Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasodilation has been implicated in the pathophysiology of some headaches, but the mechanisms behind such abnormalities remain unknown. Calcitonin gene related peptide (CGRP), a peptide present in sensory trigeminal fibres, induces strong and long lasting vasodilation in cranial vessels, and has been found to be increased in jugular blood during migraine attacks. Endothelin (ET) is a recently identified potent vasoconstrictor peptide, which also induces long-lasting responses. ET-CGRP interactions may be of importance in vascular beds putatively involved in pain development in the head, and were therefore studied in isolated porcine ophthalmic arteries. Both peptides were found to induce strong and long-lasting reactions in this artery. CGRP decreased ET-induced contractions and ET decreased CGRP-induced relaxations. These effects were additive rather than synergistic.
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PMID:Mutual modification of vasoactivity by calcitonin gene-related peptide and endothelin-1 in isolated porcine ophthalmic artery. 147 29

These studies of cluster headache (CH) focus on two key features of pain transmission: a) sensory nerves when stimulated, as well as the expected afferent transmission, also display an efferent function which affects capillaries, glands, and smooth muscle (of the iris in CH); substance P (SP) and allied transmitters such as Vasoactive Intestinal Peptide (VIP) and Calcitonin Gene-Related Peptide (CGRP) are the main agonists of this dual afferent-efferent function; b) impaired pain transmission (deafferentation-like condition) provokes a rostral spread of neuronal irritability and automatic firing ("quasi epileptic foci") producing a clinical predilection for pain with the generation of "spontaneous" pains along the sensory pathways. The substrates studied in the present experiments are the iris, salivary glands, and nasal mucosa. 1) Iris: the conjunctival instillation of SP induces isocoric miosis both in CH sufferers and in normals, thus excluding gross SP receptoral dysfunction of the iris muscle in CH. Electrical stimulation of extraocular (infratrochlear) endings of the first branch of the trigeminal nerve provokes a miosis, which is significantly less in the symptomatic eye than in the contralateral one. This miosis is ascribed to a retrograde release of SP, induced by electrical stimulation of the trigeminal ophthalmic branch. The relatively poor miosis in the painful eye could correlate with a deficient release of SP from the sensory terminals in the iris. 2) Salivary glands: an increase of substance P-like immunoreactivity is found in the saliva taken from the asymptomatic side, but not from the painful side during a cluster headache attack, thus showing at this level also an asymmetry as previously shown in other head structures. 3) Nasal mucosa: intranasal application of capsaicin, a powerful releaser of SP from sensory terminals, evokes an immediate burning pain in the ipsilateral nasal, ocular, and temporal areas, as well as lacrimation and rhinorrhea. A gradual decrease (tachyphylaxis) of these phenomena is consistently observed after few days of daily nasal administration of capsaicin. When this treatment is applied to CH patients, a rapid decrease in the number and intensity of attacks, and even disappearance of symptoms accompanies the decline of the capsaicin-induced manifestations. Local (nasal) capsaicin, in spite of evoking immediately the same vegetative (rhinorrhea, lacrimation, conjunctival congestion) and in part nociceptive (transient nasal, ocular, temporal burning) phenomena of CH, never has been able to provoke delayed spontaneous-CH like attacks. Such delayed provoked attacks, one of the most pregnant phenomena in CH investigations, are almost constantly evoked by systemic stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
Headache 1990 Jan
PMID:Substance P theory: a unique focus on the painful and painless phenomena of cluster headache. 168 82

