Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V
Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks.
Cephalalgia. 2000 Dec;20(10):907-18.
Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the L-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be confirmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of five patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha, the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the first hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (ANOVA, statistical significance: P<0.001; P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha, as well as cAMP levels also significantly increased at the first hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively). Our results support early activation of the L-arginine/NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase. [Abstract]

Jenkins DW, Feniuk W, Humphrey PP
Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones.
Br J Pharmacol. 2001 Nov;134(6):1296-302.
1. Prostaglandins and the vasodilator neuropeptide, calcitonin-gene related peptide (CGRP), have both been implicated in the pathogenesis of migraine headache. We have used primary cultures of adult rat trigeminal neurones to examine the effects of prostanoids on CGRP release in vitro. 2. CGRP release was stimulated by prostaglandin E2 (PGE2) and the IP receptor agonist, carbaprostacyclin (cPGI2). These responses were extracellular calcium-dependent, and the PGE2-induced CGRP release was unaltered by inhibition of nitric oxide synthase (NOS), ATP receptor blockade, or the addition of adenosine deaminase. 3. Increases in CGRP levels were also observed in response to prostaglandin D2 (PGD2), and the EP2 receptor selective agonist, butaprost. No increases in CGRP release were observed in response to prostaglandin F2alpha (PGF2alpha) or the TP receptor selective agonist, U46619, or the EP3 receptor selective agonist, GR63799X. 4. The selective DP receptor antagonist, BWA868C, antagonized the PGD2-, but not PGE2- or cPGI2-induced release. Furthermore, the EP1 selective antagonist, ZM325802, failed to antagonize the PGE2-induced CGRP release from these cells. 5. These data indicate that activation of DP, EP and IP receptors can each cause CGRP release from trigeminal neurones, and suggest that the predominant EP receptor subtype involved may be the EP2 receptor. Together with evidence that the cyclo-oxygenase inhibitor, aspirin, particularly when administered intravenously is effective in treating acute migraine, these findings further suggest a role for prostaglandins in migraine pathophysiology. [Abstract]

Soragna D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F, Mostacciuolo ML
A locus for migraine without aura maps on chromosome 14q21.2-q22.3.
Am J Hum Genet. 2003 Jan;72(1):161-7.
Migraine is a common and disabling neurological disease of unknown origin characterized by a remarkable clinical variability. It shows strong familial aggregation, suggesting that genetic factors are involved in its pathogenesis. Different approaches have been used to elucidate this hereditary component, but a unique transmission model and causative gene(s) have not yet been identified. We report clinical and molecular data from a large Italian pedigree in which migraine without aura (MO) segregates as an autosomal dominant trait. After exclusion of any association between MO and the known familial hemiplegic migraine and migraine with aura loci, we performed a genomewide linkage analysis using 482 polymorphic microsatellite markers. We obtained significant evidence of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a region of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These results indicate the first evidence of a genetic locus associated with MO on chromosome 14. [Abstract]

OMIM - Online Mendelian Inheritance in Man: Prostaglandin E Receptor 2 (EP2)
[The PTGER2 gene has been located at 14q22]

OMIM - Online Mendelian Inheritance in Man: Prostaglandin D2 synthase
[The PGDS gene has been located at 14q21-q22]

Jenkins DW, Langmead CJ, Parsons AA, Strijbos PJ
Regulation of calcitonin gene-related peptide release from rat trigeminal nucleus caudalis slices in vitro.
Neurosci Lett. 2004 Aug 19;366(3):241-4.
Calcitonin gene-related peptide (CGRP) released from trigeminal primary afferents has been implicated in the pathophysiology of migraine. Here, we have used an in vitro slice preparation to investigate its release from nerve terminals in the rat trigeminal nucleus caudalis. Extracellular-calcium dependent CGRP release was stimulated by both capsaicin and neuronal depolarization with KCl. The capsaicin (1microM)-evoked CGRP release was blocked by capsazepine and was also attenuated in the presence of the cyclooxygenase inhibitor, indomethacin, an effect that was reversed when slices were stimulated with capsaicin in the presence of the cyclooxygenase metabolite, prostaglandin E(2). Taken together, these data further highlight the importance of prostaglandins as enhancers of neuropeptide release and suggest that CGRP released from the central terminals of trigeminal neurones has the potential to be involved in the transmission of nociceptive information of relevance to migraine headache. [Abstract]

