Review
Introduction
Serotonergic biology and genetics
Enzyme | Gene | Locus | Function | Significance for migraine |
Tryptophan hydroxylase 1 | TPH1 | 11p15.3-p14 | TPH1, peripheral form, converts tryptophan to 5 hydroxy tryptophan, rate-limiting step in the synthesis of 5-HT, determines the availability of 5-HT and its rate of production. | TPH enzymes regulate brain-specific serotonin deficiency, weak association [43]. |
Tryptophan hydroxylase 2 | TPH2 | 12q21.1 | TPH2, neuronal form, synthesis of serotonin. | |
Monoamine oxidase A | MAO-A | Xp11.3 | MAO-A, outer mitochondrial membrane, oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. | Enzymes metabolise triptans. |
Monoamine oxidase B | MAO-B | Xp11.23 | MAO-B, both subtypes have a widespread occurrence in the brain and in peripheral tissues. | MAO inhibitors promote the accumulation of monoamines and reduce uncontrolled vasodilation, and were used in treating migraine but discontinued due to side effects [73]. |
Amino acid decarboxylase | DDC | 7p12.2 | DDC, catalyses the decarboxylation of L-5-hydroxytryptophan to 5-HT and L-tryptophan to tryptamine. | Gene variations have been investigated in relation to neuropsychiatric disorders. |
Aldehyde dehydrogenase 2 | ALDH2 | 12q24.2 | ALDH2, located in mitochondria produce 5-hydroxyindole acetic acid as the major excreted metabolite of serotonin. | |
Receptor Protein | Gene | Locus | Potential and mechanism | Significance for migraine |
5HT1 | HTR1A | 5q11.2-q13 | Inhibitory, decreasing cellular levels of cAMP | |
HTR1B | 6q13 | Triptans have high affinity for serotonin receptors. | ||
HTR1D | 1p36.3-p34.3 | |||
HTR1E | 6q14-q15 | |||
HTR1F | 3p12 | Lasmiditan is a 5-HT1F receptor agonist by non-vascular mechanism [75]. | ||
5HT2 | HTR2A | 13q14-q21 | Excitatory, increasing cellular levels of IP3 and DAG | Cortical density of the excitatory 5-HT2 receptor, which is involved in pain processing, is not altered interictally in migraine patients [76]. |
HTR2B | 2q36.3-q37.1 | |||
HTR2C | Xq24 | Positive association in SNP in HTR2C promoter in Turkish population with migraine [40]. | ||
5HT3 | HTR3A | 11q23.1 | Excitatory, depolarizing plasma membrane | Role in facilitation of inflammatory and neuropathic pain [77]. |
HTR3B | 11q23.1 | |||
HTR3C | 3q27.1 | |||
HTR3D | 3q27.1 | |||
HTR3E | 3q27.1 | |||
5HT4 | HTR4A | 5q31-q33 | Excitatory, increasing cellular levels of cAMP | Central 5-HT4 receptor binding might serve as a biomarker of serotonergic tonus in the human brain [78]. |
5HT5 | HTR5A | 7q36.1 | Inhibitory, Decreasing cellular levels of cAMP | |
HTR5B | 2q14.1 | |||
5HT6 | HTR6A | 1p36-p35 | Excitatory, increasing cellular levels of cAMP | |
5HT7 | HTR7A | 10q21-q24 | Excitatory, increasing cellular levels of cAMP | |
Transporter protein | Gene | Locus | Function | Significance for migraine |
Serotonin transporter, SERT | SLC6A4 | 17q11.2 | Reuptakes serotonin from the synapse, role in psychiatric disease | |
Plasma membrane monoamine transporter, PMAT | SLC629A4 | 7p22.1 | Transport of both serotonin and dopamine |
Migraine therapy and triptans
Metabolic routes of serotonin
Reference | Study design | Cases and migraine type | Daily dose and duration | Primary endpoint | Result |
---|---|---|---|---|---|
Peres et al., 2004 [122] | open-labelled | Total adults, 32 | 3 mg/day, 30 min before bedtime for 3 months | Percentage of patients with >50% reduction in migraine frequency | positive |
Miano et al., 2008 [123] | open-labelled | Total children, 22 13 MO 1 MA 8 CTTH | 3 mg/day for 3 months | Reduced the frequency of headache attacks by >50% from baseline | positive |
Alstadhaug et al., 2010 [124] | randomized, double-blind, placebo-controlled crossover study | Total adults, 46 25 MO 13 MA | 2 mg/day prolonged release melatonin, given 1 h before bedtime for 2 months | Migraine attack frequency (AF) | negative |
