Diet-induced obesity alters dural CGRP release and potentiates TRPA1-mediated trigeminovascular responses.

Background Clinical studies suggest a link between obesity and the primary headache disorder migraine. In our study we aimed to reveal the effect of obesity on meningeal nociceptor function in rats receiving a high-fat, high-sucrose diet. Methods Transient receptor potential ankyrin 1 (TRPA1) receptor activation-induced changes in meningeal blood flow, release of calcitonin gene-related peptide (CGRP) from trigeminal afferents and TRPA1 protein expression in the trigeminal ganglia were measured in control and obese rats. Metabolic parameters of the animals were assessed by measuring glucose and insulin homeostasis as well as plasma cytokine concentrations. Results The present experiments revealed an enhanced basal and TRPA1 receptor agonist-induced CGRP release from meningeal afferents of obese insulin-resistant rats and an attenuated CGRP release to potassium chloride. Obesity was also associated with an augmented vasodilatation in meningeal arteries after dural application of the TRPA1 agonist acrolein, a reduction in TRPA1 protein expression in the trigeminal ganglia and elevations in circulating proinflammatory cytokines IL-1ß and IL-6 in addition to increased fasting blood glucose and insulin concentrations. Conclusions Our results suggest trigeminal sensitisation as a mechanism for enhanced headache susceptibility in obese individuals after chemical exposure of trigeminal nociceptors.

The role of nitric oxide in vascular headache.

Shortly after the invention of nitroglycerin (NTG), it was noticed that this substance is capable of inducing a violent headache. Only recently, it became known that this was due to the release of nitric oxide (NO) by NTG. As the molecular mechanism of migraine pain remains to be determined, NTG, being pro-drug for NO, has been used to study the aetiology and pathophysiology of migraine. Such studies with NTG- and also histamine-induced headaches, have led to propose that NO may be the causative molecule in migraine pain. The evidence supporting the role of NO in migraine is discussed, e.g. substances capable of inducing experimental vascular headache do so with NO as the common mediator, while drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. The importance of NO as a potential initiator of the migraine attack opens new directions for the pharmacological treatment of migraine and other vascular headaches.

Pathophysiology of primary headaches.

The cerebral circulation is innervated by sympathetic, parasympathetic, and sensory nerves, which store a considerable number of neurotransmitters. The role of these has been evaluated in primary headaches. A clear association between head pain and the release of calcitonin gene-related peptide was demonstrated. In cluster headache and in a case of chronic paroxysmal headache there was in addition the release of vasoactive intestinal peptide, which was associated with the facial symptoms (nasal congestion, rhinorrhea). In parallel with sumatriptan treatment, head pain subsided and neuropeptide release normalized. These data show the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headaches.

[Peptide modulation in vascular headache]. / Peptiderg modulering ved vaskulaer hodepine.

This article reviews recent developments in the field of vasoactive peptides in relation to certain types of headache. The equilibrium existing in the brain between contraction and dilatation of blood vessels is controlled by, among other factors, vasoactive peptides. Several of these have been discovered only recently and constitute a rapidly expanding field of research with exciting perspectives. Cranial blood vessels are innervated by sympathetic, parasympathetic and sensory nerve fibres, all of which contain certain vasoactive peptides as co-transmitters. Others, like endothelin, can be produced by the endothelium. There is evidence to suggest that vasoactive peptides of the trigeminovascular system are liberated in response to abnormal constriction of cranial blood vessels and contribute to headache. New drug therapies based on the activity of such substances are now being developed.

Defective expression of IL-2 receptors on peripheral blood lymphocytes from patients with cluster headache.

In a previous study we demonstrated that cluster headache (CH) patients present an increased Natural Cytotoxic response after incubation of their peripheral blood lymphocytes (PBL) with Interleukin-2 (IL-2). This phenomenon led to an investigation of the phenotypic expression of PBL before and after IL-2 incubation, and of the IL-2 lymphocyte receptor. IL-2 receptor is expressed on T-lymphocytes activated with an high-affinity binding site. The analysis of the function of human IL-2 receptor was facilitated by the production of a specific monoclonal antibody (MAb). This MAb identifies the IL-2 receptors by blocking the binding of radiolabelled IL-2 to T-cells. In addition, we studied the expression of Leu-4, specific for T-cells; of Leu-11b, specific for FC receptor on NK cells; and the Transferrin Receptor, specific for lymphoblasts and monocytes. Twenty-three episodic CH patients were selected for this study. Ten sex and age-matched healthy volunteers were used as the control group. We evaluated the PBL phenotypic expression of cells subsets before incubation with IL-2 (1,000 I.U./ml) and after 72 hours. The following Becton Dickinson MAbs have been used: anti-Leu-4 (CD3), anti-IL-2 receptors (CD25), anti-Transferrin receptor (TFR) and anti-Leu-11b (CD16). Indirect fluorescence with a Becton Dickinson FACS-420 flow cytometer was used to analyze the cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensory neuropeptides (substance P, calcitonin gene-related peptide) and vasoactive intestinal polypeptide in human saliva: their pattern in migraine and cluster headache.

