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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical studies indicate anti-migrane efficacy of the probably GABAergic anticonvulsants valproate and gabapentin. For the GABAergic anticonvulsants vigabatrin and tiagabine, studies about antimigrane efficacy are missing. The aim of this study was to test the GABAergic potency of these drugs in vitro before further clinical studies. Intracellular recordings were obtained from hippocampal pyramidal cells. Spontaneous GABAergic hyperpolarizations (SGH) elicited by 75 microM 4-aminopyridine were used to test the effect of these drugs on GABA-dependent potentials. Tiagabine (0.1 mM) prolonged the duration of SGH. Furthermore, monophasic SGH turned over into triphasic typical GABAergic membrane potential fluctuations within 20 min. In contrast, valproate, gabapentin, and vigabatrin failed to affect SGH up to 60 min of application. The reason for the fast action of tiagabine on SGH may be caused by a faster increase of synaptic GABA levels compared with other drugs. As migraine therapy benefits from an augmentation of GABA activity, we recommend clinical studies of tiagabine as a fast-acting agent in migraine attacks.
Cephalalgia 2000 Jul
PMID:Different effects of GABAergic anticonvulsants on 4-aminopyridine-induced spontaneous GABAergic hyperpolarizations of hippocampal pyramidal cells--implication for their potency in migraine therapy. 1107 35

1. GABA (gamma-aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat. 2. Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L-glutamate. 3. Cell firing evoked by microiontophoretic application of L-glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABA(A) agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws. 4. The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABA(A) antagonist N-methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABA(B) antagonist 2-hydroxysaclofen (n=11). 5. R(-)-baclofen, a GABA(B) agonist, inhibited the firing of three out of seven cells activated by L-glutamate. Where tested, this inhibition could be antagonized by 2-hydroxysaclofen. These baclofen-inhibited cells were characterized as having low threshold mechanoreceptor/WDR input. 6. GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABA(A) receptors. GABA(A) receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders.
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PMID:GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex. 1160 31

As a foundation for evaluating potential mechanisms of the neurological effects (e.g. headache, nausea, dizziness) of some octane boosters, we studied the gamma-aminobutyric acid(A) (GABA(A)) receptor in a series of binding assays in membranes from rat brain. The GABA(A) receptor was probed using the radioligand [3H]t-butylbicycloorthobenzoate ([3H]TBOB) which binds to the convulsant recognition site of the receptor. The results demonstrated that the short-chain t-ethers and their t-alcohol metabolites inhibit binding at the convulsant site of the GABA(A) receptor. The potency of the inhibition tended to correlate with carbon chain length. For agents having an equal number of carbon atoms, potency of inhibition of [3H]TBOB binding was greater in magnitude for the alcohols than for the ethers. The descending rank order of potency for the ethers and alcohols were as follows, t-amyl alcohol (TAA); t-amyl-methyl ether (TAME); ethyl-t-butyl ether (ETBE)>t-butyl alcohol (TBA)>methyl-t-butyl ether (MTBE)>ethanol. In additional saturation binding assays, MTBE reduced apparent density of convulsant binding (B(max)).
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PMID:Influence of oxygenated fuel additives and their metabolites on the binding of a convulsant ligand of the gamma-aminobutyric acid(A) (GABA(A)) receptor in rat brain membrane preparations. 1188 5

Antiepileptic drugs (AEDs) are promising agents for the prevention of migraine and other head pain. Migraine and epilepsy share several clinical features and respond to many of the same pharmacologic agents, suggesting that similar mechanisms may be involved in their pathophysiology. The mechanisms of action of AEDs are not fully understood, and a single drug may have more than one mechanism, both in epilepsy and in migraine. Valproate, topiramate, and gabapentin are likely to affect nociception by modulating gamma-aminobutyric acid- (GABA-) and/or glutamate-mediated neurotransmission. All three AEDs enhance GABA-mediated inhibition. Valproate and gabapentin interfere with GABA metabolism to prevent its ultimate conversion to succinate, and topiramate potentiates GABA-mediated inhibition by facilitating the action of GABA receptors. In addition, topiramate acts directly on non-N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate glutamate receptors. Valproate, topiramate, and possibly gabapentin inhibit sodium ion channels. All three drugs modulate calcium ion channel activity. Valproate blocks T-type calcium ion channels; topiramate inhibits high-voltage-activated L-type calcium ion channels; and gabapentin binds to the alpha2delta subunit of L-type calcium ion channels. AEDs may be useful in migraine prevention through such mechanisms as modulating the biochemical phenomena of aura or acting directly on the nociceptive system. Further evaluations of AEDs in migraine models will provide a better understanding of the pathophysiology and prevention of migraine.
Headache
PMID:Antiepileptic drugs: how they work in headache. 1190 34