Trigeminal sensory innervation of cerebral vessels and the surrounding dura is responsible for most intracranial head pain. Small-diameter fibers containing substance P (Sub P) have been observed in the periadventitia around feline cerebral blood vessels, and it has been suggested that these fibers are the trigeminal substrate for vascular pain associated with cluster and migraine headaches. Calcitonin gene related peptide (CGRP) coexists with Sub P in some of these fibers and with some Sub P containing neurons in the trigeminal ganglion. In addition, a population of trigeminal neurons containing CGRP but not Sub P has been observed. We now report that the population of trigeminal ganglion cells projecting to the cerebral vasculature is enriched in CGRP-containing neurons, and especially in the population of neurons containing CGRP and not Sub P. Using retrograde tracing of fluorescent tracers combined with immunocytochemistry after explant culture, we found approximately 32% of trigeminal ganglion cells projecting to the cerebral vasculature contained CGRP. Approximately 18 and 17% of these cells contained Sub P and cholecystokinin (CCK), respectively. The 32% of ganglion cells projecting to the cerebral vasculature that contain CGRP stands in contrast to the 12% CGRP positive seen in the population of ganglion cells projecting out to another target (the forehead), and the 21 and 23% CGRP positive observed in the mandibular branch and entire ganglion, respectively. Sub P and CCK are not enriched in the trigeminal innervation of the vasculature compared with their presence in cells throughout the ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enrichment of a vasoactive neuropeptide (calcitonin gene related peptide) in the trigeminal sensory projection to the intracranial arteries. 247 Aug 72

Hypocalcemia is common in toxic-shock syndrome (TSS); however, the role of magnesium deficiency in TSS remains to be defined. A previously healthy nurse on no maintenance medication developed hypocalcemia and hypomagnesemia in association with characteristic TSS, presenting with fever, headache, mental confusion, erythroderma, watery diarrhea and abnormal liver functions tests. Coagulase-positive Staphylococcus aureus as well as staphylococcal toxin were isolated from the cervix. Calcitonin levels were normal. Serum magnesium and calcium levels were low at presentation and later intravenous magnesium loading demonstrated a marked rise in 1,25-(OH)2 vitamin D and parathormone (PTH), with high retention of the infused load consistent with functional hypoparathyroidism. Intracellular magnesium deficiency may be a significant factor in the pathogenesis of hypocalcemia in TSS and warrants routine clinical consideration.
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PMID:Hypomagnesemia, hypocalcemia, and toxic-shock syndrome. A case report. 344 8

Cluster headache is a rare very severe disorder that is clinically well characterized with a relatively poorly understood pathophysiology. In this study patients with episodic cluster headache fulfilling the criteria of the International Headache Society were examined during an acute spontaneous attack of headache to determine the local cranial release of neuropeptides. Blood was sampled from the external jugular vein ipsilateral to the pain before and after treatment of the attack. Samples were assayed for calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P and neuropeptide Y. Attacks were treated with either oxygen inhalation, sumatriptan or an opiate. Thirteen patients were studied of whom 10 were male and three female. All had well-established typical attacks of cluster headache when blood was sampled. During the attacks external jugular vein blood levels of CGRP and VIP were raised while there was no change in neuropeptide Y or substance P. Calcitonin gene-related peptide levels rose to 110 +/- 7 pmol/l (normal: < 40) while VIP levels rose to 20 +/- 3 pmol/l (normal: < 7). Treatment with both oxygen and subcutaneous sumatriptan reduced the CGRP level to normal, while opiate administration did not alter the peptide levels. These data demonstrate for the first time in vivo human evidence for activation of the trigeminovascular system and the cranial parasympathetic nervous system in an acute attack of cluster headache. Furthermore, it is shown that both oxygen and sumatriptan abort the attacks and terminate activity in the trigeminovascular system.
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PMID:Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. 751 21