Ebersberger A, Averbeck B, Messlinger K, Reeh PW
Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro.
Neuroscience. 1999 Mar;89(3):901-7.
Neurogenic inflammation of the dura, expressed in plasma extravasation and vasodilatation, putatively contributes to different types of headache. A novel in vitro preparation of the fluid-filled skull cavities was developed to measure mediator release from dura mater encephali upon antidromic electrical stimulation of the trigeminal ganglion and after application of a mixture of inflammatory mediators (serotonin, histamine and bradykinin, 10(-5) M each, pH 6.1) to the arachnoid side of rat dura. The release of calcitonin gene-related peptide, substance P and prostaglandin E2 from dura mater was measured in 5-min samples of superfusates using enzyme immunoassays. Orthodromic chemical and antidromic electrical stimulation of dural afferents caused significant release of calcitonin gene-related peptide (2.8- and 4.5-fold of baseline). The neuropeptide was found to be increased during the 5-min stimulation period and returned to baseline (20.9 +/- 12 pg/ml) in the sampling period after stimulation. In contrast, release of substance P remained at baseline levels (19.3 +/- 11 pg/ml) throughout the experiment. Prostaglandin E2 release was elevated during chemical and significantly also after antidromic electrical stimulation (6- and 4.2-fold of baseline, which was 305 +/- 250 pg/ml). Prostaglandin E2 release outlasted the stimulation period for at least another 5 min. The data support the hypothesis of neurogenic inflammation being involved in headaches and provide new evidence for prostaglandin E2 possibly facilitating meningeal nociceptor excitation and, hence, pain. [Abstract]

Davis RJ, Murdoch CE, Ali M, Purbrick S, Ravid R, Baxter GS, Tilford N, Sheldrick RL, Clark KL, Coleman RA
EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries.
Br J Pharmacol. 2004 Feb;141(4):580-5.
1. Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E(2) (PGE(2)) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2. In the presence of indomethacin (3 microm) and the TP receptor antagonist GR32191 (1 microM), PGE(2) was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC(50) 8.0+/-0.1, n=5). 3. Establishment of a rank order of potency using the EP(4)>EP(2) agonist 11-deoxy PGE(1), and the EP(2)>EP(4) agonist PGE(1)-OH (mean pEC(50) of 7.6+/-0.1 (n=6) and 6.4+/-0.1 (n=4), respectively), suggested the presence of functional EP(4) receptors. Furthermore, the selective EP(2) receptor agonist butaprost at concentrations <1 microM failed to relax the tissues. 4. Blockade of EP(4) receptors with the EP(4) receptor antagonists AH23848 and EP(4)A caused significant rightward displacements in PGE(2) concentration-response curves, exhibiting pA(2) and pK(B) values of 5.7+/-0.1, n=3, and 8.4, n=3, respectively. 5. The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC(50) values 8.3+/-0.1 (n=4) and 8.1+/-0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD(2) and PGF(2 alpha) failed to cause appreciable relaxation or contraction at concentrations of up to 30 microm. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC(50) 7.4+/-0.3, n=3). 6. These data demonstrate the presence of prostanoid EP(4) receptors mediating PGE(2) vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated. [Abstract]

Zimmermann K, Reeh PW, Averbeck B
ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater.
Pain. 2002 Jun;97(3):259-65.
Trigeminal afferent neurons express ionotropic P2X receptors for extracellular ATP which are known to be sensitive to low interstitial pH. Both conditions - ATP release and tissue acidosis - may occur in the dura following the ischemia phase of migraine attacks. Aim of this study was to investigate whether and how ATP and protons may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres hemisected scull cavities of adult Wistar rats were used as organ bath of their own lining, the dura mater. The dura was chemically stimulated and the amounts of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2) (PGE(2)) released into incubation fluid were measured using enzyme immunoassays. Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently whereas iCGRP secretion was minimally enhanced only if the dura had previously been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH 5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2) release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M) were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M) suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced facilitation of the proton response. The facilitating effect of ATP was also blocked under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, a P2X-antagonist. The present results provide evidence that ATP has poor, if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings in the isolated dura and its facilitatory action seems to depend on G-protein coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist profile is indicative for the P2Y(2) receptor subtype. [Abstract]

