was significant compared with healthy subjects or patients with tension-type headache, providing support for dysfunction of the sympathetic system.

TABLE 34-1 Principal Findings Regarding Peripheral Blood Serotonin in Migraine

	*Attack*	*Headache-Free Phase*	*Authors*
Plasma 5-HT	Increase of at least two-fold compared with the interictal period with values similar to those of controls	Reduction compared with controls	Somerville (97)
			Humphrey (49)
			Ferrari (31)
			Saxena and Ferrari (91)
Plasma 5-HIAA	Slight reduction	Increased compared with controls	Ferrari and Odink (34)
Serum 5-HT	Increase of 2-fold both in migraine with and without aura	Slight increase only in migraine with aura compared with controls	Ribeiro et al. (77)
Urinary 5-HT	Increased		Anthony (3)
Urinary 5-HIAA	Contradictory results	Contradictory results	Sicuteri et al. (94)
			Anthony (3)
			Eadie and Tyrer (25)
			Ferrari (31)
Platelet 5-HT	Reduction of at least 40% compared with values in the interictal period		Humphrey (49)
			Ferrari (31)
Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine.

Dopamine

Hypersensitivity of the dopaminergic system in migraine pathogenesis is suggested by premonitory symptoms of yawning and somnolence and by increased presentation of these symptoms or nausea after pharmacologic challenge with apomorphine (8,15). That this might be caused by hypofunction of the dopaminergic system was further suggested by increased density of both D3 and D4 receptors on peripheral blood lymphocytes in migraineurs (8), giving rise to the so-called migraine trait (23). Mascia et al. (60) hypothesized that reduced release of serotonin between attacks could lower dopamine release leading to dopamine receptor hypersensitivity.

TABLE 34-2 Serotonin Metabolism in Migraineurs’ Platelets

*Authors*	*Headache-Free Period*
D’Andrea et al. (22)	Decrease in serotonin turnover
	Increase in the number of dense bodies
	Reduced secretion from dense bodies
Joseph et al. (51)	Altered coupling among cytosol ionized calcium, secretion from dense bodies and platelet activation
	*Attack*
Ferrari and Odink (34)	Reduced platelet serotonin content owing to intrinsic modifications by a plasmatic releasing factor

Endogenous Opioids

Dysfunction of the opioid system in migraine was first hypothesized by Sicuteri in 1979 (95); he compared the migraine attack to a condition similar to morphine abstinence. Functional derangement of the endorphin system was suggested by low levels of β-endorphin in peripheral blood that were associated with frequency of attacks and chronic head pain (44,66) (Table 34-3). Based on changes in blood mononuclear cells studied as a model of central neurotransmitter pathways (54), reduced β-endorphin levels were also recorded between migraine attacks. Increased plasma levels of met-enkephalin during migraine attacks have been attributed to its release from platelets as a compensatory mechanism to antagonize release of other sensory neuropeptides (65).

Excitatory and Inhibitory Amino Acids

The neuronal theory of migraine has focused on the involvement of both glutamic (Glu) and aspartic (Asp) acids in the induction and propagation of cortical spreading depression (CSD), believed to be the neurophysiologic expression of migraine aura (73). The demonstration of Glupositive neurons in migraine pain-relay centers, including the trigeminal ganglion, trigeminal nucleus caudalis, and thalamus, and the evidence of activation of the trigeminal
nucleus caudalis by Glu prompted the hypothesis of its involvement in trigeminovascular activation. More recently, an increased glutamatergic transmission, via N-methyl-D-aspartate (NMDA) and non-NMDA receptor activation, has been advocated in the phenomenon of central sensitization, which plays a pivotal role in head pain chronicity. Preclinical and clinical observations of effectiveness of glutamate receptor-subtype antagonists further argue for a strong link between migraine and the glutamatergic system. Higher plasma levels of Glu and Asp were found in the blood of patients with episodic migraine with aura between attacks than in controls and tension-type headache patients. In addition, patients with migraine without aura (MO) showed low plasma histidine levels. During migraine attacks, Glu, and to a lesser extent, Asp levels were even further increased. These results suggested a defective cellular reuptake mechanism for the two excitatory amino acids. Possibly a similar defect at the neuronal-glial cell level predisposes the brain of migraineurs to develop CSD.

