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)

The interactions of four abortive anti-migraine agents and four prophylactic anti-migraine agents with 5-HT1D receptors in bovine brain were analyzed using radioligand binding techniques and adenylate cyclase assays. In bovine caudate, the affinities of abortive anti-migraine agents (i.e. 5-hydroxytryptamine, ergotamine, dihydroergotamine, sumatriptan) for 5-HT1D receptors range from 4.0-34 nM while the affinities of prophylactic anti-migraine agents (i.e. methysergide, amitriptyline, (-)propranolol, verapamil) range from 46-11,000 nM. In adenylate cyclase studies in bovine substantia nigra, all four abortive anti-migraine agents dose-dependently inhibit forskolin-stimulated adenylate cyclase activity, a biochemical effect mediated by 5-HT1D receptors. No agonist effect on cyclase activity is observed with the four prophylactic anti-migraine agents. These data support the hypothesis that abortive anti-migraine agents are 5-HT1D receptor agonists and that this effect may underlie their anti-migraine efficacy.
Headache 1991 Apr
PMID:5-Hydroxtryptamine1D receptor agonism predicts antimigraine efficacy. 164 76

Previous studies have indicated that membrane structure and function may be abnormal in cluster headache. This has been further investigated by analysis of membrane phosphatidylcholine, total phospholipids, and cholesterol in erythrocytes and by assay of receptor-mediated transduction. The stimulation of lymphocyte adenylate cyclase with isoprenaline and prostacyclin was used as the test system. A significant increase in the ratio of membrane phosphatidylcholine to cholesterol without change in cholesterol was found in cluster headache patients as compared with control subjects. This indicated a reduced turnover of phosphatidylcholine, since erythrocyte choline is significantly reduced in this condition. Abnormal membrane function was also indicated from the significant depression of high-affinity prostaglandin receptor stimulation of lymphocyte adenylate cyclase and the similar trend in the beta-adrenoceptor response. Since no change in agonist affinity and beta-adrenoceptor density occurred, this depression indicates a generalized defect in coupling of receptors to adenylate cyclase. It is hypothesized that the impaired function that would result might contribute to the aetiology of cluster headache.
Cephalalgia 1986 Sep
PMID:Abnormal membrane composition and membrane-dependent transduction mechanisms in cluster headache. 302 32

The sensory innervation of intracranial vessels originate in the trigeminal ganglion and comprise the following signal substances; calcitonin gene-related peptide (CGRP), substance P, neurokinin A, pituitary adenylate cyclase activating peptide (PACAP) and nitric oxide (NO). Studies in patients have revealed a clear association between head pain and the release of CGRP. In cluster headache and in a case of chronic paroxysmal headache there is in addition release of vasoactive intestinal peptide (VIP), which was associated with the facial symptoms (nasal congestion, rhinorrhea). In parallel with triptan administration, acting via 5-HT(1B/1D) receptors, head pain subside and neuropeptide release normalise. These data show the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headaches.
Cephalalgia 2001 Sep
PMID:Sensory nerves in man and their role in primary headaches. 1159 8

In migraine and other primary headaches there is a strong vascular component. Besides the trigeminovascular components some of the associated symptoms point to the involvement of brain stem regions. The central limb of the trigeminal vascular pathway is its projection to the trigeminal nucleus caudalis (TNC) and to the C1-C2 levels of the spinal cord. The aim of the present study was to demonstrate the occurrence of some neurotransmitters in these regions in man. In both the TNC and in the Rexed's laminae I and II of the dorsal horns at the C1 and C2 levels there were numerous substance P immunoreactive fibres. Fibres containing calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) were moderately dense in number. Fibres containing vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) were not seen in the TNC or at the C1 and C2 levels of the spinal cord.
Cephalalgia 2002 Mar
PMID:Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. 1197 78

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.
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PMID:Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis. 1522 97

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention.
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PMID:The role of mast cells in migraine pathophysiology. 1596 Sep 87