Tulunay FC
NSAIDs: behind the mechanisms of action.
Funct Neurol. 2000;15 Suppl 3202-7.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of compounds. These heterogeneous agents have a similar therapeutic action for the treatment of pain, fever and inflammation. The major mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX), the enzyme catalysing the synthesis of prostaglandins (PGs). Appropriate and effective treatment for migraine depends upon an accurate diagnosis. The goals of treatment are amelioration of the symptoms of an acute attack and prevention of further attacks. [Abstract]

McNeely W, Goa KL
Diclofenac-potassium in migraine: a review.
Drugs. 1999 Jun;57(6):991-1003.
The NSAID diclofenac is a potent inhibitor of prostaglandin synthesis and an established antipyretic and analgesic agent. Diclofenac-potassium was developed as an immediate-release tablet with the aim of providing rapid onset of action after oral administration. This formulation has been investigated in the acute treatment of migraine. Data from available placebo-controlled clinical trials indicate that diclofenac-potassium 50 or 100mg as an immediate-release tablet is more effective than placebo and as effective as oral sumatriptan 100mg and ergotamine plus caffeine at reducing pain intensity in patients with migraine 2 hours after initial administration. Duration of pain relief is similar for the 3 drugs but onset appears to be faster with diclofenac-potassium than with oral sumatriptan or ergotamine plus caffeine. Diclofenac-potassium appears to have favourable effects on some accompanying symptoms such as nausea and vomiting. The frequency of these symptoms was significantly lower with diclofenac-potassium than with sumatriptan in 1 study, although only a few patients had vomiting at baseline. Effects on phonophobia or photophobia did not differ between diclofenac-potassium, sumatriptan and ergotamine plus caffeine. The need for rescue medication is consistently less with diclofenac-potassium than with placebo. Data are inconsistent or scarce regarding the effects of diclofenac-potassium versus placebo on other measures such as headache recurrence and working ability. Diclofenac-potassium was generally well tolerated in clinical trials in patients with migraine. Adverse events reported most frequently (abdominal pain, tiredness and fatigue and nausea) were typically mild to moderate. CONCLUSION: Diclofenac-potassium provides rapid pain relief (within 60 to 90 minutes), is well tolerated and reduces the frequency of some of the accompanying symptoms in patients with migraine. Available trials indicate that diclofenac-potassium provides similar pain relief to sumatriptan and is at least as effective as ergotamine plus caffeine, but appears to have a greater effect on nausea and vomiting than sumatriptan and a faster onset of action than both drugs. Comparisons with other NSAIDs are lacking. Diclofenac-potassium is likely to find a role as a useful first-line option in the acute treatment of migraine. [Abstract]

Castellano AE, Micieli G, Bellantonio P, Buzzi MG, Marcheselli S, Pompeo F, Rossi F, Nappi G
Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications.
Cephalalgia. 1998 Nov;18(9):622-30.
Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks. [Abstract]

Boyle CA
Management of menstrual migraine.
Neurology. 1999;53(4 Suppl 1):S14-8.
Migraines may occur at any time during the menstrual cycle but are commonly associated with the menses. Migraine-specific medications, such as the triptans, may be effective for acute management of menstrual migraine. However, it is important to recognize the relationship between migraines and the menstrual cycle because these headaches may not respond to the usual antimigraine medications. In that case, management may involve perimenstrual migraine prophylaxis, with migraine-specific medications used in addition for severe breakthrough migraines. Prostaglandin inhibitors started just before the time of headache vulnerability may prevent menstrual migraine attacks or reduce the severity of the headaches. Estrogen withdrawal has been shown to precipitate migraine headaches, and a sustained elevated level of estrogen will postpone the migraine. Transdermal estrogen started just before menstruation can provide a sustained low level of estrogen, decreasing the degree of estrogen decline, and thus may prevent induction of migraines. Ergotamine tartrate is usually taken only for acute migraine, but may also be effective for prevention of menstrual migraine when used regularly once or twice per day during the time of risk. By understanding the underlying pathophysiology of the relationship between migraines and the menstrual cycle, the physician can successfully treat migraines associated with menses. [Abstract]

