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 compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.
Cephalalgia 2003 Mar
PMID:Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation. 1260 68

The first International Headache Society classification defined tension-type headaches (TTHs) by itemising those characteristics of migraines TTHs did not possess [1]. As a result, TTHs, both episodic and chronic, remain the most nonspecific of all the commonly observed primary headaches. Until recently, there has been little impetus on the part of the pharmaceutical industry to investigate TTHs; many of the potentially useful drugs are now generic and unprofitable. In addition, few investigators have pursued the study of TTHs in lieu of its more glamorous neighbour, migraine. As a result, there are few well-designed studies on the pharmacotherapy of TTHs. The few studies that exist support the use of age-old standard drug classes, the tricyclic antidepressants and the NSAIDs. New research is now emerging that points to the potential utility of botulinum toxin type A, NMDA-receptor antagonists including Mg(2+) and nitric oxide synthase inhibitors. More scientifically rigorous clinical studies are needed.
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PMID:New developments in the pharmacotherapy of tension-type headaches. 1464 Sep 22

Nitric oxide (NO) is suggested to play a causative role in the pathogenesis of primary headaches. Infusion of NO donors can trigger headache attacks, and products of NO metabolism are found to be increased in the cranial circulation in patients suffering from such headaches. To examine if NO is involved in mediating and maintaining spinal trigeminal neuronal activity, an animal model of meningeal nociception was used. In barbiturate-anesthetized rats, a cranial window was made to expose the parietal dura mater. An access to the medullary brain stem allowed extracellular action potentials to be recorded from neurons in the spinal trigeminal nucleus that received afferent input from the exposed dura. Slow intravenous infusion of the NO donor, sodium nitroprusside (SNP, 50 microg/kg), transiently increased spontaneous activity in a subset of neurons and, with a latency of 50 min, caused a progressive increase in impulse activity across the entire sample of neurons. A similar pattern of delayed activation was seen after topical application of the same dose of SNP onto the exposed medulla. Slow injection of the nonspecific inhibitor of NO synthase, N(omega)-nitro-l-arginine methyl ester (20 mg/kg), reduced the spontaneous activity in all neurons within 15 min. The results suggest that NO can induce delayed, slowly developing activation of central trigeminal neurons and that endogenous release of NO may contribute to the ongoing activity of these neurons. The delayed changes in neuronal activity may include gene expression of pro-nociceptive mediators. These mechanisms may be relevant for the pathogenesis of chronic headaches.
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PMID:Biphasic response to nitric oxide of spinal trigeminal neurons with meningeal input in rat--possible implications for the pathophysiology of headaches. 1511 84

Nitric oxide (NO) donors such as glyceryl trinitrate cause headache, which suggests involvement of NO in trigeminovascular sensory processing. Sensory transmission at first-order synapses is believed to involve glutamate and the question arises as to whether it is also involved in trigeminovascular sensation and whether it might interact with nitrergic mechanisms. We investigated these questions at the first central synapse in the trigeminovascular sensory system of the cat. Neuronal action potentials in the trigeminal nucleus were recorded while the superior sagittal sinus (SSS) or facial receptive field (RF) were stimulated electrically. Drugs, including the neuronal excitant glutamate, were applied to neurons via microiontophoresis. Results were obtained from 152 neurons activated with A-delta latencies by SSS stimulation and by glutamate. The NO donor S-nitrosoglutathione (SNOG, 50 nA) was applied iontophoretically to 41 neurons during SSS stimulation and 13 neurons during pulsatile glutamate ejection. Responses to both modes of stimulation were enhanced by SNOG; the proportion of neurons enhanced was 56% to SSS stimulation and 59% to glutamate. The inhibitor of nitric oxide synthase (NOS), N(omega)-propyl-L-arginine (p-ARG, 50 nA) was applied iontophoretically to 17 neurons during stimulation of SSS and to 10 neurons during pulsatile glutamate ejection. Responses to both stimuli were suppressed by p-ARG: The proportion of neurons suppressed were: to SSS stimulation 59% and to glutamate 80%. Microiontophoretic ejection of eletriptan (50 nA) reversibly suppressed responses of neurons to SSS stimulation, to RF electrical stimulation and to pulsatile iontophoretic application of glutamate. This suppression of responses was antagonised by the concurrent local iontophoretic application of the 5-HT1B/1D receptor antagonist GR127935 or by concurrent iontophoretic application of the selective 5-HT1D receptor antagonist BRL155732. These results suggest that glutamatergic mechanisms are important in sensory transmission in the trigeminovascular system and that they can be modulated by nitrergic and serotonergic mechanisms.
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PMID:Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. 1516 37