Fallah et al., 2015 [125] | open-labelled, non-randomized, uncontrolled | Total children, 60 32 MO 28 MA | 0.3 mg/kg for 3 months | Percentage of patients with >50% reduction in migraine frequency | positive |
Bougea et al., 2016 [120] | open-labelled | Total children, 41 12 TTH 37 M | 4 mg/day 30 min before bedtime for 6 months | Reduced headache frequency | positive |
PET imaging studies of serotonin
Biochemical studies of serotonin in CSF and saliva
Biochemical studies of serotonin in platelets
Reference | Substance | Material and methods | Cases/ Controls | Results |
---|---|---|---|---|
(Dalsgaard-Nielsen et al., 1974) [210] | 5-HT | 5-HT in platelets estimated by Udenfriends method | M = 8 NC = 10 | No change in the uptake or the endogenous release of 5-HT |
(Kalendovsky , 1975) [211] | 5-HT | Platelets from whole venous blood | M = 19 NC = 23 | Migraine patients demonstrate platelet hyperaggregability more than normal subjects to all aggregating agents tested |
(Dvilansky et al., 1976) [184] | 5-HT | Platelets | MO = 22 MA = 16 | Plasma during attacks released significantly more 5-HT |
(Muck-Seler et al., 1979) [212] | 5-HT | Platelet poor-plasma (PPP) using spectrophotofluorimetric method of Crawford and Rudd | M = 24 NC = 25 | Unchanged 5-HT platelet level during migraine attack |
(Rolf et al., 1981) [213] | 5-HT | Platelets | MCH = 23 NC = 20 | ↓ 5-HT observed in patients with muscle contraction headache |
(Carroll et al., 1982) [214] | 5-HT | Platelets | MO = 25 NC = 18 | ↓ reduced transport of 5-HT in platelets |
(Oxman et al., 1982) [215] | 5-HT | Platelets | M = 16 NC = 10 | Membrane lipid composition may play a role in disease |
(Launay et al., 1982) [216] | 5-HT | Platelets | MO = 11 NC = 15 | ↓ Kinetic factor Vmax and K
m, PRP 5-HT levels |
(Pradalier et al., 1983) [217] | 5-HT | Platelets | MO = 19 NC = 15 | Unconjugated serotonin concentration was decreased during the attacks and decrease in 5-HT uptake by platelets, with a fall in Km and Vmax |
(Kruglak et al., 1984) [218] | 5-HT | Platelets | M = 18 NC = 26 | Increased aggregability during attacks |
(Lechner et al., 1985) [219] | 5-HT, EN, ADP | Optical density method | M =14 NC = 30 | ↑ enhanced platelet aggregation and platelet sensitivity in migraine patients |
(Lingjaerde, 1986) [220] | 5-HT | Platelets in platelet rich-plasma (PRP). This method measures Km and Vmax | MO = 14 MA = 10 NC = 25 | The size of the granular compartment was larger for classic than for common migraine, and the efflux rate from compartment III was |
(Shukla et al., 1987) [221] | 5-HT | Platelets | TTH = 20 M = 19 NC = 15 | ↑ uptake of 5-HT in platelets |
(Kozubski et al., 1987) [222] | 5-HT | Platelets | M = 12 NC = 10 | ↑ Increased number and affinity of fibrinogen receptors on the platelet surface in migraineurs. |
(Joseph et al., 1988) [223] | 5-HT | Plasma | MO = 7 MA = 5 NC = 6 | Abnormal sensitivity to PAF |
(D'Andrea et al., 1989a) [224] | 5-HT, DA, E, NE, | Platelets obtained from PRP from whole blood HPLC colourimetric detection | MO = 19 MA = 9 NC = 15 | High NE levels and low 5-HT/NE ratio in platelets of patients with MA platelet dense body hyposecretion |
(D'Andrea et al., 1989b) [225] | 5-HT | Platelets | MO = 19 MA = 9 NC = 15 | Adhesion, surface activation, aggregation were investigated. Platelet dense bodies were increased. Increase in the content of serotonin, not evident in MA |
(Herman et al., 1989) [226] | 5-HT | Platelet aggregation was monitored using PRP, in a computerized four-channel aggregometer (CARAT) | M = 10 NC = 9 | PAF may be involved in the 'pathogenesis of migraine and suggest that specific PAF receptor antagonists or synthesis blockers may help in the therapy of this disease |
(Takeshima et al., 1989) [227] | 5-HT | Cold pressor test. Blood was sampled three times through the three-way cock: before the stimulus, 1 min after the start of the stimulus, and 5 min after the start of the stimulus | MCH = 15 M = 13 NC = 14 | Both PF4 and NE increased significantly, whereas FFA showed no remarkable changes. The increase of PF4, however, was independent of NE increase and FFA changes |
