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)

Calcitonin gene-related peptide (CGRP), nitric oxide (NO) and histamine are implicated in primary headaches but their role in vascular and nociceptive events in the dura mater is not well described. In an in vitro preparation of the hemisected rat skull, CGRP and histamine release from the cranial dura was measured using enzyme-linked immunoassays. While the NO donator NONO(ate) (10(-4) M) was without effect, CGRP (10(-5) M) induced considerable histamine release from the rat cranial dura, which was blocked by the CGRP receptor antagonist CGRP(8-37) (10(-5) M). Conversely, histamine (10(-4) M) did not stimulate CGRP release. In vitro recordings from single rat meningeal afferents showed that only one of 12 mechanically identified units but several mechanically insensitive units responded to histamine (up to 10(-5) M). Increases in meningeal blood flow after histamine application (10(-4) M) to the rat cranial dura remained unchanged during CGRP receptor blockade with CGRP(8-37), inhibition of NO synthesis with L-NAME (20 mg/kg i.v.) and H(3) receptor blockade with thioperamide (10(-4) M). We conclude that histamine produces direct vasodilatation and activates a subset of largely non-mechanically sensitive, non-CGRP containing afferents in the rat meninges. Histamine is released from meningeal mast cells which are stimulated by CGRP. Similar mechanisms may be involved in the pathogenesis of headaches.
Cephalalgia 2007 Jun
PMID:Interaction of calcitonin gene-related peptide, nitric oxide and histamine release in neurogenic blood flow and afferent activation in the rat cranial dura mater. 1744 73

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
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PMID:Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. 1803 58

Calcitonin gene-related peptide (CGRP) is a key mediator in primary headaches including migraine. Animal models of meningeal nociception demonstrate both peripheral and central CGRP effects; however, the target structures remain unclear. To study the distribution of CGRP receptors in the rat trigeminovascular system we used antibodies recognizing two components of the CGRP receptor, the calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 1 (RAMP1). In the cranial dura mater, CLR and RAMP1 immunoreactivity (-ir) was found within arterial blood vessels, mononuclear cells, and Schwann cells, but not sensory axons. In the trigeminal ganglion, besides Schwann and satellite cells, CLR- and RAMP1-ir was found in subpopulations of CGRP-ir neurons where colocalization of CGRP- and RAMP1-ir was very rare ( approximately 0.6%). CLR- and RAMP1-ir was present on central, but not peripheral, axons. In the spinal trigeminal nucleus, CLR- and RAMP1-ir was localized to "glomerular structures," partly colocalized with CGRP-ir. However, CLR- and RAMP1-ir was lacking in central glia and neuronal cell bodies. We conclude that CGRP receptors are associated with structural targets of known CGRP effects (vasodilation, mast cell degranulation) and targets of unknown function (Schwann cells). In the spinal trigeminal nucleus, CGRP receptors are probably located on neuronal processes, including primary afferent endings, suggesting involvement in presynaptic regulation of nociceptive transmission. Thus, in the trigeminovascular system CGRP receptor localization suggests multiple targets for CGRP in the pathogenesis of primary headaches.
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PMID:Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. 1818 28

Calcitonin gene-related peptide (CGRP) and substance P (SP) play an important role in the development of pain and hyperalgesia. Experimental models have demonstrated that nitroglycerin (NTG)--a nitric oxide donor--provokes a hyperalgesic state, probably via the activation of second-order neurons in the nucleus trigeminalis caudalis. In order to gain further insight into the role of CGRP and SP in different types of experimental pain, we evaluated and compared changes in immunoreactivity (-ir) for these two neuropeptides at different levels of the central nervous system [nucleus trigeminalis caudalis (NTC) and dorsal horns of the lumbar spinal cord] in two animal models of hyperalgesia: systemic NTG administration and formalin test. Following NTG administration, CGRP-ir decreased steadily in the NTC, whereas SP-ir increased transiently. In the lumbar dorsal horns, NTG induced a decrease in SP-ir 1 h after its administration. Formalin injection induced an ipsilateral increase in both CGRP and SP immunostaining at 1 and 2 h in the lumbar dorsal horns. In the NTC, a significant decrease in CGRP-ir was observed at 1 h. The changes in the staining intensities were paralleled by changes in the numbers of CGRP and of SP varicosities in both the NTC and the lumbar dorsal horns. These findings show specific changes in CGRP and SP at different levels of the central nervous system in the different models of pain. In the case of the formalin test, the changes involve both neuropeptides synchronously and to the same extent, whereas in the case of NTG administration, CGRP seems to play a more prevalent and long-lasting role, particularly at the NTC level.
Cephalalgia 2008 Feb
PMID:Role of calcitonin gene-related peptide and substance P in different models of pain. 1819 82

Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are two molecules shown to have a role in migraine pathophysiology. Our objective was to test the hypothesis that migraine subjects are particularly sensitive to these signal molecules. The cutaneous microvascular responses to endothelial and non-endothelial dependent dilators were tested using laser Doppler flowmetry in combination with iontophoresis. The blood flow responses to iontophoretic administration of the endothelium-dependent vasodilator acetylcholine (ACh), or to the endothelium-independent dilators sodium nitroprusside (SNP) and CGRP, and to local warming (44 degrees C) were compared in this controlled trial. The design was that of two arms: patients diagnosed with migraine without aura (n = 9) for >10 years were compared with nine healthy subjects matched for age and gender (seven female and two male, age range 30-60 years). Iontophoretic administration resulted in local vasodilation. ACh induced a relaxation of 1225 +/- 245% (relative to baseline) in controls and 1468 +/- 368% (P > 0.05) in migraine. The responses to SNP were 873 +/- 193% in controls and 1080 +/- 102% (P > 0.05) in migraine subjects. The responses to CGRP were 565 +/- 89% in controls and 746 +/- 675% (P > 0.05) in migraine patients. The responses to local heating which induced maximum dilation did not differ between the groups (1976 +/- 314% for controls and 1432 +/- 226% in migraine; P > 0.05. We conclude that there is no change in the microvascular responsiveness of the subcutaneous microvasculature in migraine.
Cephalalgia 2008 May
PMID:Comparison of CGRP and NO responses in the human peripheral microcirculation of migraine and control subjects. 1838 19

Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (halphaCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of halphaCGRP (2 mug/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (V (mean)) in the middle cerebral artery (MCA), as well as the heart rate and blood pressure, were the outcome parameters. No change of rCBF was observed at the end of infusion [1.2% +/- 1.7 with halphaCGRP, vs. -1.6% +/- 3.1 with placebo (mean +/- SD)] (P = 0.43). V (mean) in MCA decreased to 13.5% +/- 3.6 with halphaCGRP versus 0.6% +/- 1.8 with placebo (P < 0.005). Since rCBF was unchanged, this indicates a dilation of the MCA. halphaCGRP induced a decrease in MAP (12%) (P < 0.005) and an increase in heart rate (58%) (P < 0.0001). CGRP dilates cerebral arteries, but the effect is so small that it is unlikely to be the only mechanism of CGRP-induced migraine.
J Headache Pain 2008 Jun
PMID:Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. 1843 88

Calcitonin gene-related peptide (CGRP) is linked to migraine and other primary headache disorders. It is found in every location described in migraine genesis and processing, including meninges, trigeminal ganglion, trigeminocervical complex, brainstem nuclei, and cortex. It is released in animal models following stimulation of the CNS similar to that seen in migraine, and triptans inhibit this release. Injection of CGRP into migraineurs results in delayed headache similar to migraine. Elevation of CGRP occurs during migraine, resolving following migraine-specific treatment. Finally, and most importantly, CGRP receptor antagonists terminate migraine with efficacy similar to triptans. Both intravenous olcegepant (BIBN 4096 BS) and oral telcagepant (MK-0974) have been effective, safe, and well tolerated in phase I and II studies. Telcagepant is currently in phase III trials, and preliminary results are favorable. The potential for a migraine-specific medication without vasoconstrictive or vascular side effects is enormous. CGRP receptor blockade may also have applications in other pathologic and pain syndromes.
Headache 2008 Sep
PMID:Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine. 1880 6

Calcitonin gene-related peptide (CGRP) is known to increase during acute attack of migraine and tension type headache (TTH). However, its concentration during inter-ictal period is not known. This may help us to understand the pathophysiology of these headaches. The objectives of this study are to find out the concentration of CGRP in plasma during inter-ictal period among migraineurs and TTH and to compare it with control group through cross-sectional study from headache clinic of a tertiary centre. Study sample comprised of three groups: migraineurs, TTH subjects as well as a healthy control group. Fifty subjects in each group were included after screening for the respective inclusion criteria and exclusion criteria. None of the subjects was blood relatives of other subject. Their venous blood was drawn and plasma was separated to be kept at -70 degrees C. CGRP was analysed with commercially available ELISA kit. Data were analysed with the help of SPSS V 11.0 for Windows. Chi-square, independent sample t test and one-way ANOVA with post hoc Tukey and univariate regression were performed. Plasma CGRP concentration was not different among three diagnostic groups (F = 0.78; P = 0.49). Similarly, plasma CGRP concentration was not different among episodic TTH and chronic TTH groups (t = 0.32; P = 0.97) and comparison of episodic and chronic migraine groups also revealed similar results in this study (1.14 vs. 0.94 ng/ml; P = 0.23). The presence of aura did not affect the inter-ictal CGRP levels among migraineurs (F = 0.16; P = 0.85). In conclusion, this study suggests that migraine and TTH could be episodic disorders and subjects have comparable CGRP levels during inter-ictal period.
J Headache Pain 2009 Jun
PMID:Plasma calcitonin gene-related peptide concentration is comparable to control group among migraineurs and tension type headache subjects during inter-ictal period. 1969 Sep 42

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81-92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT(1B/1D) receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients.
J Headache Pain 2009 Dec
PMID:Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment. 1982 Aug 95

Calcitonin gene-related peptide (CGRP) has a widespread distribution throughout the trigeminovascular system and other brain areas involved in migraine pathogenesis. Serum levels of CGRP are elevated during the migraine attack and return to normal with alleviation of pain. Intravenous injection of CGRP in migraineurs results in delayed headache similar to migraine. Since CGRP receptor antagonists lack direct vasoconstrictor activity, this therapeutic approach may offer advantages over the current mainstay of specific acute migraine treatment with 5-HT1B/1D receptor agonists (triptans), contra-indicated in patients with underlying cardiovascular disease. Intravenous BIBN4096BS (olcegepant) and oral MK-0974 (telcagepant), two CGRP-receptor antagonists, were safe and effective in the treatment of migraine attacks in Phase I and II trials. In a Phase III clinical trial, the efficacy of telcagepant 300 mg was comparable to that of zolmitriptan 5 mg. We intend to review the rationale for the use of CGRP-receptor antagonists, and to outline current developments and future perspectives.
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PMID:CGRP antagonists: hope for a new era in acute migraine treatment. 2012 Feb 4


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