Neuropeptide release and the expression of c-fos like immunoreactivity (c-fos LI) within trigeminal nucleus caudalis neurons (TNC) are activation markers of the trigeminal nerve system. Glyceryltrinitrate (GTN) is believed to stimulate the trigeminal nerve system, thereby causing headache. We examined the effects of a 30 min NO-donor infusion on CGRP release in jugular vein blood and c-fos LI within TNC of the rat. GTN (2 and 50 microg/kg/min) or NONOate infusion (25 nmol/kg/min) did not cause any CGRP release during and shortly after infusion, whereas administration of capsaicin resulted in strongly increased CGRP levels. GTN infusion (2 microg/kg/min for 30 min) did not lead to enhanced c-fos LI after 2 h and 4 h, whereas capsaicin infusion caused a time- and dose-dependent expression of c-fos LI within laminae I and II of the TNC. Surprisingly, GTN attenuated capsaicin-induced c-fos expression by 64%. The nitric oxide synthase (NOS) inhibitor L-NAME (5 and 50 mg/kg) reduced capsaicin-induced c-fos LI dose dependently (reduction by 13% and 59%). We conclude that GTN may lead to headaches by mechanisms independent of CGRP release from trigeminal nerve fibres. GTN doses comparable to those used in humans did not activate or sensitize the trigeminal nerve system. Both GTN and L-NAME reduced capsaicin-induced c-fos LI. This is most likely due to a feedback inhibition of nitric oxide synthases, which indicates that the c-fos response to capsaicin within TNC is mediated by NO dependent mechanisms.
Cephalalgia 2005 Mar
PMID:CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. 1568 99

There is now evidence that melatonin may have a role in the biological regulation of circadian rhythms, sleep, mood, and ageing. Altered melatonin levels in cluster headache and migraine have been documented. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin. Treatment of headache disorders with melatonin and other chronobiotic agents is promising. A double-blind, placebo-controlled trial shows melatonin is effective in cluster headache prevention, other studies also show benefit in other disorders. Melatonin plays an important role in headache disorders, offering new avenues for studying their pathophysiology and treatment.
Cephalalgia 2005 Jun
PMID:Melatonin, the pineal gland and their implications for headache disorders. 1591 May 64

Tension-type headache is one of the most common primary headache disorders. Advances in basic pain and clinical research have improved our understanding of pathophysiologic mechanisms of tension-type headache. Increased excitability of the central nervous system generated by repetitive and sustained pericranial myofascial input may be responsible for the transformation of episodic tension-type headache into the chronic form. Studies of nitric oxide (NO) mechanisms suggest that NO may play a key role in the pathophysiology of tension-type headache and that the antinociceptive effect of nitric oxide synthase inhibitors may become a novel principle in the future treatment of chronic headache. Future studies should focus on investigation of the source of peripheral nociception, the role of descending pain modulation, and the development of an animal model of tension-type headache to support the pathophysiologic importance of central sensitization in tension-type headache.
Curr Pain Headache Rep 2005 Dec
PMID:Pathophysiology of tension-type headache. 1628 42

Stress is the leading precipitating factor for migraine attacks but the underlying mechanism is currently unknown. Nitric oxide (NO) has been implicated in migraine pathogenesis based on the ability of NO donors to induce migraine attacks. In the present study, we investigated in Wistar rats the effect of air stress on nitric oxide synthase (NOS) mRNA and protein expression in dura and pia mater using real-time polymerase chain reaction and Western blotting, respectively. Endothelial (e)NOS protein expression was significantly increased in dura and pia mater after air stress. Significantly augmented neuronal (n)NOS protein expression was detected in pia mater after air stress but not in dura mater. Inducible NOS mRNA and protein expression levels in dura and pia mater were unaffected by stress. The increased expression of eNOS in dura mater and eNOS and nNOS in pia mater seen after stress could not be antagonized by treatment with the migraine drug sumatriptan. These findings point towards the involvement of increased NO concentrations in dura and pia mater in response to air stress. However, the role of these findings in relation to migraine pathophysiology remains unclear.
Cephalalgia 2006 Jan
PMID:Increased expression of endothelial and neuronal nitric oxide synthase in dura and pia mater after air stress. 1639 62

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.
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PMID:Potential therapeutic use of melatonin in migraine and other headache disorders. 1654 86

Several species of Ferula genus have been used in folk medicine in digestive disorders, rheumatism, headache, arthritis, and as tranquilizers, antispasmodic and aphrodisiac. From the dry and powdered roots of Ferula hermonis Boiss was extracted the oxygenated sesquiterpene 1,5-trans-daucane type: ferutinine (1). The structure of (1) was established by spectroscopic methods as: IR, (1)H RMN, (13)C RMN, COSY, HMBC, HMQC, NOESY, EIMS, and CIMS. The possible signaling pathway of ferutinin (1) in nervous tissue in vitro was assessed and the results showed that this compound is able to increase nitric oxide synthase activity and inositol monophosphate accumulation (49%, each) in the median eminence of the rat brain, suggesting that compound (1) is associated to the activation of phosphoinositide breakdown and nitric oxide production (NO), the last is a gaseous intercellular messenger known to play a broad role in human biology from homeostasis to pathology.
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PMID:Ferutinin stimulates nitric oxide synthase activity in median eminence of the rat. 1657 58


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