Parantainen J, Vapaatalo H, Hokkanen E
Relevance of prostaglandins in migraine.
Cephalalgia. 1985 May;5 Suppl 293-7.
Prostaglandins (PG), particularly PGE, may be linked to the pathophysiology of migraine in several important ways. PGE1 may "simulate" a migraine attack in healthy volunteers. PGE may be elevated in patients with migraine. In animal experiments and in human infusions, PGEs cause vasodilation and hyperalgesia, both typical reactions of inflammation. The view that vascular headache is an "inflammatory reaction" allows the best concept concerning the local role of PGs and the effectiveness of PG-inhibitors in the treatment of migraine. The local role of PGs may provide a common denominator in several hormonal, neural and other influences on vessels. The common triggers of a migraine attack like menstruation, alcohol and stress influence the PG-system and even the dietary reactions, hormonal influences, sleep and reserpine have some connections with the PG-system. A local role for PGs does not diminish the importance of other pathophysiological mechanisms operating during an attack. On the contrary, PGs may fill in gaps in our understanding of how the overt pain of attacks is produced. [Abstract]

Nattero G, Allais G, De Lorenzo C, Benedetto C, Zonca M, Melzi E, Massobrio M
Relevance of prostaglandins in true menstrual migraine.
Headache. 1989 Apr;29(4):233-8.
Eighteen patients suffering from true menstrual migraine and 12 control subjects were studied. We evaluated in different phases of the menstrual cycle and during the migraine crisis the peripheral plasma concentrations of 6-keto-PGF1 alpha (the stable metabolite of PGI2), thromboxane B2 (the stable metabolite of thromboxane A2), PGF2 alpha and PGE2. The mean values of 6-keto-PGF1 alpha in menstrual migraine sufferers are lower than in normal women throughout the whole cycle. The difference between the trends observed in the two groups is statistically significant (p less than 0.05). The plasma levels of TXB2 and of PGF2 alpha are similar in the two groups investigated, both in basal conditions and during the attack. The plasma concentrations of PGE2 are slightly lower in migraineurs in basal conditions than in normals. However, during the crisis they increase significantly (p less than 0.05). In conclusion, among all the parameters considered, PGE2 seems to play the most important role during the pain phase of the attack. The results of the present study suggest that a deficit of PGI2, one of the most important protecting agents against ischemia, might be a typical feature of menstrual migraine and might cause in these patients a vascular hypersensitivity to different ischemic stimuli. [Abstract]

Stirparo G, Zicari A, Favilla M, Lipari M, Martelletti P
Linked activation of nitric oxide synthase and cyclooxygenase in peripheral monocytes of asymptomatic migraine without aura patients.
Cephalalgia. 2000 Mar;20(2):100-6.
Many reports indicate that nitric oxide (NO) could be involved in migraine without aura (MWA), an extremely diffuse clinical event. Since monocyte may be a relevant source of NO, we analysed monocyte activation in MWA patients, in a period in which they were free of symptoms. NO basal production by MWA peripheral monocytes was significantly higher than in healthy subjects (91.25+/-8.6 microM/10(6) cells vs. 22.6+/-3.2 microM/106 cells). Interestingly, even the release of prostaglandin E2 (PGE2), was higher in MWA patients than in healthy subjects (3137+/-320 pg/10(6) cells vs. 1531+/-220 pg/10(6) cells). The incubation of monocytes from healthy subjects and MWA patients with N-nitro-L-arginine methyl ester caused a marked decrease of both NO and PGE2 release. We hypothesise that NOS and cyclooxygenase pathways in monocytes are linked and are, in MWA patients, up-regulated, even in a symptoms-free period. NO and PGE2 hyperproduction could therefore be involved in the neurovascular modifications leading to migraine attacks. [Abstract]