Substance P, calcitonin gene-related peptide and vasoactive intestinal polypeptide-like immunoreactivities have been evaluated in the saliva of 15 subjects suffering from migraine without aura and 16 control subjects. All three peptides were also measured in the symptomatic/non-symptomatic side saliva sampled from 10 cluster headache sufferers during the cluster period, 5 cluster headache sufferers out of the cluster period, as well as in the right and left side saliva of 18 control subjects. The most interesting result gives a clear difference in common migraine and cluster headache salivary vasoactive intestinal polypeptide-like immunoreactivity contents. In fact, these are enhanced during cluster headache attack and decreased during migraine attack when compared with the interictal period vasoactive intestinal polypeptide-like immunoreactivity levels. Another remarkable finding concerns the significant increase of substance P-like immunoreactivity and calcitonin gene-related peptide-like immunoreactivity levels, from basal values, in the saliva sampled during both migraine and cluster headache attacks. Control subjects showed a calcitonin gene-related peptide-like immunoreactivity and substance P-like immunoreactivity salivary contents significantly higher than migraine sufferers' saliva sampled in basal conditions. Conversely, calcitonin gene-related peptide-like immunoreactivities levels in controls were lower than in cluster headache sufferers' saliva obtained during intervals. Finally, during cluster headache attacks the enhancement of substance P-like immunoreactivity and vasoactive intestinal polypeptide-like immunoreactivity salivary contents interest the non-symptomatic side, whereas the symptomatic side salivary substance P-like immunoreactivity and vasoactive intestinal polypeptide-like immunoreactivity contents remain unchanged. These findings do not allow any final conclusion. However, this biochemical evaluation indicates relevant changes of the salivary neuropeptides in diseases, such as migraine and cluster headache, in which pain transmission is surely involved.

[Immunologic and biochemical changes in patients with cranio-facial pain]. / Immunologicheskie i biokhimicheskie izmeneniia u bol'nykh kranio- fatsialgiiami.

The authors provide the results of an analysis of the interrelation between the immunologic and biochemical parameters in 6 groups of patients suffering from facial pains or headaches (a total of 153 patients). Significant correlations were revealed in the patients' groups with trigeminal neuralgia and periodic migrainous Horton's neuralgia. The main attention was concentrated on the following parameters: IgA in the serum, secretory IgA in the patients' saliva, % CD4 of lymphocytes and histamine concentration in the peripheral blood, concentration of beta-endorphin in the plasma, catecholamine content in the urine.

Cluster headache in the male: sex steroid pattern and gonadotropic response to luteinizing hormone releasing hormone.

Serum testosterone, dihydrotestosterone, delta 4-androstendione and 17 beta-estradiol, sex hormone binding globulin (SHBG) and gonadotropic response to luteinizing hormone releasing hormone (LHRH) were studied in 34 male subjects with episodic or chronic cluster headache (CH). The sex steroid free fractions and those bound to SHBG and albumin were determined by a simulatory computerized method based on the mass action law. Individual steroid values were dispersed over a wide range in CH patients. Total, free and carrier protein-bound testosterone levels were significantly diminished only in chronic CH, where luteinizing hormone (LH) peak values after intravenous administration of LHRH were also decreased. Basal and peak follicle stimulating hormone (FSH) levels were significantly increased in episodic and in chronic CH groups, in comparison to healthy controls.

[Vascular headache, thrombopenia and serotonin metabolism]. / Céphalées vasculaires, thrombopénie et métabolisme de la sérotonine.

The role of platelet serotonin in migraine remains a subject of controversy. However, the frequency of association of migraine with antibody-mediated thrombocytopenia would suggest that platelet dysfunction or impaired serotonin metabolism might play a role in migrainous attack. We report three new cases, two involving chronic idiopathic thrombocytopenia and one lupus. The observation of high levels of anti-platelet antibodies in close correlation with the occurrence of attacks suggests that the Serotonin Releasing Factor (SRF) could be concerned. This was suspected previously on the basis of in vitro studies. The hypothesis that other forms of migraine might be linked to an immunopathological process involving other immunoglobulins is proposed (Acta neurol. belg., 1988, 88, 290-296).

Substance P in the human iris: possible involvement in echothiophate-induced miosis in cluster headache.

Substance P-like immunoreactivity (SP-LI) was measured by radioimmunoassay in iris, choroid, and retina obtained from men after death. Although present in different amounts, SP-LI, eluting as authentic SP or SP sulfoxide in the high-performance liquid chromatography system, was found in the three ocular structures. The retina contained higher concentrations of SP-LI than the iris and choroid. The possible functional involvement of iris SP was studied in 22 episodic cluster headache (CH) patients by using the anticholinesterase agent echothiophate iodide (EI), which also induces an atropine-resistant miosis, putatively due to release of SP from trigeminal sensory neurons. In CH patients EI eye drops instilled into both eyes provoked a prolonged miosis with a more marked response in the pupil of the symptomatic eye. It is proposed that the hyperfunction of SP-containing neurons may coexist with the previously documented sympathetic hypofunction in the innervation of the symptomatic pupil of CH.