TABLE 34-3 Main Findings Relative to Endogenous Opioids in Peripheral Blood in Migraineurs

β*-Endorphin*		*Authors*	*Between Attacks*	*Attacks*
Plasma and serum		Bach et al. (6)		Reduced levels
		Nappi et al. (67,68)
		Facchinetti et al. (27)
Lymphomonocytes		Leone et al. (54)	Reduced levels compared with controls and tension-type headache patients
		Battistella et al. (9)
Met-enkephalin
	Plasma	Mosnaim et al. (66)	Reduced levels compared with controls	Increased levels
	Platelets	Ferrari et al. (33)	Higher levels compared with controls	Increased release
Dynorphin
	Plasma	Bach et al. (7)	Reduced levels compared with controls

Platelet levels of Glu, Asp, and glycine were measured by D’Andrea et al. (19) in patients with migraine with aura (MA), MO, tension-type headache, and cluster headache. High levels of each were found in patients with MA compared with normal subjects and other headache groups; during headache, glutamate levels further increased in MA patients. Cananzi et al. confirmed these findings (11), but did not find significant changes in plasma and platelet levels of glutamine in MA and MO patients between attacks. They also showed higher plasma Glu levels and normal platelet levels in MO patients, but normal plasma and high platelet glutamate levels in MA patients. These differing peripheral profiles of excitatory amino acids, if reflecting central events, might be associated with susceptibility to CSD in MA compared with MO patients.

Recently, elevated levels of Glu, glutamine, glycine, cysteic acid, and homocysteic acid, with reduction of total thiols (cysteine/cystine) were demonstrated in MA and MO patients compared with tension-type headache patients and normal controls (1). Tryptophan was elevated only in MO. Contradictory results indicated that plasma levels of Glu and Asp were lower in migraine patients than in controls, whereas CSF concentrations of Glu were higher (13,59). These results were interpreted as evidence of an excess of neuroexcitatory amino acids in the CNS of migraine patients during attacks, possibly favoring a state of neuronal hyperexcitability.

In another study, plasma and erythrocyte amino acids were determined in children affected by MA and MO (24); lower plasma Glu and Asp levels and higher erythrocyte/plasma concentration ratios of these amino acids were found with respect to controls. Erythrocyte concentrations of Asp also were significantly elevated in children compared with controls, and erythrocyte concentrations of Glu showed no significant differences. Similar results were observed in both migraine sub-types, suggesting higher activity of the erythrocytes’ Glu/Asp transport system and indirectly similar changes at the neuronal-glial cell level in the CNS.

Elusive Amines

The role of trace amines such as tyramine, octopamine, and synephrine in the pathogenesis of migraine has been debated for decades, but remained for many years unresolved because of the inability to demonstrate specific receptors for these compounds and the lack of sensitive nonradioactive methods for their detection. The recent identification of a new, large family of G-protein-coupled receptors, some of which bind and are activated by trace amines, has focused renewed attention on these compounds. The recent demonstration of an increase of trace amines in the blood not only of migraineurs but also of cluster headache patients provides novel insights into their pathophysiologic role in both primary headaches and
offers new opportunities for pharmacologic strategies acting on their specific receptors (21).

Magnesium

Several clinical and experimental studies carried out in recent years supported the role of magnesium deficiency in contributing to the lower threshold to and in the triggering of migraine attacks (106). The mechanisms through which magnesium deficiency may be involved in migraine are increase in cerebral vascular tone and vasoconstriction (first phase of the migraine aura), increase in neuronal excitability through the activation of NMDA and non-NMDA receptors (responsible for the induction of CSD), increase in platelet aggregability, and increased release of vasoactive neuropeptides from perivascular terminals (migraine pain phase). Magnesium concentrations also influence NO synthesis and release, and the function of a variety of other receptors and neurotransmitters implicated in migraine pathogenesis, including serotonin.

The in vivo evidence for brain Mg²⁺ deficiency, demonstrated by using ³¹P magnetic resonance spectroscopy (MRS) (56,74^*), prompted several authors to investigate magnesium nutritional status in the peripheral blood of migraineurs. Research carried out in both adult and young migraine patients confirmed a reduction of Mg²⁺ levels in blood, serum, red blood cells, and mononuclear cells, as well as in salivary secretions (2,38,41,42,89,92,103). More recent evidence suggests that up to 50% of patients have lowered levels of ionized magnesium (IMg²⁺) during an acute migraine attack, substantiated by the rapid and sustained relief of an acute migraine in such patients with magnesium infusion (61). Evidence for IMg²⁺ deficiency and an elevated ionized calcium/IMg²⁺ ratio during menstrual migraine confirmed previous findings of magnesium deficiency in erythrocytes in menstrual migraine and premenstrual syndrome (28,62). Another aspect of migraine in which magnesium seems to be involved is the so-called neuromuscular hyperexcitability, detected by the electromyographic (EMG) recording of motor unit potential activity during the interictal period (63,64). About two thirds of young and adult migraineurs had low intraerythrocyte and mononuclear cell levels of Mg²⁺, associated with positive ischemic EMG tests.

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