Biological clock and magnesium status are linked. Central magnesium regulation may be hypothetized. Balanced magnesium status is requested to obtain efficiency of suprachiasmatic nuclei and of pineal gland. Conventional bright light therapy appears as a speedy and efficient antidepressant medication useful for the treatment of various types of depression, and of non migrainous headaches also. Although decrease in melatonin production seems accessory, increases of serotonergy and perhaps of Reactive Oxygen Species constitute the main mechanisms of action. Chromatotherapy emphazizes the effects of short exposure to specific colors. Although the increased production of melatonin constitutes the best marker of darkness, it is only an accessory mechanism of its action. The psycholeptic sedative effects of darkness, like those of magnesium, rely on direct membraneous and oxidant actions, neural mediated effects (i.e. stimulation of inhibitory neuromodulators such as GABA and taurine), and on antagonism of neuroactive gases (CO and NO). Darkness therapyper se, partial substitutive therapy with melatonin and with their mimicking agents (Mg, L-Tryptophan,Taurine) apply to all the chronopathological forms of magnesium depletion with decreased production of melatonin: sleep disorders, migraine, chronic fatigue syndrome, fibromyalgia, some forms of asthma and of sudden infant death syndrome. Further research should assess the importance of the chronopathological forms of magnesium depletion in the physiopathology of these disorders.
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PMID:Biorhythms and possible central regulation of magnesium status, phototherapy, darkness therapy and chronopathological forms of magnesium depletion. 1203 Apr 24

Pregabalin (S-[+]-3-isobutylgaba) was designed as a lipophilic GABA (gamma-aminobutyric acid) analogue substituted at the 3'-position in order to facilitate diffusion across the blood-brain barrier. It was originally developed as an anticonvulsant agent, however it has been shown to be effective in the treatment of several disorders including hyperalgesia and behavioural disorders. Although its exact mode of action remains unclear, pregabalin interacts with the same binding site and has a similar pharmacological profile as its predecessor, gabapentin (1-[aminomethyl] cyclohexane acetic acid). Its main site of action appears to be on the alpha(2)delta subunit of voltage-dependent calcium channels, widely distributed throughout the peripheral and central nervous system. Pregabalin appears to produce an inhibitory modulation of neuronal excitability. In healthy volunteers, it is rapidly absorbed with peak blood concentrations within 1 h and it has a bioavailability of approximately 90%. In preclinical trials of anticonvulsant activity, pregabalin is three to ten times more potent than gabapentin. It is well-tolerated and associated with dose-dependent adverse effects (ataxia, dizziness, headache and somnolence) that are mild-to-moderate and usually transient. There are no known pharmacokinetic drug-drug interactions reported to date. Preliminary animal and human studies showed beneficial effects in both ethological and conflict models of anxiety, as well as having some sleep-modulating properties. In Phase II and III trials, pregabalin shows promising anxiolytic action when compared to placebo in generalised anxiety disorder, social phobia and panic disorder.
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PMID:Pregabalin: a new anxiolytic. 1266 21

Baclofen, tizanidine and botulinum toxin A, agents used to treat disorders of muscle tone, have been studied as potential preventative treatments for migraine, tension-type headache and other related disorders. The most extensive work has been completed with botulinum toxin A. However, there is still a paucity of well controlled, clinical trials with this agent, and overall there have been conflicting and oftentimes equivocal results: studies of its use in migraine headache have suggested efficacy, whereas those of tension-type headache have not shown significant evidence of efficacy. There were few significant adverse events associated with the use of botulinum toxin A in these trials. The mechanism by which botulinum toxin A may work to prevent headache is not clear. Although changes in muscle tone may play a role in the effect of the drug, central mechanisms such as effects on neuropeptides involved in the pathogenesis of migraine may also be relevant. Further clinical trial work is in progress to help determine optimal administration schedules and choice of injection locations with botulinum toxin A for specific headache disorders. There has been limited study of the use of baclofen, an agent that acts centrally via GABA(A) receptors, in migraine and cluster headache, with only two open trials conducted to date. Both of these studies support the use of baclofen in the preventive treatment of headache.Tizanidine, which may have both a peripheral and a central mechanism in the locus ceruleus in migraine headache, has been studied in several clinical trials. Although the primary mechanism of action of this agent is, like clonidine, as an alpha-adrenoceptor agonist, it has little antihypertensive effect. Open trials of tizanidine have shown it to be useful in chronic headache. One well controlled trial, conducted as a follow-up to an open-label trial in the preventive treatment of chronic daily headache, reported tizanidine as having a statistically significant benefit over placebo. Also of interest is its use in conjunction with a long-acting NSAID to aid in the treatment of rebound headache accompanying the discontinuation of overused acute migraine therapies. In conclusion, though limited, the studies suggest the efficacy of botulinum toxin A, baclofen and tizanidine in primary headache disorders.
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PMID:Preventative treatment for migraine and tension-type headaches : do drugs having effects on muscle spasm and tone have a role? 1269 98