Gallai V, Sarchielli P, Trequattrini A, Paciaroni M
Monocyte chemotactic and phagocytic responses in migraine and tension-type headache patients.
Ital J Neurol Sci. 1993 Mar;14(2):153-64.
Monocyte chemotactic and phagocytic responses were assessed in two groups of migraine patients (with and without aura) and in two groups of tension-type headache patients (episodic and chronic). The chemotactic but not the phagocytic response, assessed interictally, is significantly lower in migraine patients (p < 0.006) and in episodic tension-type headache patients, though not so significantly in the latter (p < 0.05), than in the control individuals. The chemotactic response tends to increase significantly during attack in migraine patients both with and without aura (p < 0.008 and p < 0.007 respectively). The same was evident for the phagocytic response in both migraine patient groups (p < 0.007 and 0.0004). No modifications of monocyte functions were found during attacks neither in episodic nor chronic tension-type headache patients. These findings suggest that one or more mediators of neurogenic inflammation having phagocytic and chemotactic enhancing properties (substance P, prostaglandin E and thromboxane A2 etc.) are implicated in the modification of monocyte function. The demonstration of a defect in monocyte function during the interictal period in migraine patients confirms the results of recent research which evidenced reduced capacity of monocyte to phagocyte and kill microorganisms in the course of migraine. [Abstract]

Mohammadian P, Hummel T, Arora C, Carpenter T
Peripheral levels of inflammatory mediators in migraineurs during headache-free periods.
Headache. 2001 Oct;41(9):867-72.
OBJECTIVES: The present study investigated the peripheral inflammatory changes of the trigeminovascular system by measuring the inflammatory mediators leukotriene B4 (LTB(4)), prostaglandin E2 (PGE(2)), and thromboxane B2 (TXB(2)) in the nasal fluid, as well as saliva, of patients with migraine. BACKGROUND: Migraine has been hypothesized to be as a result of changes in the peripheral or central nervous system or both. It is still unclear whether peripheral changes in the trigeminovascular system are involved in the pathogenesis of migraine. METHODS: Participants were 18 subjects, 9 patients with migraine and 9 controls, matched for age and sex. Each subject took part in one experimental session during which nasal lavage fluid and saliva samples were collected. These samples were analyzed by competitive enzyme immunoassay using goat anti-rabbit polyclonal antibody. RESULTS: With the exception of TXB(2), correlational analyses indicated good correlations between results obtained using nasal lavage or saliva (LTB(4), r(18) = 0.91; PGE(2), r(18) = 0.95). When comparing inflammatory mediators measured in controls and migraineurs, the LTB(4) level was significantly lower in migraineurs, while no differences were found for PGE(2) and TXB(2). CONCLUSIONS: The study demonstrated that nasal lavage, a noninvasive method, can be easily used for investigations of pathophysiological mechanisms of migraine. In addition, the results may indicate that there is no peripheral trigeminal sensitization in the headache-free period of migraineurs compared with controls when PGE(2), LTB(4), and TXB(2) in saliva and nasal lavage samples are measured. [Abstract]

Bic Z, Blix GG, Hopp HP, Leslie FM, Schell MJ
The influence of a low-fat diet on incidence and severity of migraine headaches.
J Womens Health Gend Based Med. 1999 Jun;8(5):623-30.
Migraine headaches are a common, debilitating syndrome causing untold suffering and loss of productivity. A review of the literature indicates that high levels of blood lipids and high levels of free fatty acids are among the important factors involved in triggering migraine headaches. Under these conditions, platelet aggregability, which is associated with decreased serotonin and heightened prostaglandin levels, is increased. This leads to vasodilation, the immediate precursor of migraine headache. A high-fat diet is one factor that may directly affect this process. This study, undertaken to evaluate the impact of dietary fat intake on incidence and severity of migraine headache, was conducted over a 12-week period on 54 previously diagnosed migraine headache patients. During the first 28 days, the study subjects recorded all food consumption in a diet diary and maintained a headache diary. At the conclusion of this 28-day baseline period, subjects were individually counseled to limit fat intake to no more than 20 g/day. A 28-day run-in period was allowed for adaptation to the low-fat diet. Results are reported on the final 28-day postintervention period. Subjects significantly decreased the ingestion of dietary fat in grams between baseline (mean 65.9 g/day, p < 0.0001) and the postintervention period (mean 27.8 g/day). The decreased dietary fat intervention was associated with statistically significant decreases in headache frequency, intensity, duration, and medication intake (all p < 0.0001). There was a significant positive correlation between baseline dietary fat intake and headache frequency (r = .44, p = 0.02). This study indicates that a low-fat diet can reduce headache frequency, intensity, and duration and medication intake. [Abstract]