(Riddle et al., 1989) [228] | 5-HT | Electron microscope | MO = 21 MA = 15 NC = 15 | Demonstrated structural alterations and increase in the number of dense bodies |
(Kovacs et al., 1990) [179] | 5-HT | Platelets in platelet rich-plasma (PRP) | MO = 17 MA = 14 NC = 13 | Migraineurs have altered platelet aggregation properties and PAF may play a role. The EC50 value for ADP and platelet-activating factor were significantly higher. |
(Govitrapong et al., 1992) [229] | 5-HT | Platelets | M = 12 NC = 12 | ↓ in the maximal number of receptors (Bmax) on platelet membrane of migraine patients when compared to the normal healthy group |
(Cotrim et al., 1993) [230] | 5-HT | Platelet membrane fluidity was measured using the fluorescent probe TMA-DPH | MO = 11 MA = 20 NC = 17 | Migraine have decreased membrane fluidity |
(Jensen, 1994) [231] | 5-HT | Platelet poor-plasma (PPP) | TTH = 13 NC = 29 | Increased 5HT during attacks |
(Kitano et al., 1994) [232] | 5-HT | Platelets | MO = 19 MA = 10 TH = 22 NC = 27 | ↑ 11-dehydrothromboxane B2, platelet hyperfunction |
(Jarman et al., 1996) [233] | 5-HT | Platelets [14C]5HT release measured by Lingjaerde and Monstad method | M = 8 NC = 10 | No change in release of platelet 5-HT |
(Fioroni et al., 1996) [234] | 5-HT, 5-HIAA, MAO-B | Platelets | M = 7 NC = 8 | ↓ reduced 5-HT and ↑ increased 5HIAA in luteal phase, suggesting a greater susceptibility |
(Srikiatkhachorn, 1996) [235] | 5-HT | Platelets in platelet rich-plasma (PRP) | M = 20 NC = 20 | ↓ Kinetic factor Vmax and K
m, = uptake of 5-HT |
(Pukhal'skaya et al., 1998) [236] | 5-HT | Platelets in platelet rich-plasma (PRP) | M = 8 NC = 8 | 5-HT transport systems in migraine patients and healthy donors are different |
(Oishi, 1998) [237] | 5-HT | Platelets | ETH = 10 CTH = 10 NC = 10 | ↑ platelet factor 4, D-thromboglobulin, thromboxane B, and 1 1-dehydrothromboxane B, concentrations in the plasma were significantly higher in the episodic tension- type headache group |
(Srikiatkhachorn, 1998) [238] | 5-HT | Platelets | M = 10 AAG = 10 NC = 10 | Excessive use of analgesics depletes 5-HT from its storage sites and results in the hyposerotonergic state. |
(Sarchielli et al., 2004) [239] | 5-HT | Platelet-activating factor (PAF) HPLC radioimmunoassay method, internal jugular venous blood | MO = 5 | ↑ production of PAF levels no change in activity of PAF acetyl-hydrolase (PAF-AH), enzyme involved in the catabolism of this phospholipid mediator, in migraine attacks |
(Yucel et al., 2014) [240] | 5-HT | Blood fibrinogen, D-dimer, galectin-3 determined by ELISA | M = 59 NC = 30 | ↑ levels of fibrinogen, D-dimer, galectin-3 in migraine patients ↑ higher D-dimer levels during migraine attacks may indicate hypercoagulability |
Reference | Substance | Material and methods | Cases/ controls | Results |
---|---|---|---|---|
(Couch, 1976) [241] | 5-HT | Platelet aggregation was tested to 1.7uM adenosine diphosphate employing light transmission methods modified after Born | M = 33 NC = 33 | ↑ platelet aggregability was measured by a) grading aggregation curves and b) by measuring percent disaggregation 3 min after peak aggregation was less |
(Couch, 1977) [242] | 5-HT | Platelets, optical density methods | M = 46 NC = 46 | ↑ migraine patients demonstrate platelet hyperaggregability, lower threshold for the platelet-release reaction and increased platelet stickiness following aggregation |
(Deshmuck, 1977) [243] | 5-HT | Platelets | M = 27 NC = 35 | Platelet adhesiveness to glass beads and platelet aggregation response to ADP, epinephrine, thrombin and serotonin increased during the prodrome phase of migraine |
(Manotti et al., 1983) [244] | 5-HT | ADP induced platelet aggregation, ADP threshold concentration, platelet malondialdehyde production stimulated by thrombin, Beta-Thromboglobuli level in PPP | M = 30 NC = 30 | Significant activation of platelet function |