Substance P mechanism in cluster headache: evaluation in plasma and cerebrospinal fluid.

Substance P (SP), present in sensory afferent neurons, seems to process nociceptive information in the trigeminal system. SP, released from peripheral trigeminal endings, causes typical cluster headache (CH) signs, e.g. vasodilatation, conjunctival and nasal edema and miosis. Opiates and somatostatin (SRIF), both active in relieving CH attack, inhibit SP release from the central and peripheral trigeminal system. In the present study, plasma and cerebrospinal fluid (CSF), SP-like immunoreactivity (SPLI) and enkephalinase activity (EKA), and plasma SRIF-like immunoreactivity (SRIFLI) have been evaluated during spontaneous and histamine induced attacks in the cluster phase. During the histamine provoked attacks, CSF SPLI and plasma SRIFLI and EKA were unchanged, while plasma SPLI decreased significantly. During spontaneously occurring attacks, plasma SRIFLI was found to be unmodified and a significant lowering of SPLI was detected when compared with controls. Moreover, both during and between attacks in the cluster phase, plasma EKA was increased in comparison with the values in controls. It remains to be seen whether variations of plasma SPLI and EKA levels play a role in the CH mechanism.

Endocrinological responses in cluster headache.

Growth hormone and prolactin levels and their response to various stimuli were studied in patients with cluster headache. All the endocrine responses evaluated were normal.

A putative 5-HT central feedback in migraine and cluster headache attacks.

5-HT is considered to play a role in the migraine mechanism; its decrease in the midbrain during migraine attacks has been postulated. CSF TP and plasma and platelet 5-HT levels in migraine and cluster headache sufferers have been evaluated; the values registered were compared to those of neurological and carcinoid patients, respectively. The following results were obtained: (a) no significant difference in the time course of free and total TP after l-TP intravenous loading, (b) increased levels of CSF TP during migraine and cluster headache attacks, (c) impressively increased levels of plasma 5-HT only in carcinoid patients. These findings suggest the existence of a positive 5-HT central feedback mechanism during attacks of migraine and cluster headache and thus exclude peripheral 5-HT effects in the generation of pain.

Low biological availability of ergotamine tartrate after oral dosing in cluster headache.

An attempt was made to determine the plasma ergotamine concentrations in nine male patients with cluster headache 15-600 min after oral therapeutic doses of ergotamine tartrate (Cafergot). Some of the patients were studied twice. Five patients received a constant dose of 2-4 mg daily for at least seven days. Four patients were given 1 mg five times on one day and three patients a single oral dose of 2 mg. Ergotamine was determined by means of high performance liquid chromatography with fluorescence detection--a new highly sensitive, specific method, the detection limit of which is less than 100 pg/ml for ergotamine. Ergotamine tartrate was not discovered in any of the plasma samples. In one patient ergotamine could not be detected in the cerebrospinal fluid one hour after a single oral dose of 2 mg. The oral biological availability is less than 1%, which is the maximal available fraction of unchanged ergotamine after oral administration. A clinical benefit was observed in several of our patients. These effects of the drug may be because of active metabolites being formed and/or to high affinity of ergotamine to cranial vessels.

[Xylose test in patients with attacks of headaches (migraine, Horton's headache)]. / Test ksylozowy u chorych z napadowymi bólami glowy (migrena, ból glowy Hortona).

The aim of this work was to study digestive tract function by means of xylose test in patients with attacks of headaches. The investigations were carried out in 14 patients with migraine, 10 with Horton's headache and 1 patient with both these conditions. In patients with migraine or Horton's headache the xylose test was normal in 65% of cases, in the remaining 35% (8 patients, 4 in each group) xylose elimination was abnormal, because it was below 30%. The authors discuss the factors which could influence the abnormal results of xylose test in these patients, since they had no signs of other diseases than the mentioned headaches.

Histamine metabolism in cluster headache and migraine. Catabolism of 14C histamine.

Various parameters of histamine metabolism were studied in patients with migraine, cluster headache and chronic paroxysmal hemicrania. These included urinary excretion of radioactivity and of 14C histamine and its metabolites, exhaled 14CO2 and fecal radioactivity after oral as well as subcutaneous administration of radioactive histamine. No marked deviation from the normal was found except in one patient with the cluster headache variant, chronic paroxysmal hemicrania, in whom an aberration in 14C histamine degradation seemed to be present. Only minute quantities of the 14C histamine metabolite C14 imidazoleacetic acid riboside seemed to be formed during a period with severe paroxysms. During a symptom-free period no deviation from normal was observed. The most likely explanation for this finding seems to be a defect in the conversion of imidazoleacetic acid to its riboside. This defect may possibly explain the increased urinary excretion of histamine in this particular patient. The relationship of this metabolic aberration to the production of headache still remains dubious for various reasons.