Gulf War syndrome (GWS) is a perplexing multi-symptom condition comprising a constellation of signs and symptoms consistently described in the literature. These include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. Excessive chemical sensitivity and odour intolerance is reported. Epidemiological analysis suggests association with pyridostigmine bromide (PB) use as nerve gas prophylaxis, insect repellent, certain vaccination regimes, a variety of possible chemical exposures and physical and psychological stress. Pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are potent vasoactive (vasodilatory) neuropeptides (VNs) having pleiotropic functions as immunomodulators, neuroregulators and hormones. VNs also have neurotrophic and anti-apoptotic roles. VNs act on G protein-coupled receptors (GPCRs) to activate adenylate cyclase, an important step in cyclic AMP metabolism. Autoimmune dysfunction of these VNs or their receptors is postulated to give rise to fatigue-related conditions such as chronic fatigue syndrome (CFS). Complex mechanisms involving heat shock proteins (hsps) and cytosine-guanine dinucleotide (CpG) DNA fragments may also be associated with autoimmunity to VNs or their GPCRs in contributing to fatigue-related conditions. Dysfunction of certain VNs may be the missing link in explaining the nebulous nexus between PB and GWS. This paper explores a possible link between exposures to PB and other chemical, physical and psychological stressors in producing a fatigue-related illness possibly related to autoimmune dysfunction of certain VNs. Treatment options involving restoration of VN function are considered in the context of analogues with other neurotransmitter fatigue-related conditions such as myasthenia gravis (MG). While evidence associating these conditions is thin, vasoactive neuropeptide neurotransmitters of the VIP/PACAP family have acetylcholine co-transmission functions via specific GPCRs. Autoimmune reactions to these receptors may have parallels with muscarinic (e.g., Sjogren's syndrome) and nicotinic (e.g., MG) acetylcholine neurotransmission. Hence theoretically, treatment options such as thymectomy, corticosteroids, plasma exchange, anti-idiotype antibodies and receptor genomic expression reactivation/suppression may be considered. Paradoxically pyridostigmine may prove to have a role in therapy although VN treatment/replacement may be associated with tachyphylaxis.
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PMID:Do vasoactive neuropeptide autoimmune disorders explain pyridostigmine's association with Gulf War syndrome? 1600 38

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.
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PMID:PACAP38 induces migraine-like attacks in patients with migraine without aura. 1909 31

Intravital microscopy on a closed cranial window allows one to measure change in the diameter of cranial blood vessels after intravenous (i.v.) administration of pharmacodynamic substances. Putative targets being pursued in migraine are large vasodilating peptide molecules such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase polypeptide (PACAP)-38. High i.v. doses are required to study their craniovascular pharmacology. Unfortunately, this leads to a drop in blood pressure (BP) that subsequently causes blood vessels to dilate by autoregulation. Hence it is difficult to decipher what effect is caused by direct receptor agonist interaction or contributed by autoregulation. In the present study we infused substances with an ingenious indwelling catheter in the common carotid artery in rats. Intracarotidly seven-, 12- and 17-fold lower doses of CGRP, PACAP-38 and capsaicin were required, respectively, compared with i.v. infusion to induce the same dilation in dural artery. Dilating intracarotid (i.c.) doses caused no or a minimal fall in BP, whereas equi-responsive i.v. doses caused a marked BP reduction. The CGRP blocking potential of olcegepant was amplified by > 20 times on i.c. infusion. Pial artery responses to CGRP did not change with i.c. infusion, demonstrating that dilations after i.v. CGRP are mediated by autoregulation rather than through specific receptors. We applied CGRP topically, which induced concentration-dependent dural vasodilation, but no effect on pial artery or on BP. In conclusion, this new approach offers an improvement of the existing model by allowing more accurate assessment of effects of pharmaca on the cranial vasculature without inducing significant systemic effects.
Cephalalgia 2010 Jan
PMID:Improvement of the closed cranial window model in rats by intracarotid infusion of signalling molecules implicated in migraine. 1943 25

Pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) belong to the same secretin-glucagon superfamily and are present in nerve fibers in dura and skin. Using a model of acute cutaneous pain we explored differences in pain perception and vasomotor responses between PACAP38 and VIP in 16 healthy volunteers in a double-blind, placebo-controlled, crossover study. All participants received intradermal injections of 200 pmol PACAP38, 200 pmol VIP and placebo into the volar forearm. Measurements included pain intensity on a visual analog scale (VAS), blood flow by laser Doppler flowmetry, visual flare and wheal. Pain intensities after PACAP38 and VIP were mild and limited to a short time of about 100 s after injection. The area under the VAS-time curve was larger following PACAP38 (P = 0.004) and VIP (P = 0.01) compared to placebo. We found no statistical difference in pain perception between PACAP38 and VIP. Skin blood flow increase, flare and wheal were larger after both PACAP38 (P = 0.011) and VIP (P = 0.001) compared to placebo. VIP induced a considerably larger increase in skin blood flow, flare and wheal than PACAP38 (P = 0.002). In conclusion, we found that peripheral nociceptive cutaneous responses elicited by PACAP38 and VIP are similar in healthy volunteers. This suggests that acute pain and vasomotor responses following intradermal injections of PACAP38 and VIP are primarily mediated by VPAC receptors.
J Headache Pain 2010 Aug
PMID:Cutaneous nociception and neurogenic inflammation evoked by PACAP38 and VIP. 2045 93


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