The pathophysiological basis for the pain of migraine has been the subject of substantial attention and must include activation of elements of the trigeminal innervation of the cranial vessels, the trigeminovascular system. Recently, consideration of trigeminal-evoked neurogenic plasma protein extravasation (PPE) as a model for the pain has driven the search for compounds with specific anti-extravasation properties. Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D)agonist drugs but does not itself produce PPE. It has been suggested that 5HT(1B/1D)agonists may have an anti-migraine effect via inhibition of PPE in the dura mater. Avitriptan and CP122,288 both have strong binding affinities for 5HT(1B/1D)receptors, but only CP122,288 is a potent inhibitor of PPE. In this study we sought to compare the effects of CP122,288 and avitriptan on jugular vein CGRP release after stimulation of the superior sagittal sinus (SSS) in the cat. In eleven anaesthetized cats external jugular vein blood samples were analyzed by radioimmunoassay for CGRP levels in three settings: a) control, b) 1 min after SSS stimulation and c) 1 min after SSS stimulation in presence of drug. Stimulation of the SSS resulted in release of CGRP from the external jugular vein (77+/-1 pmol/L). At a PPE-inhibitory dose in rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77+/-6 pmol/L) whereas at a clinically relevant dose (50 microgram/kg intravenously) avitriptan blocked CGRP release. This study demonstrates that the potent inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be ineffective in treating acute migraine attacks, had no effect on CGRP release, whereas the effective anti-migraine drug and relatively impotent inhibitor of PPE, avitriptan, blocked CGRP release. These data emphasize the importance of CGRP release and its possible independence from PPE in migraine and more importantly suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.
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PMID:Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288. 1065 70

Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT(1B/1D)-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 microg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78+/-4 pmol/l compared to a post-4991W93 level of 79+/-3 pmol/l (n=4). In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.
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PMID:4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT(1B/1D) receptor agonist activity? 1124 61

Calcitonin gene related peptide (CGRP) released from the C-fibers projecting from the trigeminal ganglion to the meninges has been suggested to play a crucial role in the pathophysiology of headache, particularly migraine. In humans it has been shown that CGRP is released during migraine-attacks, and this is attenuated by the administration of typical anti-migraine drugs such as dihydroergotamine or sumatriptan. We describe a new rat model which allows the study of CGRP release from the meninges into venous blood following activation of the trigeminal vascular system. The effects of classical and new anti-migraine drugs such as acetylsalicylic acid (ASA), sumatriptan and the new high efficacy 5-HT1B/1D agonist donitriptan (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl]benzonitrile) were evaluated in comparison with the established model of neurogenic inflammation in the meninges. Sumatriptan and donitriptan inhibited CGRP release as well as neurogenic inflammation. ASA, however, attenuated neurogenic inflammation, but not CGRP release, confirming the concept of prejunctional inhibition of CGRP release by 5-HT1B/1D receptors. This new model allows the further study of prejunctional pharmacology and mechanisms of neuropeptide release in the trigeminal vascular system, which might be crucial for the further development of potent, more effective anti-migraine drugs.
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PMID:An in vivo rat model to study calcitonin gene related peptide release following activation of the trigeminal vascular system. 1132 31

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.
Cephalalgia 2002 Feb
PMID:CGRP may play a causative role in migraine. 1199 14

Calcitonin gene-related peptide (CGRP) is involved in the underlying pathophysiology of all vascular headaches, including migraines. Elevated levels of CGRP during migraine are restored to normal coincident with headache relief after treatment with the antimigraine drug sumatriptan. We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter. Using reporter genes in transient transfection assays, we demonstrate that an 18 bp enhancer containing a helix-loop-helix element is both necessary and sufficient for full promoter activity. NGF treatment and cotransfection with an upstream activator of the extracellular signal-regulated MAP kinases (MAPKs) activated the enhancer. Treatment with sumatriptan repressed NGF- and MAPK-stimulated CGRP promoter activity. Repression was also observed using a synthetic MAPK-responsive reporter gene. Sumatriptan regulation of CGRP gene expression did not couple to a G(i)/G(o) pathway, but rather caused a prolonged increase in intracellular calcium. The importance of the prolonged calcium signal in repression of MAPK activity was demonstrated by using the ionophore ionomycin to mimic sumatriptan action. We propose that activation of MAPK pathways may increase CGRP gene expression during migraine, and that sumatriptan can diametrically oppose that activation via a prolonged elevation of intracellular calcium.
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PMID:Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons. 1257 9


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