(Waldenlind et al., 1985) [245] | Platelets | Platelets | CH = 33 M = 34 NC = 50 | ↓ Kinetic factor Vmax and K
m, = uptake of 5-HT |
(Buttinelli et al., 1985) [246] | 5-HT | Platelet Aggregate Ratio (PAR) studied by Wu and Hoak’s technique | MO = 37 MA = 20 CM = 16 NC = 90 | ↑ circulating platelet aggregates |
(Walkowiak et al., 1989) [247] | 5-HT | Platelets and radioimmunoassay | MO = 34 NC = 28 | Migraineurs have a higher receptor capacity for fibrinogen in platelets activated by ADP |
(Joseph et al., 1989) [248] | 5-HT | Platelets | M = 66 NC = 64 | Increased number of dense bodies; altered coupling of 5-HT secretion from dense bodies and ionised calcium; decreased serotonin secretion. |
(Ribeiro et al., 1990) [249] | 5-HT, 5-HIAA | Serum serotonin (5-HT) measured by HPLC-EC | MO = 58 MA = 43 TH = 10 NC = 39 | Significant decrease in Bmax, which suggests down-regulation of 5-HT2 receptors |
(Jha et al., 1992) [250] | 5-HT | Platelets | MA = 40 | ↑ platelet aggregation during the aura and headache phase of the migraine attack |
(Leira et al., 1993) [251] | 5-HT | Platelets in platelet rich-plasma (PRP) | TTH = 30 NC = 20 | No change in PRP 5-HT levels |
(D'Andrea et al., 1994) [178] | 5-HT | Platelet-rich plasma (PRP) Serotonin was measured by HPLC and platelet factor 4 (PF4) with an enzyme immunoassay kit | MO = 41 MA = 62 NC = 26 | Increased basal platelet 5-HT and increased 5-HTsecretion induced by both collagen and |
(D'Andrea et al., 1995) [252] | 5-HT | Platelet-rich plasma (PRP) | MO = 41 MA = 62 TH = 28 NC = 26 | Plasma and platelet 5-HT peak in MM in ovulatory phase; 5-HT peak evident in follicular phase in TH and controls. |
(Allais et al., 1997) [253] | 5-HT | Platelet aggregation was stimulated by ADP 1 μM during the luteal phase of the menstrual cycle in Menstrual migraine patients | MM = 46 NC = 27 | ↑ platelet aggregation during luteal phase of the menstrual cycle |
(Zeller et al., 2005) [254] | 5-HT | Platelets during attack free interval | MO = 48 MA = 25 NC = 72 | MA patients ↑ numbers of aggregates MO patients ↑ numbers of platelet-leucocyte aggregation and activation-dependent epitope expression |
(Taffi et al., 2005) [255] | 5-HT | Platelets in platelet rich-plasma (PRP). Membrane Na+/K + −ATPase activity and fluidity were determined with the fluorescent probes TMA-DPH and DPH | MO = 57 NC = 35 | Migraine patients show intercritic changes in platelet membrane fluidity and activity that may be related to the oxidative stress caused by increased ONOO– levels |
(Yucel et al., 2014) [240] | 5-HT | Blood fibrinogen, D-dimer, galectin-3 determined by ELISA | M = 59 NC = 30 | ↑ levels of fibrinogen, D-dimer, galectin-3 in migraine patients ↑ higher D-dimer levels during migraine attacks may indicate hypercoagulability |
Biochemical studies of serotonin in plasma
Biochemical studies of serotonin in urine
Reference | Migraine classification | Controls/cases | Sample tested | Levels | Controls/cases | Sample tested | Levels |
---|---|---|---|---|---|---|---|
(Sicuteri et al., 1961) [17] | Not reported | Controls: 15 | Urine | ||||
M: 15 | ↑ | ||||||
(Curran et al., 1965) [187] | Not reported | Controls: 10 | Urine | Controls: 21 | Plasma | ||
M: 18 | ↑ | M: 11 | ↓ | ||||
(Curzon et al., 1966) [149] | Not reported | Controls: 4 | Urine | ||||
M: 9 | = | ||||||
(Kangasni et al., 1972) [149] | Not reported | Controls: 6 | Urine | Controls: 6 | CSF | ||
M: 9 | ↑ | M: 14 | ↑ | ||||
(Deanovic et al., 1975) [190] | (Headache, 1962) [193] | Controls: 4 | Urine | ||||
M: 14 | ↑ | ||||||
(Bousser et al., 1986) [191] | (Headache, 1970) [194] | Controls: 33 | Urine | ||||
M: 44 | ↓ | ||||||
(Milovanovic et al., 1999) [186] | (ICHD-I, 1988) [195] | Controls: 11 | Urine | Controls: 5 | Plasma | ||
M: 8 | ↓ | M: 5 | ↑ | ||||
TTH: 10 | ↓ | TTH: 7 |