Anderson JA
Mechanisms in adverse reactions to food. The brain.
Allergy. 1995;50(20 Suppl):78-81.
Specific chemical mediator release such as histamine and the prostaglandins (PG2a or PGD2) associated with headaches has been found in a few patients who were repeatedly challenged with specific foods, using DBPCFC techniques. [Abstract]

Cerneca F, de Luyk S, Radillo O, Simeone R, Mangiarotti M
Migraine: possible role of platelet insensitivity to prostaglandin E1 (PGE1).
Funct Neurol. 1993 Nov-Dec;8(6):403-8.
Platelet aggregation inhibition, induced by prostaglandin E1 (PGE1), was evaluated in 38 patients affected by migraine. Our data indicate a complete insensitivity to PGE1 in these subjects. The insensitivity to PGE1 leads to decreased cyclic-AMP (cAMP) levels, determining an imbalance in the inhibitory mechanism. From this observation we can suppose that the decreased affinity of PGE1-receptors, causing decreased cAMP levels, may be involved in pathogenesis of migraine. [Abstract]

Mezei Z, Kis B, Gecse A, Tajti J, Boda B, Telegdy G, Vécsei L
Platelet arachidonate cascade of migraineurs in the interictal phase.
Platelets. 2000 Jun;11(4):222-5.
Morphological and functional alterations of platelets in migraineurs may be linked to the development of migraine. We examined the eicosanoid synthesis of platelets of untreated female migraineurs in a headache-free period and compared it to that of age- and blood group-matched healthy female volunteers. In the platelets of headache-free migraineurs significantly less amounts of anti-aggregatory prostaglandin D2 and prostacyclin, as well as of 12-L-hydroxy-5,8,10-heptadecatrienoic acid (a potent endogenous inducer of endothelial prostacyclin production) were produced, while the synthesis of platelet aggregatory thromboxane did not differ when compared to that of healthy women. These results suggest that the platelet eicosanoids of migraineurs in the headache-free period might promote the development of cellular, vascular and neurological events inducing headache. [Abstract]

Helmersson J, Mattsson P, Basu S
Prostaglandin F(2alpha) metabolite and F(2)-isoprostane excretion rates in migraine.
Clin Sci (Lond). 2002 Jan;102(1):39-43.
The pathophysiology theory of migraine postulates a local, neurogenic inflammation and the possible involvement of oxidative stress. We analysed the levels of 15-oxo-dihydro-prostaglandin F(2alpha) (a metabolite of prostaglandin F(2alpha)) and 8-iso-prostaglandin F(2alpha) (a major isoprostane), which are biomarkers for inflammation and oxidative stress respectively, in urine from 21 patients with migraine, with and without aura. Urine samples from migraine patients were collected during a migraine attack, and control samples were collected from the same subjects on a migraine-free morning. The mean basal levels of 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) in the morning control urine samples were 0.54+/-0.11 and 0.31+/-0.13 nmol/mmol of creatinine respectively. The mean levels of 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) in the urine samples collected during the migraine attack in the 21 patients were 0.53+/-0.13 and 0.32+/-0.11 nmol/mmol of creatinine respectively. Thus there were no differences in the 15-oxo-dihydro-prostaglandin F(2alpha) and 8-iso-prostaglandin F(2alpha) excretion rates during the migraine attack compared with on the migraine-free day. However, the basal 8-iso-prostaglandin F(2alpha) excretion levels on the migraine-free day were significantly lower in pre-menopausal women (0.24+/-0.08 nmol/mmol of creatinine, n=11) compared with post-menopausal women (0.39+/-0.14 nmol/mmol of creatinine; n=7; P=0.009). In conclusion, in this study we found no support for the involvement of inflammation and oxidative stress in migraine pathophysiology. Our results indicate, however, a lower level of oxidative stress in pre-menopausal compared with post-menopausal women. [Abstract]

Uchiyama M, Sakai K
Increased main urinary metabolite of prostaglandin F2 alpha excretion in childhood migraine.
Arch Dis Child. 1988 Mar;63(3):342. [Abstract]