Sleep bruxism (SB) is reported by 8% of the adult population and is mainly associated with rhythmic masticatory muscle activity (RMMA) characterized by repetitive jaw muscle contractions (3 bursts or more at a frequency of 1 Hz). The consequences of SB may include tooth destruction, jaw pain, headaches, or the limitation of mandibular movement, as well as tooth-grinding sounds that disrupt the sleep of bed partners. SB is probably an extreme manifestation of a masticatory muscle activity occurring during the sleep of most normal subjects, since RMMA is observed in 60% of normal sleepers in the absence of grinding sounds. The pathophysiology of SB is becoming clearer, and there is an abundance of evidence outlining the neurophysiology and neurochemistry of rhythmic jaw movements (RJM) in relation to chewing, swallowing, and breathing. The sleep literature provides much evidence describing the mechanisms involved in the reduction of muscle tone, from sleep onset to the atonia that characterizes rapid eye movement (REM) sleep. Several brainstem structures (e.g., reticular pontis oralis, pontis caudalis, parvocellularis) and neurochemicals (e.g., serotonin, dopamine, gamma aminobutyric acid [GABA], noradrenaline) are involved in both the genesis of RJM and the modulation of muscle tone during sleep. It remains unknown why a high percentage of normal subjects present RMMA during sleep and why this activity is three times more frequent and higher in amplitude in SB patients. It is also unclear why RMMA during sleep is characterized by co-activation of both jaw-opening and jaw-closing muscles instead of the alternating jaw-opening and jaw-closing muscle activity pattern typical of chewing. The final section of this review proposes that RMMA during sleep has a role in lubricating the upper alimentary tract and increasing airway patency. The review concludes with an outline of questions for future research.
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PMID:Neurobiological mechanisms involved in sleep bruxism. 1276 18

In anaesthetized rats, extracellular recordings were made from neurones of the spinal trigeminal nucleus, involved in the processing of nociceptive input from the dura. Blockers of voltage-gated calcium channels (VGCCs) were administered topically to the exposed brainstem. Blockade of N-type (CaV2.2) channels reduced spontaneous activity and responses of the neurones to cold and chemical stimuli applied to the dura, suggesting that N-type channels regulate excitatory synaptic activation. Blockade of L-type (CaV1) channels enhanced spontaneous discharges of the neurones. Blockade of P/Q-type (CaV2.1) channels slightly decreased responses to chemical and cold stimuli but markedly increased spontaneous activity, an effect which was absent during concomitant application of GABA to the brainstem. The data suggest that P/Q-type VGCCs regulate a tonic synaptic inhibitory control of the brainstem neurones. The risk of migraine by genetic modifications of P/Q-type channels may thus be sought in disturbed inhibition in the network that processes nociceptive dura input.
Cephalalgia 2004 Apr
PMID:Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. 1503 May 33

Migraine is the most common type of chronic episodic headache. Several population-based family studies have suggested a strong genetic predisposition to migraine, especially migraine with aura (MA). Although several susceptibility loci have been identified, none of the numerous studies performed to date have led to the identification of a gene responsible for the more common forms of migraine. GABA-A receptors and their modulator sites seem to be involved in the pathophysiological events that underlie migraine. We report on clinical and molecular data from a total of 10 families with MA, in which MA segregates as an autosomal dominant trait and presents with homogeneous clinical features. After excluding linkage with the known candidate loci, we used a functional candidate approach and genotyped these families with markers from the 15q11-q13 genomic region, which contains the genes encoding GABA-A receptor subunits. Evidence of linkage was obtained with a parametric two-point linkage analysis (maximum LOD score of 5.56 at a recombination fraction of 0.001 for marker GABRB3) and was supported by multipoint analysis (maximum LOD score of 6.54 between markers D15S113 and D15S1019). The critical region spanned 3.6 Mb. These results provide the basis for further investigation of the hypothesized relationship between a GABA-A receptor dysfunction and migraine.
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PMID:A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes. 1558 24


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