Elmquist JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, Saper CB
Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages.
J Comp Neurol. 1997 May 5;381(2):119-29.
Production of prostaglandins is a critical step in transducing immune stimuli into central nervous system (CNS) responses, but the cellular source of prostaglandins responsible for CNS signalling is unknown. Cyclooxygenase catalyzes the rate-limiting step in the synthesis of prostaglandins and exists in two isoforms. Regulation of the inducible isoform, cyclooxygenase 2, is thought to play a key role in the brain's response to acute inflammatory stimuli. In this paper, we report that intravenous lipopolysaccharide (LPS or endotoxin) induces cyclooxygenase 2-like immunoreactivity in cells closely associated with brain blood vessels and in cells in the meninges. Neuronal staining was not noticeably altered or induced in any brain region by endotoxin challenge. Furthermore, many of the cells also were stained with a perivascular microglial/macrophage-specific antibody, indicating that intravenous LPS induces cyclooxygenase in perivascular microglia along blood vessels and in meningeal macrophages at the edge of the brain. These findings suggest that perivascular microglia and meningeal macrophages throughout the brain may be the cellular source of prostaglandins following systemic immune challenge. We hypothesize that distinct components of the CNS response to immune system activation may be mediated by prostaglandins produced at specific intracranial sites such as the preoptic area (altered sleep and thermoregulation), medulla (adrenal corticosteroid response), and cerebral cortex (headache and encephalopathy). [Abstract]

Schepelmann K, Ebersberger A, Pawlak M, Oppmann M, Messlinger K
[Activation of trigeminal brain stem neurons by chemical stimulation of the dura mater encephali--preparation for studying meningeal nociception in the rat]
Schmerz. 1997 Oct 24;11(5):322-7.
INTRODUCTION: Headache is thought to be generated by nociceptive processes within the meninges, followed by activation of trigeminal neurons within the brainstem. The noxious stimuli initially involved in these nociceptive processes are unknown. A preparation was developed in the barbiturate-anesthetized rat, in which the activation of trigeminal brain stem neurons by selective local stimulation of the dura mater could be observed. METHODS: The dura mater encephali was exposed by trepanizing the parietal bone up to the sagittal superior sinus. The surface of the dura was stimulated with electrical pulses using bipolar electrodes. Extracellular recordings were made from neurons in the subnucleus interpolaris and caudalis of the spinal trigeminal nucleus. Neurons driven by meningeal afferents were identified by electrical stimulation and by probing their receptive fields on the dura mater. For chemical stimulation a combination of several inflammatory mediators (bradykinin, serotonin, histamine and prostaglandin E(2), each 10(-4)M, 6.1) was topically applied to the dura mater or injected through a catheter into the sagittal sinus. RESULTS: Most of the trigeminal brain stem neurons with input from the parietal dura mater had convergent input from the facial skin with preponderance of the periorbital region. A high proportion of neurons (69%) could be activated by the combination of inflammatory mediators administered to the dura mater. CONCLUSION: We conclude that chemical stimuli activating the meningeal nociceptive system may play a decisive role in the generation of headache. This is particularly relevant for the nociceptive processes during neurogenic inflammation, which is believed to be an important step in the pathophysiology and development of migraine pain. The preparation presented here may be a valuable model for further studying the neurophysiological changes that are involved in the generation of headache. [Abstract]

Knight YE, Levy MJ, O'Shaughnessy CT, Goadsby PJ
Prostaglandin E2 injected into the posterior hypothalamus has no effect on trigeminal nociception in the rat.
Neurosci Lett. 2003 Oct 23;350(2):85-8.
Craniovascular prostaglandin E2 (PGE2) release is elevated in the headache phase of migraine and in experimental models of headache. PGE2 synthesised in the brain may be involved in modulating trigeminal nociception. We examined whether PGE2 injected into the posterior hypothalamus could modulate trigeminovascular nociception. In seven rats, electrophysiological recordings were made from trigeminal nucleus caudalis neurons responsive to noxious middle meningeal artery stimulation and inhibited by bicuculline activation of the posterior hypothalamus. Microinjection into the posterior hypothalamus of a non-pyrogenic dose of PGE2 (2.5 microg/ml) produced no effect on nociceptive trigeminal nucleus caudalis neurons compared with saline injection (P=0.29). The mean response to PGE2 injection was 97% of baseline. We conclude that PGE2 in the posterior hypothalamus is unlikely to play a significant role in modulating trigeminal nociception. [Abstract]